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Song X, Xu S, Song D, Wang J, Bai B, An Y, Yang B, Wang S, Zhao Q, Yu P. TGFB1/CXCL5 axis regulation by LCN2 overexpression: a promising strategy to inhibit colorectal cancer metastasis and enhance prognosis. Front Immunol 2025; 16:1548635. [PMID: 40313933 PMCID: PMC12043584 DOI: 10.3389/fimmu.2025.1548635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 03/31/2025] [Indexed: 05/03/2025] Open
Abstract
Background Distant metastasis remains a major reason for the high recurrence and mortality of colorectal cancer (CRC). However, the underlying molecular mechanisms driving metastasis in CRC remain poorly understood. In this study, we investigated the mechanisms underlying the inhibitory effects of lipocalin-2 (LCN2) on CRC metastasis. Methods We assessed the expression and clinical significance of LCN2 in human CRC specimens and CRC cell lines using, immunohistochemistry, and western blot analyses. We evaluated the migratory and invasive capabilities of CRC cells influenced by LCN2 using in vitro transwell assays and in vivo lung metastatic models. RNA sequencing and proteome analysis were employed to identify potential downstream targets of LCN2. Rescue experiments were conducted to further elucidate the potential mechanisms of LCN2 and its downstream effectors in CRC. Results LCN2 exhibited high expression levels in human CRC tissues and an inverse correlation with N classification, advanced AJCC stages, and shorter overall survival. LCN2 expression independently predicted a more favorable outcome for CRC patients. Upregulation of LCN2 effectively suppressed CRC cell metastasis both in vitro and in vivo. Mechanistically, Transforming growth factor beta 1 (TGFB1) and C-X-C motif chemokine ligand 5 (CXCL5) were identified as downstream effectors of LCN2, with LCN2 inhibiting CRC metastasis through repression of the TGFB1/CXCL5 axis. Furthermore, either TGF-βR1 inhibitor SB431542 or CXCR2 antagonist SB225002 treatment moderately decreased the migratory and invasive capabilities of DLD-1-LV-shLCN2 cells, whereas the combination treatment of the two agents dramatically decreased the migratory and invasive capabilities of DLD-1-LV-shLCN2 cells. Conclusions This study underscores LCN2 as an independent protective factor and prognostic biomarker for CRC patients. Combined treatment with the SB431542 and the SB225002 significantly attenuated LCN2-related CRC metastasis. Targeting the LCN2/TGFB1/CXCL5 axis emerges as a promising therapeutic strategy for managing LCN2-related metastatic CRC.
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Affiliation(s)
- Xiaotian Song
- Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
| | - Shuai Xu
- Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
| | - Dan Song
- Department of Gastrointestinal Surgery, Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Juan Wang
- Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
| | - Bin Bai
- Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
| | - Yanxin An
- Department of General Surgery, The First Affiliated Hospital of Xi’an Medical University, Xi’an, China
| | - Bin Yang
- Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
| | - Shiqi Wang
- Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
| | - Qingchuan Zhao
- Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
| | - Pengfei Yu
- Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
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Zhang J, Xu Q, Sun G. Lipocalin-2 promotes NSCLC progression by activating the JAK2/STAT3 signaling pathway. J Transl Med 2025; 23:419. [PMID: 40211270 PMCID: PMC11987316 DOI: 10.1186/s12967-025-06418-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 03/25/2025] [Indexed: 04/12/2025] Open
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Lipocalin-2 (LCN2), a pleiotropic protein implicated in tumorigenesis and cancer progression, has been associated with multiple malignancies. However, its precise role in NSCLC and the underlying molecular mechanisms remain incompletely understood. This study aimed to elucidate the function of LCN2 in NSCLC, with a particular focus on its involvement in the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway. METHODS LCN2 expression in NSCLC tissues was comprehensively analyzed using bioinformatics tools, including the Universal Analysis of Cancer (UALCAN), The Cancer Genome Atlas (TCGA), UCSC-XENA, and Gene Expression Omnibus (GEO) databases. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were employed to assess LCN2 expression levels in NSCLC cell lines. The functional impact of LCN2 on NSCLC cells, including proliferation, apoptosis, and metastasis, were assessed through a series of in vitro assays, such as Cell Counting Kit-8 (CCK-8), EdU, wound healing, and transwell migration and invasion assays. An in vivo xenograft model was established to investigate the effects of LCN2 on tumor growth and metastasis. Additionally, the involvement of the JAK2/STAT3 signaling pathway was examined using western blotting and pharmacological inhibition with AG490. RESULTS LCN2 was significantly upregulated in NSCLC tissues and cell lines, and its elevated expression correlated with poor prognosis. Functional analyses demonstrated that LCN2 knockdown suppressed NSCLC cell proliferation, migration, and invasion while promoting apoptosis. Mechanistically, LCN2 was found to activate the JAK2/STAT3 pathway by interacting with SOCS3, and pharmacological blockade of this pathway effectively abrogated the oncogenic effects of LCN2 overexpression. CONCLUSIONS This study identifies LCN2 as a potential oncogene in NSCLC, driving tumor progression through activation of the JAK2/STAT3 signaling pathway. These findings suggest that targeting LCN2 or its downstream signaling components may represent a promising therapeutic strategy for NSCLC.
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Affiliation(s)
- Jinjin Zhang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Anhui Province, 230022, Hefei, China
| | - Qin Xu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Anhui Province, 230022, Hefei, China
| | - Gengyun Sun
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Anhui Province, 230022, Hefei, China.
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Xu Y, Qian X, Cai G, Lin Z, Huang W, Wang C, Wu H, Zhang Y, Sun J, Zhang Q. WTX-L/β-arrestin2/LCN2 axis controls vulnerability to ferroptosis in gastric cancer. iScience 2025; 28:111964. [PMID: 40109379 PMCID: PMC11919608 DOI: 10.1016/j.isci.2025.111964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 10/20/2024] [Accepted: 02/04/2025] [Indexed: 03/22/2025] Open
Abstract
Gastric cancer (GC) is one of the most prevalent and lethal cancers worldwide. Ferroptosis is a form of iron-dependent regulated cell death emerging as a promising strategy for cancer therapy, whereas the regulation mechanism remains unclear. WTX has been recognized as a potential tumor suppressor, but attempts at targeted therapy have not achieved substantial progress. Further research into the structure, function, and mechanisms is urgently needed. Herein, we identified a long isoform of WTX (WTX-L) as a potent ferroptosis effector in GC. Mechanistically, WTX-L competitively interacts with β-arrestin2, disrupting its direct binding to IκBα and subsequently activating the NF-κB/LCN2 pathway. LCN2 further triggers ferroptosis by significantly increasing the labile Fe2+ pool and promoting excessive lipid peroxidation. Blockade of the WTX-L/β-arrestin2/NF-κB/LCN2 axis significantly diminished the activity of ferroptosis inducers (erastin and RSL3) in vivo. Collectively, these findings reveal that targeting the ferroptosis vulnerabilities through WTX-L may represent a promising strategy for GC.
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Affiliation(s)
- Yangwei Xu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
| | - Xuexia Qian
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
- Department of Pathology, Xijing Hospital, Fourth Military Medical University (Air Force Medical University), Xi'an, Shanxi 710032, China
| | - Guixing Cai
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
- Department of Orthopedic Oncology, Guangdong Provincial People's Hospital, Southern Medical University, Guangzhou, Guangdong 510080, China
| | - Zhihao Lin
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
| | - Weiye Huang
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
| | - Chuangyuan Wang
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, China
| | - Hongmei Wu
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
| | - Yiqiong Zhang
- School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510282, China
| | - Jingbo Sun
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
| | - Qingling Zhang
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China
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HUANG BAOXING, JIA ZICHANG, FU CHENCHEN, CHEN MOXIAN, SU ZEZHUO, CHEN YUNSHENG. Oncogenic and tumor-suppressive roles of Lipocalin 2 (LCN2) in tumor progression. Oncol Res 2025; 33:567-575. [PMID: 40109857 PMCID: PMC11915076 DOI: 10.32604/or.2024.051672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 06/17/2024] [Indexed: 03/22/2025] Open
Abstract
Lipocalin-2 (LCN2) is a member of the lipocalin superfamily with multiple functions and can participate in the transport of a variety of small lipophilic ligands in vivo. LCN2 is significantly expressed in various tumors and plays an important role in regulating tumor cell proliferation, invasion, and metastasis. The specific actions of LCN2 in tumors may vary depending on the particular type of cancer involved. In this review, we provide an extensive overview of the transcriptional and post-transcriptional regulation of LCN2 in health and disease. Furthermore, we summarize the impact of LCN2 dysregulation in a broad range of tumors. Lastly, we examine the mechanisms of action of LCN2 during tumorigenesis, progression, and metastasis. Understanding the complex relationships between LCN2 and tumor development, progression, and metastasis is vital for advancing our knowledge of cancer biology, developing biomarkers for diagnosis and clinical decision-making, and creating therapeutic strategies to improve the management of patients with cancer.
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Affiliation(s)
- BAOXING HUANG
- Clinical Laboratory, Shenzhen Children’s Hospital, Shenzhen, 518038, China
| | - ZICHANG JIA
- Clinical Laboratory, Shenzhen Children’s Hospital, Shenzhen, 518038, China
| | - CHENCHEN FU
- State Key Laboratory of Tree Genetics and Breeding, Co-Innovation Center for Sustainable Forestry in Southern China, Key Laboratory of Tree Genetics and Biotechnology of Educational Department of China, Key Laboratory of State Forestry and Grassland Administration on Subtropical Forest Biodiversity Conservation, College of Life Sciences, Nanjing Forestry University, Nanjing, 210037, China
| | - MOXIAN CHEN
- State Key Laboratory of Tree Genetics and Breeding, Co-Innovation Center for Sustainable Forestry in Southern China, Key Laboratory of Tree Genetics and Biotechnology of Educational Department of China, Key Laboratory of State Forestry and Grassland Administration on Subtropical Forest Biodiversity Conservation, College of Life Sciences, Nanjing Forestry University, Nanjing, 210037, China
| | - ZEZHUO SU
- Department of Orthopaedics and Traumatology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - YUNSHENG CHEN
- Clinical Laboratory, Shenzhen Children’s Hospital, Shenzhen, 518038, China
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Kwon D, Kim Y, Cho SH. Antidepressant Effects of Ginsenoside Rc on L-Alpha-Aminoadipic Acid-Induced Astrocytic Ablation and Neuroinflammation in Mice. Int J Mol Sci 2024; 25:9673. [PMID: 39273621 PMCID: PMC11396248 DOI: 10.3390/ijms25179673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 08/29/2024] [Accepted: 09/05/2024] [Indexed: 09/15/2024] Open
Abstract
Depression is a prevalent and debilitating mental disorder that affects millions worldwide. Current treatments, such as antidepressants targeting the serotonergic system, have limitations, including delayed onset of action and high rates of treatment resistance, necessitating novel therapeutic strategies. Ginsenoside Rc (G-Rc) has shown potential anti-inflammatory and neuroprotective effects, but its antidepressant properties remain unexplored. This study investigated the antidepressant effects of G-Rc in an L-alpha-aminoadipic acid (L-AAA)-induced mouse model of depression, which mimics the astrocytic pathology and neuroinflammation observed in major depressive disorder. Mice were administered G-Rc, vehicle, or imipramine orally after L-AAA injection into the prefrontal cortex. G-Rc significantly reduced the immobility time in forced swimming and tail suspension tests compared to vehicle treatment, with more pronounced effects than imipramine. It also attenuated the expression of pro-inflammatory cytokines (TNF-α, IL-6, TGF-β, lipocalin-2) and alleviated astrocytic degeneration, as indicated by increased GFAP and decreased IBA-1 levels. Additionally, G-Rc modulated apoptosis-related proteins, decreasing caspase-3 and increasing Bcl-2 levels compared to the L-AAA-treated group. These findings suggest that G-Rc exerts antidepressant effects by regulating neuroinflammation, astrocyte-microglia crosstalk, and apoptotic pathways in the prefrontal cortex, highlighting its potential as a novel therapeutic agent for depression.
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Affiliation(s)
- Dohyung Kwon
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Yunna Kim
- College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Neuropsychiatry of Korean Medicine, Kyung Hee University Medical Center, Kyung Hee University, Seoul 02447, Republic of Korea
- Research Group of Neuroscience, East-West Medical Research Institute, WHO Collaborating Center, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Seung-Hun Cho
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Neuropsychiatry of Korean Medicine, Kyung Hee University Medical Center, Kyung Hee University, Seoul 02447, Republic of Korea
- Research Group of Neuroscience, East-West Medical Research Institute, WHO Collaborating Center, Kyung Hee University, Seoul 02447, Republic of Korea
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Chinnappan R, Makhzoum T, Arai M, Hajja A, Abul Rub F, Alodhaibi I, Alfuwais M, Elahi MA, Alshehri EA, Ramachandran L, Mani NK, Abrahim S, Mir MS, Al-Kattan K, Mir TA, Yaqinuddin A. Recent Advances in Biosensor Technology for Early-Stage Detection of Hepatocellular Carcinoma-Specific Biomarkers: An Overview. Diagnostics (Basel) 2024; 14:1519. [PMID: 39061656 PMCID: PMC11276200 DOI: 10.3390/diagnostics14141519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 07/06/2024] [Accepted: 07/12/2024] [Indexed: 07/28/2024] Open
Abstract
Hepatocellular carcinoma is currently the most common malignancy of the liver. It typically occurs due to a series of oncogenic mutations that lead to aberrant cell replication. Most commonly, hepatocellular carcinoma (HCC) occurs as a result of pre-occurring liver diseases, such as hepatitis and cirrhosis. Given its aggressive nature and poor prognosis, the early screening and diagnosis of HCC are crucial. However, due to its plethora of underlying risk factors and pathophysiologies, patient presentation often varies in the early stages, with many patients presenting with few, if any, specific symptoms in the early stages. Conventionally, screening and diagnosis are performed through radiological examination, with diagnosis confirmed by biopsy. Imaging modalities tend to be limited by their requirement of large, expensive equipment; time-consuming operation; and a lack of accurate diagnosis, whereas a biopsy's invasive nature makes it unappealing for repetitive use. Recently, biosensors have gained attention for their potential to detect numerous conditions rapidly, cheaply, accurately, and without complex equipment and training. Through their sensing platforms, they aim to detect various biomarkers, such as nucleic acids, proteins, and even whole cells extracted by a liquid biopsy. Numerous biosensors have been developed that may detect HCC in its early stages. We discuss the recent updates in biosensing technology, highlighting its competitive potential compared to conventional methodology and its prospects as a tool for screening and diagnosis.
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Affiliation(s)
- Raja Chinnappan
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
- Tissue/Organ Bioengineering & BioMEMS Laboratory, Organ Transplant Centre of Excellence (TR&I-Dpt), King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia;
| | - Tariq Makhzoum
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
| | - Momo Arai
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
| | - Amro Hajja
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
| | - Farah Abul Rub
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
| | - Ibrahim Alodhaibi
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
| | - Mohammed Alfuwais
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
| | - Muhammad Affan Elahi
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
| | - Eman Abdullah Alshehri
- Tissue/Organ Bioengineering & BioMEMS Laboratory, Organ Transplant Centre of Excellence (TR&I-Dpt), King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia;
| | - Lohit Ramachandran
- Microfluidics, Sensors & Diagnostics (μSenD) Laboratory, Centre for Microfluidics, Biomarkers, Photoceutics and Sensors (μBioPS), Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India; (L.R.); (N.K.M.)
| | - Naresh Kumar Mani
- Microfluidics, Sensors & Diagnostics (μSenD) Laboratory, Centre for Microfluidics, Biomarkers, Photoceutics and Sensors (μBioPS), Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India; (L.R.); (N.K.M.)
| | - Shugufta Abrahim
- Graduate School of Science and Engineering for Education, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan;
| | - Mohammad Shabab Mir
- School of Pharmacy, Desh Bhagat University, Mandi Gobindgarh 147301, Punjab, India;
| | - Khaled Al-Kattan
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
- Lung Health Centre Department, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Tanveer Ahmad Mir
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
- Tissue/Organ Bioengineering & BioMEMS Laboratory, Organ Transplant Centre of Excellence (TR&I-Dpt), King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia;
| | - Ahmed Yaqinuddin
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
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Jiang J, Cheng R, Song A, Lou Y, Fan G. Multi-omics analysis reveals mechanism of Schisandra chinensis lignans and acteoside on EMT in hepatoma cells via ERK1/2 pathway. Funct Integr Genomics 2024; 24:112. [PMID: 38849609 DOI: 10.1007/s10142-024-01351-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 03/08/2024] [Accepted: 03/28/2024] [Indexed: 06/09/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC), a globally common cancer, often presents late and shows high resistance to chemotherapy, resulting in suboptimal treatment efficacy. Components from traditional Chinese medicines have been recognized for their anti-cancer properties. OBJECTIVE Exploring the mechanism of Schisandra chinensis lignans and acteoside in suppressing Epithelial-Mesenchymal Transition (EMT) in hepatoma cells through the Extracellular signal-Regulated Kinases (ERK)1/2 pathway and identifying biomarkers, molecular subtypes, and targets via multi-omics for precision oncology. METHODS Proliferation was assessed using cell counting kit-8 (CCK-8) assays, with scratch and transwell assays for evaluating invasion and migration. Flow cytometry quantified apoptosis rates. Expression levels of CCL20, p-ERK1/2, c-Myc, Vimentin, and E-cadherin/N-cadherin were analyzed by real-time PCR and Western blot. Tumor volume was calculated with a specific formula, and growth. RESULTS The Schisandra chinensis lignans and acteoside combination decreased CCL20 expression, inhibited hepatoma proliferation and migration, and enhanced apoptosis in a dose- and time-dependent manner. Molecular analysis revealed increased E-cadherin and decreased N-cadherin, p-ERK1/2, c-Myc, and Vimentin expression, indicating ERK1/2 pathway modulation. In vivo, treated nude mice showed significantly reduced tumor growth and volume. CONCLUSION Schisandra chinensis lignans and acteoside potentially counteract CCL20-induced EMT, invasion, and migration in hepatocellular carcinoma cells via the ERK1/2 pathway, enhancing apoptosis. Multi-omics analysis further aids in pinpointing novel biomarkers for precision cancer therapy.
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Affiliation(s)
- Jingjing Jiang
- Department of Pharmacy, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China
| | - Ru Cheng
- Department of Pharmacy, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China
| | - Aoqi Song
- Department of Pharmacy, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China
| | - Yuefen Lou
- Department of Pharmacy, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China.
| | - Guorong Fan
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, China.
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Guo D, Li X, Wang J, Liu X, Wang Y, Huang S, Dang N. Single-cell RNA-seq reveals keratinocyte and fibroblast heterogeneity and their crosstalk via epithelial-mesenchymal transition in psoriasis. Cell Death Dis 2024; 15:207. [PMID: 38472183 PMCID: PMC10933286 DOI: 10.1038/s41419-024-06583-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 02/27/2024] [Accepted: 03/01/2024] [Indexed: 03/14/2024]
Abstract
The pathogenesis of psoriasis, a chronic inflammatory autoimmune skin disease with a high global prevalence, remains unclear. We performed a high-resolution single-cell RNA sequencing analysis of 94,759 cells from 13 samples, including those from psoriasis model mice and wild-type mice. We presented a single-cell atlas of the skin of imiquimod-induced mice with psoriasis and WT mice, especially the heterogeneity of keratinocytes and fibroblasts. More interestingly, we discovered that special keratinocyte subtypes and fibroblast subtypes could interact with each other through epithelial-mesenchymal transition and validated the results with drug verification. Moreover, we conducted a tentative exploration of the potential pathways involved and revealed that the IL-17 signalling pathway may be the most relevant pathway. Collectively, we revealed the full-cycle landscape of key cells associated with psoriasis and provided a more comprehensive understanding of the pathogenesis of psoriasis.
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Affiliation(s)
- Dianhao Guo
- Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Department of Biochemistry and Molecular Biology, School of Clinical and Basic Medical Sciences, Shandong First Medical University& Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Xiaokang Li
- Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Jing Wang
- Department of Dermatology, Binzhou Medical University Hospital, Binzhou, China
| | - Xin Liu
- Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Yibo Wang
- Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Shuhong Huang
- Department of Biochemistry and Molecular Biology, School of Clinical and Basic Medical Sciences, Shandong First Medical University& Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Ningning Dang
- Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
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Han B, An Z, Gong T, Pu Y, Liu K. LCN2 Promotes Proliferation and Glycolysis by Activating the JAK2/STAT3 Signaling Pathway in Hepatocellular Carcinoma. Appl Biochem Biotechnol 2024; 196:717-728. [PMID: 37178251 DOI: 10.1007/s12010-023-04520-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/11/2023] [Indexed: 05/15/2023]
Abstract
This study aimed to explore the molecular mechanism of LCN2 regulating aerobic glycolysis on abnormal proliferation of HCC cells. Based on the prediction of GEPIA database, the expression levels of LCN2 in hepatocellular carcinoma tissues were detected by RT-qPCR analysis, western blot, and immunohistochemical staining, respectively. In addition, CCK-8 kit, clone formation, and EdU staining were used to analyze the effect of LCN2 on the proliferation of hepatocellular carcinoma cells. Glucose uptake and lactate production were detected using kits. In addition, western blot was used to detect the expressions of aerobic glycolysis-related proteins. Finally, western blot was used to detect the expressions of phosphorylation of JAK2 and STAT3. We found LCN2 was upregualted in hepatocellular carcinoma tissues. CCK-8 kit, clone formation, and EdU staining results showed that LCN2 could promote the proliferation in hepatocellular carcinoma cells (Huh7 and HCCLM3 cells). Western blot results and kits confirmed that LCN2 significantly promotes aerobic glycolysis in hepatocellular carcinoma cells. Western blot results showed that LCN2 could significantly upregulate the phosphorylation of JAK2 and STAT3. Our results indicated that LCN2 activated the JAK2/STAT3 signaling pathway, promoted aerobic glycolysis, and accelerated malignant proliferation of hepatocellular carcinoma cells.
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Affiliation(s)
- Baojun Han
- Department of Hepatobiliary Surgery, Sichuan Mianyang 404 Hospital, Mianyang, China
| | - Zhiming An
- Department of Hepatobiliary Surgery, Sichuan Mianyang 404 Hospital, Mianyang, China
| | - Teng Gong
- Department of Hepatobiliary Surgery, Sichuan Mianyang 404 Hospital, Mianyang, China
| | - Yu Pu
- Department of Hepatobiliary Surgery, Sichuan Mianyang 404 Hospital, Mianyang, China
| | - Ke Liu
- General Surgery, Santai County Hospital of Traditional Chinese Medicine, Tongchuan Town, Santai County, Mianyang, 621100, Sichuan Province, China.
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10
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Akrida I, Papadaki H. Adipokines and epithelial-mesenchymal transition (EMT) in cancer. Mol Cell Biochem 2023; 478:2419-2433. [PMID: 36715963 DOI: 10.1007/s11010-023-04670-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 01/17/2023] [Indexed: 01/31/2023]
Abstract
Obesity is a significant risk factor for cancer development. Within the tumor microenvironment, adipocytes interact with cancer cells, immune cells, fibroblasts and endothelial cells, and orchestrate several signaling pathways by secreting bioactive molecules, including adipokines. Adipokines or adipocytokines are produced predominantly by adipocytes and function as autocrine, paracrine and endocrine mediators. Adipokines can exert pro- and anti-inflammatory functions, and they play a pivotal role in the state of chronic low-grade inflammation that characterizes obesity. Epithelial-mesenchymal transition (EMT), a complex biological process whereby epithelial cells acquire the invasive, migratory mesenchymal phenotype is well-known to be implicated in cancer progression and metastasis. Emerging evidence suggests that there is a link between adipokines and EMT. This may contribute to the correlation that has been documented between obesity and cancer progression. This review summarizes the existing body of evidence supporting an association between the process of EMT in cancer and the adipokines leptin, adiponectin, resistin, visfatin/NAMPT, lipocalin-2/NGAL, as well as other newly discovered adipokines including chemerin, nesfatin-1/nucleobindin-2, AZGP1, SFRP5 and FABP4.
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Affiliation(s)
- Ioanna Akrida
- Department of General Surgery, University General Hospital of Patras, Rion, Greece.
- Department of Anatomy-Histology-Embryology, University of Patras Medical School, Rion, Greece.
- Department of Surgery, Department of Anatomy-Histology-Embryology, School of Medicine, University of Patras, 26504, Rion, Greece.
| | - Helen Papadaki
- Department of Anatomy-Histology-Embryology, University of Patras Medical School, Rion, Greece
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11
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Živalj M, Van Ginderachter JA, Stijlemans B. Lipocalin-2: A Nurturer of Tumor Progression and a Novel Candidate for Targeted Cancer Therapy. Cancers (Basel) 2023; 15:5159. [PMID: 37958332 PMCID: PMC10648573 DOI: 10.3390/cancers15215159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/20/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Within the tumor microenvironment (TME) exists a complex signaling network between cancer cells and stromal cells, which determines the fate of tumor progression. Hence, interfering with this signaling network forms the basis for cancer therapy. Yet, many types of cancer, in particular, solid tumors, are refractory to the currently used treatments, so there is an urgent need for novel molecular targets that could improve current anti-cancer therapeutic strategies. Lipocalin-2 (Lcn-2), a secreted siderophore-binding glycoprotein that regulates iron homeostasis, is highly upregulated in various cancer types. Due to its pleiotropic role in the crosstalk between cancer cells and stromal cells, favoring tumor progression, it could be considered as a novel biomarker for prognostic and therapeutic purposes. However, the exact signaling route by which Lcn-2 promotes tumorigenesis remains unknown, and Lcn-2-targeting moieties are largely uninvestigated. This review will (i) provide an overview on the role of Lcn-2 in orchestrating the TME at the level of iron homeostasis, macrophage polarization, extracellular matrix remodeling, and cell migration and survival, and (ii) discuss the potential of Lcn-2 as a promising novel drug target that should be pursued in future translational research.
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Affiliation(s)
- Maida Živalj
- Brussels Center for Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium
- Myeloid Cell Immunology Laboratory, VIB Center for Inflammation Research, 1050 Brussels, Belgium
| | - Jo A. Van Ginderachter
- Brussels Center for Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium
- Myeloid Cell Immunology Laboratory, VIB Center for Inflammation Research, 1050 Brussels, Belgium
| | - Benoit Stijlemans
- Brussels Center for Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium
- Myeloid Cell Immunology Laboratory, VIB Center for Inflammation Research, 1050 Brussels, Belgium
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12
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Marques E, Alves Teixeira M, Nguyen C, Terzi F, Gallazzini M. Lipocalin-2 induces mitochondrial dysfunction in renal tubular cells via mTOR pathway activation. Cell Rep 2023; 42:113032. [PMID: 37624695 DOI: 10.1016/j.celrep.2023.113032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 07/03/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Mitochondrial dysfunction is a critical process in renal epithelial cells upon kidney injury. While its implication in kidney disease progression is established, the mechanisms modulating it remain unclear. Here, we describe the role of Lipocalin-2 (LCN2), a protein expressed in injured tubular cells, in mitochondrial dysfunction. We show that LCN2 expression decreases mitochondrial mass and function and induces mitochondrial fragmentation. Importantly, while LCN2 expression favors DRP1 mitochondrial recruitment, DRP1 inhibition antagonizes LCN2's effect on mitochondrial shape. Remarkably, LCN2 promotes mitochondrial fragmentation independently of its secretion or transport iron activity. Mechanistically, intracellular LCN2 expression increases mTOR activity, and rapamycin inhibits LCN2's effect on mitochondrial shape. In vivo, Lcn2 gene inactivation prevents mTOR activation and mitochondrial length decrease observed upon ischemia-reperfusion-induced kidney injury (IRI) in Lcn2+/+ mice. Our data identify LCN2 as a key regulator of mitochondrial dynamics and further elucidate the mechanisms leading to mitochondrial dysfunction.
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Affiliation(s)
- Eloïse Marques
- Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Université Paris Cité, Institut Necker Enfants Malades, 160 Rue de Vaugirard, 75015 Paris, France
| | - Maraiza Alves Teixeira
- Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Université Paris Cité, Institut Necker Enfants Malades, 160 Rue de Vaugirard, 75015 Paris, France
| | - Clément Nguyen
- Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Université Paris Cité, Institut Necker Enfants Malades, 160 Rue de Vaugirard, 75015 Paris, France
| | - Fabiola Terzi
- Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Université Paris Cité, Institut Necker Enfants Malades, 160 Rue de Vaugirard, 75015 Paris, France
| | - Morgan Gallazzini
- Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Université Paris Cité, Institut Necker Enfants Malades, 160 Rue de Vaugirard, 75015 Paris, France.
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13
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Qiu X, Zhou J, Xu H, Li Y, Ma S, Qiao H, Zeng K, Wang Q, Ouyang J, Liu Y, Ding J, Liu Y, Zhang J, Shi M, Liao Y, Liao W, Lin L. Alcohol reshapes a liver premetastatic niche for cancer by extra- and intrahepatic crosstalk-mediated immune evasion. Mol Ther 2023; 31:2662-2680. [PMID: 37469143 PMCID: PMC10492032 DOI: 10.1016/j.ymthe.2023.07.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 06/22/2023] [Accepted: 07/17/2023] [Indexed: 07/21/2023] Open
Abstract
Cancer metastatic organotropism is still a mystery. The liver is known to be susceptible to cancer metastasis and alcoholic injury. However, it is unclear whether and how alcohol facilitates liver metastasis and how to intervene. Here, we show that alcohol preferentially promotes liver metastasis in colon-cancer-bearing mice and post-surgery pancreatic cancer patients. The mechanism is that alcohol triggers an extra- and intrahepatic crosstalk to reshape an immunosuppressive liver microenvironment. In detail, alcohol upregulates extrahepatic IL-6 and hepatocellular IL-6 receptor expression, resulting in hepatocyte STAT3 signaling activation and downstream lipocalin-2 (Lcn2) upregulation. Furthermore, LCN2 promotes T cell-exhaustion neutrophil recruitment and cancer cell epithelial plasticity. In contrast, knocking out hepatocellular Stat3 or systemic Il6 in alcohol-treated mice preserves the liver microenvironment and suppresses liver metastasis. This mechanism is reflected in hepatocellular carcinoma patients, in that alcohol-associated signaling elevation in noncancerous liver tissue indicates adverse prognosis. Accordingly, we discover a novel application for BBI608, a small molecular STAT3 inhibitor that can prevent liver metastasis. BBI608 pretreatment protects the liver and suppresses alcohol-triggered premetastatic niche formation. In conclusion, under extra- and intrahepatic crosstalk, the alcoholic injured liver forms a favorable niche for cancer cell metastasis, while BBI608 is a promising anti-metastatic agent targeting such microenvironments.
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Affiliation(s)
- Xiaofang Qiu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jiaqi Zhou
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Hong Xu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yongyin Li
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Shudong Ma
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Hang Qiao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Kangxin Zeng
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Qiongqiong Wang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jiahe Ouyang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yuanhan Liu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jian Ding
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yantan Liu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Junhao Zhang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Min Shi
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yulin Liao
- Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Wangjun Liao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Li Lin
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
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14
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Alshahrani SH, Rakhimov N, Gupta J, Hassan ZF, Alsalamy A, Saleh EAM, Alsaab HO, Al-Aboudy FK, Alawadi AR, Mustafa YF. The mechanisms, functions and clinical applications of miR-542-3p in human cancers. Pathol Res Pract 2023; 248:154724. [PMID: 37542861 DOI: 10.1016/j.prp.2023.154724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 07/24/2023] [Accepted: 07/26/2023] [Indexed: 08/07/2023]
Abstract
MicroRNAs, as a major type of noncoding RNAs, have crucial roles in various functions during development. Available data have shown that miR-542-3p decreased in various types of cancers. MiR-542-3p is engaged in various cancer-related behaviors like glycolysis, metastasis, epithelial-to-mesenchymal transition (EMT), cell cycle, apoptosis, and proliferation via targeting at least 18 genes and some important signaling pathways like Wnt/β-catenin, Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and Janus kinase 2 (JAK2) signaling, and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling. Current studies have proposed that the level of miR-542-3p could be modulated by several upstream regulators like transcription factors, long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs). In addition, the level of miR-542-3p or its related lncRNAs/circRNAs are correlated with poor prognosis and clinicopathological features of cancer-affected patients. Here, we have discussed the biogenesis, function, and regulation of miR-542-3p as well as its aberrant expression in various types of neoplastic cells. Moreover, we have discussed the prognostic value of miR-542-3p in cancer. Finally, we have added the underlying molecular mechanism of miR-542-3p in cancer pathogenesis.
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Affiliation(s)
| | - Nodir Rakhimov
- Head of the Department of Oncology, Samarkand State Medical University, Amir Temur street 18, Samarkand, Uzbekistan; Department of Scientific Affairs, Tashkent State Dental Institute, Makhtumkuli 103, Tashkent, Uzbekistan
| | - Jitendra Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura Pin Code 281406, U. P., India.
| | | | - Ali Alsalamy
- Department of Computer Technical engineering, College of Information Technology Imam Ja'afarAl-Sadiq University Al-Muthanna, Iraq
| | - Ebraheem Abdu Musad Saleh
- Department of Chemistry, Prince Sattam Bin Abdulaziz University, Wadi Al-Dawasir 11991, Saudi Arabia
| | - Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, Taif, Saudi Arabia
| | | | - Ahmed Radhi Alawadi
- Medical Analysis Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
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15
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Zhang J, Wang Z, Zhang H, Li S, Li J, Liu H, Cheng Q. The role of lipocalin 2 in brain injury and recovery after ischemic and hemorrhagic stroke. Front Mol Neurosci 2022; 15:930526. [PMID: 36187347 PMCID: PMC9520288 DOI: 10.3389/fnmol.2022.930526] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 08/02/2022] [Indexed: 12/03/2022] Open
Abstract
Ischemic and hemorrhagic stroke (including intracerebral hemorrhage, intraventricular hemorrhage, and subarachnoid hemorrhage) is the dominating cause of disability and death worldwide. Neuroinflammation, blood-brain barrier (BBB) disruption, neuronal death are the main pathological progress, which eventually causes brain injury. Increasing evidence indicated that lipocalin 2 (LCN2), a 25k-Da acute phase protein from the lipocalin superfamily, significantly increased immediately after the stroke and played a vital role in these events. Meanwhile, there exists a close relationship between LCN2 levels and the worse clinical outcome of patients with stroke. Further research revealed that LCN2 elimination is associated with reduced immune infiltrates, infarct volume, brain edema, BBB leakage, neuronal death, and neurological deficits. However, some studies revealed that LCN2 might also act as a beneficial factor in ischemic stroke. Nevertheless, the specific mechanism of LCN2 and its primary receptors (24p3R and megalin) involving in brain injury remains unclear. Therefore, it is necessary to investigate the mechanism of LCN2 induced brain damage after stroke. This review focuses on the role of LCN2 and its receptors in brain injury and aiming to find out possible therapeutic targets to reduce brain damage following stroke.
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Affiliation(s)
- Jingwei Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Zeyu Wang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Hao Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Shuwang Li
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Jing Li
- Department of Rehabilitation, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Hongwei Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Changsha, China
- Clinical Diagnosis and Therapy Center for Glioma of Xiangya Hospital, Central South University, Changsha, China
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
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16
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Wu Y, Li X, Li Q, Cheng C, Zheng L. Adipose tissue-to-breast cancer crosstalk: Comprehensive insights. Biochim Biophys Acta Rev Cancer 2022; 1877:188800. [PMID: 36103907 DOI: 10.1016/j.bbcan.2022.188800] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/29/2022] [Accepted: 09/06/2022] [Indexed: 10/14/2022]
Abstract
The review focuses on mechanistic evidence for the link between obesity and breast cancer. According to the IARC study, there is sufficient evidence that obesity is closely related to a variety of cancers. Among them, breast cancer is particularly disturbed by adipose tissue due to the unique histological structure of the breast. The review introduces the relationship between obesity and breast cancer from two aspects, including factors that promote tumorigenesis or metastasis. We summarize alterations in adipokines and metabolic pathways that contribute to breast cancer development. Breast cancer metastasis is closely related to obesity-induced pro-inflammatory microenvironment, adipose stem cells, and miRNAs. Based on the mechanism by which obesity causes breast cancer, we list possible therapeutic directions, including reducing the risk of breast cancer and inhibiting the progression of breast cancer. We also discussed the risk of autologous breast remodeling and fat transplantation. Finally, the causes of the obesity paradox and the function of enhancing immunity are discussed. Evaluating the balance between obesity-induced inflammation and enhanced immunity warrants further study.
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Affiliation(s)
- Yuan Wu
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Xu Li
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, PR China
| | - Qiong Li
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Chienshan Cheng
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Lan Zheng
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China.
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17
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Hao P, Zhang J, Fang S, Jia M, Xian X, Yan S, Wang Y, Ren Q, Yue F, Cui H. Lipocalin-2 inhibits pancreatic cancer stemness via the AKT/c-Jun pathway. Hum Cell 2022; 35:1475-1486. [PMID: 35792978 DOI: 10.1007/s13577-022-00735-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 06/10/2022] [Indexed: 12/17/2022]
Abstract
Cancer stem cells (CSCs) are involved in cancer recurrence and metastasis owing to their self-renewal properties and drug-resistance capacity. Lipocalin-2 (Lcn2) of the lipocalin superfamily is highly expressed in pancreatic cancer. Nevertheless, reports on the involvement of Lcn2 in the regulation of pancreatic CSC properties are scant. This study is purposed to investigate whether Lcn2 plays a crucial role in CSC renewal and stemness maintenance in pancreatic carcinoma. Immunohistochemistry results of tumor tissue chips together with Gene Expression Omnibus sequencing files confirmed that Lcn2 is highly expressed in pancreatic carcinoma compared with that in normal tissues. The exogenous expression of Lcn2 attenuated CSC-associated SOX2, CD44, and EpCAM expression and suppressed sarcosphere formation and tumorigenesis in the pancreatic carcinoma cell line PANC-1, which showed low expression of Lcn2. However, Lcn2 knockout in BxPC-3 cell line, which presented high Lcn2 expression, promoted CSC stemness, further enhancing sarcosphere formation and tumorigenesis. Moreover, Lcn2 was found to regulate stemness in pancreatic cancer depending on the activation of AKT and c-Jun. Lcn2 suppresses stemness properties in pancreatic carcinoma by activating the AKT-c-Jun pathway, and thus, it may be a novel candidate to suppress the stemness of pancreatic cancer. This study provides a new insight into disease progression.
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Affiliation(s)
- Peipei Hao
- Department of Human Anatomy, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, China
- International Cooperation Laboratory of Stem Cell Research, Shijiazhuang, Hebei, China
| | - Jiamin Zhang
- Department of Human Anatomy, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, China
- International Cooperation Laboratory of Stem Cell Research, Shijiazhuang, Hebei, China
| | - Shu Fang
- Department of Human Anatomy, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, China
- International Cooperation Laboratory of Stem Cell Research, Shijiazhuang, Hebei, China
| | - Miaomiao Jia
- Department of Human Anatomy, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, China
- International Cooperation Laboratory of Stem Cell Research, Shijiazhuang, Hebei, China
| | - Xian Xian
- International Cooperation Laboratory of Stem Cell Research, Shijiazhuang, Hebei, China
- Department of Pathogenic Biology, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Sinan Yan
- Department of Otorhinolaryngology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yunpeng Wang
- Department of General Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Qian Ren
- Department of Human Anatomy, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, China
- International Cooperation Laboratory of Stem Cell Research, Shijiazhuang, Hebei, China
| | - Fengming Yue
- International Cooperation Laboratory of Stem Cell Research, Shijiazhuang, Hebei, China.
- Department of Histology and Embryology, Shinshu University School of Medicine, Matsumoto, Nagano, 390-0312, Japan.
| | - Huixian Cui
- Department of Human Anatomy, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, 050017, Hebei, China.
- International Cooperation Laboratory of Stem Cell Research, Shijiazhuang, Hebei, China.
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18
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Nishimura S, Yamamoto Y, Sugimoto A, Kushiyama S, Togano S, Kuroda K, Okuno T, Kasashima H, Ohira M, Maeda K, Yashiro M. Lipocalin-2 negatively regulates epithelial-mesenchymal transition through matrix metalloprotease-2 downregulation in gastric cancer. Gastric Cancer 2022; 25:850-861. [PMID: 35705840 PMCID: PMC9365736 DOI: 10.1007/s10120-022-01305-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/10/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Although the role of Lipocalin-2 (LCN2) in cancer development has been focused on recent studies, the molecular mechanisms and clinical relevance of LCN2 in gastric cancer (GC) still remain unclear. METHODS Transcriptome analysis of GC samples from public human data was performed according to Lauren's classification and molecular classification. In vitro, Western blotting, RT-PCR, wound healing assay and invasion assay were performed to reveal the function and mechanisms of LCN2 in cell proliferation, migration and invasion using LCN2 knockdown cells. Gene set enrichment analysis (GSEA) of GC samples from public human data was analyzed according to LCN2 expression. The clinical significance of LCN2 expression was investigated in GC patients from public data and our hospital. RESULTS LCN2 was downregulated in diffuse-type GC, as well as in Epithelial-Mesenchymal Transition (EMT) type GC. LCN2 downregulation significantly promoted proliferation, invasion and migration of GC cells. The molecular mechanisms of LCN2 downregulation contribute to Matrix Metalloproteinases-2 (MMP2) stimulation which enhances EMT signaling in GC cells. GSEA revealed that LCN2 downregulation in human samples was involved in EMT signaling. Low LCN2 protein and mRNA levels were significantly associated with poor prognosis in patients with GC. LCN2 mRNA level was an independent prognostic factor for overall survival in GC patients. CONCLUSIONS LCN2 has a critical role in EMT signaling via MMP2 activity during GC progression. Thus, LCN2 might be a promising therapeutic target to revert EMT signaling in GC patients with poor outcomes.
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Affiliation(s)
- Sadaaki Nishimura
- Molecular Oncology and Therapeutics, Osaka Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka City, Osaka 545-8585 Japan ,grid.258799.80000 0004 0372 2033Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan ,grid.258799.80000 0004 0372 2033Cancer Center for Translational Research, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Yurie Yamamoto
- Molecular Oncology and Therapeutics, Osaka Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka City, Osaka 545-8585 Japan ,grid.258799.80000 0004 0372 2033Cancer Center for Translational Research, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Atsushi Sugimoto
- Molecular Oncology and Therapeutics, Osaka Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka City, Osaka 545-8585 Japan ,grid.258799.80000 0004 0372 2033Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan ,grid.258799.80000 0004 0372 2033Cancer Center for Translational Research, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Shuhei Kushiyama
- grid.258799.80000 0004 0372 2033Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Shingo Togano
- grid.258799.80000 0004 0372 2033Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Kenji Kuroda
- grid.258799.80000 0004 0372 2033Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Tomohisa Okuno
- grid.258799.80000 0004 0372 2033Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Hiroaki Kasashima
- Molecular Oncology and Therapeutics, Osaka Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka City, Osaka 545-8585 Japan ,grid.258799.80000 0004 0372 2033Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Masaichi Ohira
- grid.258799.80000 0004 0372 2033Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Kiyoshi Maeda
- grid.258799.80000 0004 0372 2033Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Masakazu Yashiro
- Molecular Oncology and Therapeutics, Osaka Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka City, Osaka 545-8585 Japan ,grid.258799.80000 0004 0372 2033Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan ,grid.258799.80000 0004 0372 2033Cancer Center for Translational Research, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
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Yao F, Deng Y, Zhao Y, Mei Y, Zhang Y, Liu X, Martinez C, Su X, Rosato RR, Teng H, Hang Q, Yap S, Chen D, Wang Y, Chen MJM, Zhang M, Liang H, Xie D, Chen X, Zhu H, Chang JC, You MJ, Sun Y, Gan B, Ma L. A targetable LIFR-NF-κB-LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis. Nat Commun 2021; 12:7333. [PMID: 34921145 PMCID: PMC8683481 DOI: 10.1038/s41467-021-27452-9] [Citation(s) in RCA: 184] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 11/16/2021] [Indexed: 02/06/2023] Open
Abstract
The growing knowledge of ferroptosis has suggested the role and therapeutic potential of ferroptosis in cancer, but has not been translated into effective therapy. Liver cancer, primarily hepatocellular carcinoma (HCC), is highly lethal with limited treatment options. LIFR is frequently downregulated in HCC. Here, by studying hepatocyte-specific and inducible Lifr-knockout mice, we show that loss of Lifr promotes liver tumorigenesis and confers resistance to drug-induced ferroptosis. Mechanistically, loss of LIFR activates NF-κB signaling through SHP1, leading to upregulation of the iron-sequestering cytokine LCN2, which depletes iron and renders insensitivity to ferroptosis inducers. Notably, an LCN2-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on HCC patient-derived xenograft tumors with low LIFR expression and high LCN2 expression. Thus, anti-LCN2 therapy is a promising way to improve liver cancer treatment by targeting ferroptosis.
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Affiliation(s)
- Fan Yao
- Hubei Hongshan Laboratory, College of Life Science and Technology, College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| | - Yalan Deng
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yang Zhao
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Ying Mei
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yilei Zhang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Xiaoguang Liu
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Consuelo Martinez
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Xiaohua Su
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Roberto R Rosato
- Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, TX, 77030, USA
| | - Hongqi Teng
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Qinglei Hang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Shannon Yap
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Dahu Chen
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yumeng Wang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Mei-Ju May Chen
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Mutian Zhang
- Institute of Biosciences and Technology, Texas A&M University, Houston, TX, 77030, USA
| | - Han Liang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Dong Xie
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Hao Zhu
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Jenny C Chang
- Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, TX, 77030, USA
| | - M James You
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yutong Sun
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Boyi Gan
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Li Ma
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
- The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA.
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20
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Zhu S, Ma AH, Zhu Z, Adib E, Rao T, Li N, Ni K, Chittepu VCSR, Prabhala R, Garisto Risco J, Kwiatkowski D, Mouw K, Sonpavde G, Cheng F, Pan CX. Synergistic antitumor activity of pan-PI3K inhibition and immune checkpoint blockade in bladder cancer. J Immunother Cancer 2021; 9:jitc-2021-002917. [PMID: 34725212 PMCID: PMC8562536 DOI: 10.1136/jitc-2021-002917] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/31/2021] [Indexed: 01/11/2023] Open
Abstract
Background Immune checkpoint blockade (ICB) induces durable response in approximately 20% of patients with advanced bladder urothelial cancer (aUC). Over 50% of aUCs harbor genomic alterations along the phosphoinositide 3-kinase (PI3K) pathway. The goal of this project was to determine the synergistic effects and mechanisms of action of PI3K inhibition and ICB combination in aUC. Methods Alterations affecting the PI3K pathway were examined in The Cancer Genome Atlas (TCGA) and the Cancer Dependency Map databases. Human and mouse cells with Pten deletion were used for in vitro studies. C57BL/6 mice carrying syngeneic tumors were used to determine in vivo activity, mechanisms of action and secondary resistance of pan-PI3K inhibition, ICB and combination. Results Alterations along the PI3K pathway occurred in 57% of aUCs in TCGA. CRISPR (clustered regularly interspaced short palindromic repeats) knockout of PIK3CA induced pronounced inhibition of cell proliferation (p=0.0046). PI3K inhibition suppressed cancer cell growth, migration and colony formation in vitro. Pan-PI3K inhibition, antiprogrammed death 1 (aPD1) therapy and combination improved the overall survival (OS) of syngeneic mice with PTEN-deleted tumors from 27 days of the control to 48, 37, and 65 days, respectively. In mice with tumors not containing a PI3K pathway alteration, OS was prolonged by the combination but not single treatments. Pan-PI3K inhibition significantly upregulated CD80, CD86, MHC-I, and MHC-II in dendritic cells, and downregulated the transforming growth factor beta pathway with a false discovery rate-adjusted q value of 0.001. Interferon alpha response was significantly upregulated with aPD1 therapy (q value: <0.001) and combination (q value: 0.027). Compared with the control, combination treatment increased CD8+ T-cell infiltration (p=0.005), decreased Treg-cell infiltration (p=0.036), and upregulated the expression of multiple immunostimulatory cytokines and granzyme B (p<0.01). Secondary resistance was associated with upregulation of the mammalian target of rapamycin (mTOR) pathway and multiple Sprr family genes. Conclusions The combination Pan-PI3K inhibition and ICB has significant antitumor effects in aUC with or without activated PI3K pathway and warrants further clinical investigation. This combination creates an immunostimulatory tumor milieu. Secondary resistance is associated with upregulation of the mTOR pathway and Sprr family genes.
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Affiliation(s)
- Shaoming Zhu
- Department of Internal Medicine, University of California Davis, Sacramento, CA, USA.,Department of Urology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China
| | - A-Hong Ma
- Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA, USA
| | - Zheng Zhu
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Elio Adib
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Ting Rao
- Department of Internal Medicine, University of California Davis, Sacramento, CA, USA.,Department of Urology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Na Li
- Department of Internal Medicine, University of California Davis, Sacramento, CA, USA.,Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Kaiyuan Ni
- Department of Bioengienering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | | | - Rao Prabhala
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | | | - David Kwiatkowski
- Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Kent Mouw
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Guru Sonpavde
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Fan Cheng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Chong-Xian Pan
- Department of Internal Medicine, University of California Davis, Sacramento, CA, USA .,Department of Medicine, Harvard Medical School, Boston, MA, USA.,Department of Medicine, VA Boston Healthcare System, Boston, MA, USA
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21
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Lu KH, Yang JS, Hsieh YH, Chu HJ, Chou CH, Lu EWH, Lin CW, Yang SF. Lipocalin-2 Inhibits Osteosarcoma Cell Metastasis by Suppressing MET Expression via the MEK-ERK Pathway. Cancers (Basel) 2021; 13:cancers13133181. [PMID: 34202288 PMCID: PMC8268143 DOI: 10.3390/cancers13133181] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/15/2021] [Accepted: 06/22/2021] [Indexed: 12/22/2022] Open
Abstract
Simple Summary Higher neutrophil-derived cytokine lipocalin-2 (LCN2) expression possesses a versatile role in a myriad of cancers, but little is known about the role of LCN2 on osteosarcoma metastasis. In this study, we demonstrated that higher LCN2 inhibited cellular motility, migration, and invasion of osteosarcoma cells. Moreover, the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was decreased by LCN2 knockdown. Conclusively, LCN2 inhibits osteosarcoma cell metastasis by suppressing MET via the mitogen-activated protein kinases/ERK kinase (MEK)–ERK pathway. Abstract Higher neutrophil-derived cytokine lipocalin-2 (LCN2) expression possesses a versatile role in a myriad of cancers, but little is known about the role of LCN2 on osteosarcoma metastasis. In this study, we demonstrated that higher LCN2 inhibited cellular motility, migration, and invasion of osteosarcoma cells. Moreover, using RNA sequencing technology, we found that LCN2 repressed MET gene expression in U2OS cells. Manipulation of LCN2 levels influenced the migratory potential of osteosarcoma cells as cellular migration was enhanced by transfecting with vectors containing a constitutively active LCN2 cDNA and recombinant human LCN2. Moreover, the phosphorylation of mitogen-activated protein kinases/extracellular signal-regulated kinase (ERK) kinase (MEK) 1/2 and ERK 1/2 was decreased by LCN2 knockdown. Furthermore, the use of ERK inhibitor (U0126) and activator (tBHQ) confirmed that the pharmaceutic inhibition of MEK–ERK augmented the LCN2-mediated MET suppression and migration of U2OS and HOS cells. Conclusively, LCN2 inhibits osteosarcoma cell metastasis by suppressing MET via the MEK–ERK pathway.
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Affiliation(s)
- Ko-Hsiu Lu
- Department of Orthopedics, Chung Shan Medical University Hospital, Taichung 402, Taiwan;
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
| | - Jia-Sin Yang
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (J.-S.Y.); (Y.-H.H.); (H.-J.C.); (C.-H.C.)
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Yi-Hsien Hsieh
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (J.-S.Y.); (Y.-H.H.); (H.-J.C.); (C.-H.C.)
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Hsiao-Ju Chu
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (J.-S.Y.); (Y.-H.H.); (H.-J.C.); (C.-H.C.)
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Chia-Hsuan Chou
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (J.-S.Y.); (Y.-H.H.); (H.-J.C.); (C.-H.C.)
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | | | - Chiao-Wen Lin
- Institute of Oral Sciences, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- Correspondence: (C.-W.L.); (S.-F.Y.); Tel.: +886-4-24739595-34253 (S.-F.Y)
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (J.-S.Y.); (Y.-H.H.); (H.-J.C.); (C.-H.C.)
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- Correspondence: (C.-W.L.); (S.-F.Y.); Tel.: +886-4-24739595-34253 (S.-F.Y)
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22
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Takegahara K, Usuda J, Inoue T, Sonokawa T, Matsui T, Matsumoto M. Antiaging gene Klotho regulates epithelial-mesenchymal transition and increases sensitivity to pemetrexed by inducing lipocalin-2 expression. Oncol Lett 2021; 21:418. [PMID: 33841579 PMCID: PMC8020392 DOI: 10.3892/ol.2021.12679] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 11/11/2020] [Indexed: 12/17/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) is considered to serve an important role in the metastatic/invasive ability of cancer cells, in the acquisition of drug resistance, and in metabolic reprogramming. In the present study, it was hypothesized that the Klotho gene is involved in the metastatic/invasive ability of lung cancer. We previously reported an association between Klotho expression and overall survival in patients with small cell lung cancer and large cell neuroendocrine cancer. We also found that Klotho expression was associated with EMT-related molecules in lung squamous cell carcinoma. The present study aimed to analyze the function of the Klotho gene and to elucidate its relevance to the regulation of the EMT. For this purpose, GFP-Klotho plasmids were transfected into lung adenocarcinoma cells (A549) and cell lines with stable expression (A549/KL-1 and A549/KL-2) were established. A549/KL-1 cells expressed higher levels of Klotho protein by western blot analysis compared with A549/KL-2 cells. In western blotting of A549 and A549/KL-1 cells, the expression of the mesenchymal marker N-cadherin was found to be completely inhibited in A549/KL-1 cells suggesting that Klotho expression may regulate the EMT in cancer cells via the inhibition of N-cadherin. The results of the sensitivity tests demonstrated that A549/KL-1 cells were significantly more sensitive to pemetrexed compared with A549 cells (IC50 A549/KL-1 vs. A549 cells, 0.1 µM vs. 0.7 µM). The results of the microarray analysis demonstrated that a very high level of lipocalin-2 (LCN2) expression was induced in the A549/KL-1 cells. Klotho overexpression completely suppressed the expression of mesenchymal markers, such as N-cadherin and Snail1 (Snail). The results of the present study suggested that there may be a new mechanism of action for the antitumor effects of pemetrexed, namely, LCN2-mediated modulation of N-cadherin expression. Klotho expression during cancer treatment has great potential as a predictor for efficacy of pemetrexed and as a factor in the selection of personalized medicine for postoperative adjuvant chemotherapy.
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Affiliation(s)
- Kyoshiro Takegahara
- Department of Thoracic Surgery, Nippon Medical School, Tokyo 113-8603, Japan
| | - Jitsuo Usuda
- Department of Thoracic Surgery, Nippon Medical School, Tokyo 113-8603, Japan
| | - Tatsuya Inoue
- Department of Thoracic Surgery, Nippon Medical School, Tokyo 113-8603, Japan
| | - Takumi Sonokawa
- Department of Thoracic Surgery, Nippon Medical School, Tokyo 113-8603, Japan
| | - Takuma Matsui
- Department of Thoracic Surgery, Nippon Medical School, Tokyo 113-8603, Japan
| | - Mitsuo Matsumoto
- Department of Thoracic Surgery, Nippon Medical School, Tokyo 113-8603, Japan
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23
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Dertli R, Biyik M, Yolacan R, Karakarcayildiz A, Keskin M, Kayar Y, Asil M. May Neutrophil Gelatinase-Associated Lipocalin (NGAL) Level Predict Mortality in Patients with Hepatocellular Carcinoma (HCC)? J Gastrointest Cancer 2021; 51:932-938. [PMID: 31729643 DOI: 10.1007/s12029-019-00323-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
PURPOSE Hepatocellular carcinoma (HCC) ranks fifth among the common cancers worldwide. Hepatocarcinogenesis is a multiple-phases process, which involves changes in cellular genomes including high cell proliferation.In this study, we aimed to evaluate the relationship of NGAL level at the time of diagnosis with mortality in patients diagnosed with HCC. MATERIAL AND METHODS A total of 35 patients who developed HCC on the ground of HBV(+) and 30 healthy subjects were included in the study. Barcelona Clinic Liver Cancer (BCLC), Okuda staging system, and Milan criteria were used for staging of the patients with HCC. RESULTS The mean age of all patients was 59.54 ± 11.57 years. Seventeen (48.6%) HCC patients died during 1-year follow-up. Survival of the patients who met the Milan criteria was longer (log-rank (Mantel-Cox) test, χ2 = 5.353, p = 0.021). Kaplan-Meier curve was drawn for NGAL cut-off value, mortality was found to be higher in patients with a NGAL level higher than 217.50 (log-rank (Mantel-Cox) test, χ2 = 15.540, p < 0.001). CONCLUSION In this study, we found that high levels of NGAL at the time of diagnosis were associated with poor prognosis in HCC patients.
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Affiliation(s)
- Ramazan Dertli
- Department of Internal Medicine, Division of Gastroenterology, Van Education and Research Hospital, Van, Turkey.
| | - Murat Biyik
- Meram School of Medicine, Department of Internal Medicine, Division of Gastroenterology, Necmettin Erbakan University, Meram, Konya, Turkey
| | - Ramazan Yolacan
- Meram School of Medicine, Department of Internal Medicine, Necmettin Erbakan University, Meram, Konya, Turkey
| | - Ahmet Karakarcayildiz
- Meram School of Medicine, Department of Internal Medicine, Necmettin Erbakan University, Meram, Konya, Turkey
| | - Muharrem Keskin
- Meram School of Medicine, Department of Internal Medicine, Division of Gastroenterology, Necmettin Erbakan University, Meram, Konya, Turkey
| | - Yusuf Kayar
- Department of Internal Medicine, Division of Gastroenterology, Van Education and Research Hospital, Van, Turkey
| | - Mehmet Asil
- Meram School of Medicine, Department of Internal Medicine, Division of Gastroenterology, Necmettin Erbakan University, Meram, Konya, Turkey
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24
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Krizanac M, Mass Sanchez PB, Weiskirchen R, Asimakopoulos A. A Scoping Review on Lipocalin-2 and Its Role in Non-Alcoholic Steatohepatitis and Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:2865. [PMID: 33799862 PMCID: PMC8000927 DOI: 10.3390/ijms22062865] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/05/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023] Open
Abstract
Excess calorie intake and a sedentary lifestyle have made non-alcoholic fatty liver disease (NAFLD) one of the fastest growing forms of liver disease of the modern world. It is characterized by abnormal accumulation of fat in the liver and can range from simple steatosis and non-alcoholic steatohepatitis (NASH) to cirrhosis as well as development of hepatocellular carcinoma (HCC). Biopsy is the golden standard for the diagnosis and differentiation of all NAFLD stages, but its invasiveness poses a risk for patients, which is why new, non-invasive ways of diagnostics ought to be discovered. Lipocalin-2 (LCN2), which is a part of the lipocalin transport protein family, is a protein formally known for its role in iron transport and in inflammatory response. However, in recent years, its implication in the pathogenesis of NAFLD has become apparent. LCN2 shows significant upregulation in several benign and malignant liver diseases, making it a good candidate for the NAFLD biomarker or even a therapeutic target. What makes LCN2 more interesting to study is the fact that it is overexpressed in HCC development induced by chronic NASH, which is one of the primary causes of cancer-related deaths. However, to this day, neither its role as a biomarker for NAFLD nor the molecular mechanisms of its implication in NAFLD pathogenesis have been completely elucidated. This review aims to gather and closely dissect the current knowledge about, sometimes conflicting, evidence on LCN2 as a biomarker for NAFLD, its involvement in NAFLD, and NAFLD-HCC related pathogenesis, while comparing it to the findings in similar pathologies.
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Affiliation(s)
| | | | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, 52074 Aachen, Germany; (M.K.); (P.B.M.S.)
| | - Anastasia Asimakopoulos
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, 52074 Aachen, Germany; (M.K.); (P.B.M.S.)
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25
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Tong Y, Li Z, Wu Y, Zhu S, Lu K, He Z. Lotus leaf extract inhibits ER - breast cancer cell migration and metastasis. Nutr Metab (Lond) 2021; 18:20. [PMID: 33602253 PMCID: PMC7891157 DOI: 10.1186/s12986-021-00549-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 02/05/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Patients with estrogen receptor negative (ER-) breast cancer have poor prognosis due to high rates of metastasis. However, there is no effective treatment and drugs for ER- breast cancer metastasis. Our purpose of this study was to evaluate the effect of lotus leaf alcohol extract (LAE) on the cell migration and metastasis of ER- breast cancer. METHODS The anti-migratory effect of LAE were analyzed in ER- breast cancer cells including SK-BR-3, MDA-MB-231 and HCC1806 cell lines. Cell viability assay, wound-healing assay, RNA-sequence analysis and immunoblotting assay were used to evaluate the cytotoxicity and anti-migratory effect of LAE. To further investigate the inhibitory effect of LAE on metastasis in vivo, subcutaneous xenograft and intravenous injection nude mice models were established. Lung and liver tissues were analyzed by the hematoxylin and eosin staining and immunoblotting assay. RESULTS We found that lotus LAE, not nuciferine, inhibited cell migration significantly in SK-BR-3, MDA-MB-231 and HCC1806 breast cancer cells, and did not affect viability of breast cancer cells. The anti-migratory effect of LAE was dependent on TGF-β1 signaling, while independent of Wnt signaling and autophagy influx. Intracellular H2O2 was involved in the TGF-β1-related inhibition of cell migration. LAE inhibited significantly the breast cancer cells metastasis in mice models. RNA-sequence analysis showed that extracellular matrix signaling pathways are associated with LAE-suppressed cell migration. CONCLUSIONS Our findings demonstrated that lotus leaf alcohol extract inhibits the cell migration and metastasis of ER- breast cancer, at least in part, via TGF-β1/Erk1/2 and TGF-β1/SMAD3 signaling pathways, which provides a potential therapeutic strategy for ER- breast cancer.
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Affiliation(s)
- Yuelin Tong
- Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.,State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Zhongwei Li
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Yikuan Wu
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Shenglong Zhu
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Keke Lu
- Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Zhao He
- Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. .,State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China. .,Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China. .,Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
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26
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Li C, Li Y, Lou L, Han X, Wang H, Huang T, Li C. The interaction between lipocalin 2 and dipyridine ketone hydrazone dithiocarbamte may influence respective function in proliferation and metastasis-related gene expressions in HepG2 cell. J Biol Inorg Chem 2021; 26:123-133. [PMID: 33449164 DOI: 10.1007/s00775-020-01842-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 11/30/2020] [Indexed: 10/22/2022]
Abstract
LCN2 (Lipocalins) was first identified as iron transporter through associating with its siderophores and also involved in many cancer metastases, but its function is still paradoxical. We questioned that whether LCN2 might also associate exogenous iron chelator as does in inherent way and the association may influence their respective function. To address this issue, we investigated the effect of LCN2 on action of DpdtC (2,2'-dipyridine ketone hydrazone dithiocarbamte), an iron chelator in proliferation and metastasis-related gene expression. The results showed that exogenous LCN2 and DpdtC could inhibit growth of HepG2 cells, while the combination treatment enhanced their inhibitory effect both in proliferation and colony formation. This encouraged us to investigate the effect of the interaction on metastasis-related gene expression. The results revealed that both LCN2 and DpdtC impaired the wound healing of HepG2, but the inhibitory effect of DpdtC was significantly enhanced upon association with LCN2. Undergoing epithelium-mesenchymal transition (EMT) is a crucial step for cancer metastasis, LCN2 and DpdtC had opposite effects on EMT markers, the binding of DpdtC to LCN2 significantly weakened the regulation of it (or its iron chelate) on EMT markers. To insight into the interaction between LCN2 and DpdtC-iron, fluorescence titration and molecular docking were performed to obtain the association constant (~ 104 M-1) and thermodynamic parameters (ΔG = - 26.10 kJ/mol). Importantly this study provided evidence that siderophores-loading state of LCN2 may influence its function, which be helpful for understanding the contradictory role of LCN2 in the metastasis of cancer.
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Affiliation(s)
- Cuiping Li
- Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, 453003, Henan, People's Republic of China
| | - Yongli Li
- Department of Histology and Embryology, Sanquan College of Xinxiang Medical University, Xinxiang, 453003, Henan, People's Republic of China
| | - Liying Lou
- Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, 453003, Henan, People's Republic of China
| | - Xinyi Han
- Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, 453003, Henan, People's Republic of China
| | - Huihui Wang
- Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, 453003, Henan, People's Republic of China
| | - Tengfei Huang
- Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, 453003, Henan, People's Republic of China
| | - Changzheng Li
- Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, 453003, Henan, People's Republic of China. .,Experimental Teaching Center of Biology and Basic Medical Sciences, Sanquan College of Xinxiang Medical University, Xinxiang, 453003, Henan, People's Republic of China.
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Chen M, Yang N, Lechner J, Toth L, Hogg R, Silvestri G, Chakravarthy U, Xu H. Plasma level of lipocalin 2 is increased in neovascular age-related macular degeneration patients, particularly those with macular fibrosis. IMMUNITY & AGEING 2020; 17:35. [PMID: 33292361 PMCID: PMC7666483 DOI: 10.1186/s12979-020-00205-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 11/01/2020] [Indexed: 02/07/2023]
Abstract
Background Previously, we and others have reported higher populations of circulating neutrophils in patients with neovascular age-related macular degeneration (nAMD). Neutrophil gelatinase-associated lipocalin (NGAL, also known as lipocalin-2, LCN2), an important innate immune mediator, is known to be critically involved in sterile inflammation-mediated organ failure, fibrosis, cancer progression and retinal degeneration. This study investigated the plasma levels of LCN2, matrix metalloproteinase 9 (MMP9) and LCN2/MMP9 complex in different types of nAMD and examined whether the levels were related to patients’ responsiveness to anti-VEGF therapy. Results One hundred and seventy-four nAMD patients, including 108 with choroidal neovascularisation (CNV), 32 with retinal angiomatous proliferation (RAP), 23 with polypoidal choroidal vasculopathy (PCV) and 11 unclassified patients, and 43 healthy controls were recruited to this case-control study. Fifty-eight nAMD patients had macular fibrosis and 110 patients did not. Out of the 174 nAMD patients, 80 patients responded completely, 90 responded partially, and 4 did not respond to the anti-VEGF therapy. The plasma levels of LCN2 in nAMD patients (181.46 ± 73.62 ng/ml) was significantly higher than that in healthy controls (152.24 ± 49.55 ng/ml, P = 0.047). However, the difference disappeared after adjusting for age. A positive correlation between plasma level of LCN2 and age was observed in nAMD patients (r = 0.29, P = 0.0002) but not in healthy controls. The plasma level of LCN2 was also positively correlated with circulating neutrophils in nAMD patients (r = 0.34, p = 0.0007) but not in healthy controls (r = 0.057, p = 0.77). No correlation was observed between age and circulating neutrophils. Further analysis of nAMD subtypes uncovered a significantly higher level of LCN2 in patients with macular fibrosis even after adjusting for age. No relationship was observed between plasma levels of LCN2 and patients’ responsiveness to anti-VEGF therapy. The plasma levels of MMP9 and LCN2/MMP9 complex were comparable between nAMD and controls. Conclusions Our results suggest that higher plasma levels of LCN2 in nAMD are related to ageing and increased population of circulating neutrophils. Our results also suggest that higher levels of LCN2 may increase the risk of macular fibrosis in nAMD.
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Affiliation(s)
- Mei Chen
- Centre for Experimental Medicine, The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Nan Yang
- Centre for Experimental Medicine, The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Judith Lechner
- Centre for Experimental Medicine, The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Levente Toth
- Centre for Experimental Medicine, The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Ruth Hogg
- Centre for Public Health, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | | | - Usha Chakravarthy
- Centre for Public Health, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Heping Xu
- Centre for Experimental Medicine, The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK.
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Hao P, Li H, Wu A, Zhang J, Wang C, Xian X, Ren Q, Hao N, Wang Y, Yue F, Cui H. Lipocalin2 promotes cell proliferation and migration in ovarian cancer through activation of the ERK/GSK3β/β-catenin signaling pathway. Life Sci 2020; 262:118492. [PMID: 32980390 DOI: 10.1016/j.lfs.2020.118492] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 09/19/2020] [Accepted: 09/20/2020] [Indexed: 12/01/2022]
Abstract
Lipocalin2 (Lcn2) has been shown to be a vital regulator of tumorigenesis in a variety of different cancers. However, its expression patterns and possible roles in ovarian cancer remain obscure. The aim of this study was to investigate the expression of Lcn2 in ovarian cancer cells and to determine any potential association between Lcn2 and ovarian tumor development and cancer progression. Our results indicated that Lcn2 was upregulated in tumor tissue from ovarian cancer patients as well as in three ovarian cancer cell lines compared to normal tissues and cells. Overexpression of Lcn2 promoted both cell proliferation and migration in ovarian cancer cells. Conversely, knockdown of Lcn2 in cell lines suppressed both migration and proliferation. Moreover, upregulation of Lcn2 contributed to tumor growth in nude mice in vivo. Mechanistically, Lcn2 was found to lead to tumor progression in ovarian cancer cells through activation of the ERK/GSK3β/β-catenin signaling pathway. In summary, Lcn2 promotes cell proliferation and migration in ovarian cancer through activation of the ERK/GSK3β/β-catenin signaling pathway, suggesting that Lcn2 might be a novel therapeutic target for ovarian cancer.
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Affiliation(s)
- Peipei Hao
- Department of Human Anatomy, Hebei Medical University, Shijiazhuang 050017, Hebei, China; Hebei Research Center for Stem Cell Medical Translational Engineering, Shijiazhuang 050017, Hebei, China; International Cooperation Laboratory of Stem Cell Research, Shijiazhuang 050017, Hebei, China
| | - Haili Li
- Department of Gynecology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
| | - Aiyuan Wu
- The 3rd Affiliated Teaching Hospital of Xinjiang Medical University (Affiliated Cancer Hospital), Suzhou Dong Street No.789, Urumqi 830011, China
| | - Jiamin Zhang
- Department of Human Anatomy, Hebei Medical University, Shijiazhuang 050017, Hebei, China
| | - Chang Wang
- Department of Human Anatomy, Hebei Medical University, Shijiazhuang 050017, Hebei, China; Neuroscience Research Center, Hebei Medical University, Shijiazhuang 050017, Hebei, China
| | - Xian Xian
- Hebei Research Center for Stem Cell Medical Translational Engineering, Shijiazhuang 050017, Hebei, China; International Cooperation Laboratory of Stem Cell Research, Shijiazhuang 050017, Hebei, China
| | - Qian Ren
- Department of Human Anatomy, Hebei Medical University, Shijiazhuang 050017, Hebei, China; Hebei Research Center for Stem Cell Medical Translational Engineering, Shijiazhuang 050017, Hebei, China; International Cooperation Laboratory of Stem Cell Research, Shijiazhuang 050017, Hebei, China
| | - Nana Hao
- Department of Neurology, HanDan Central Hospital, HanDan, Hebei, China
| | - Yunpeng Wang
- Department of General Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei, China
| | - Fengming Yue
- Hebei Research Center for Stem Cell Medical Translational Engineering, Shijiazhuang 050017, Hebei, China; International Cooperation Laboratory of Stem Cell Research, Shijiazhuang 050017, Hebei, China; The Department of Histology and Embryology, Medical School of Shinshu University, Japan
| | - Huixian Cui
- Department of Human Anatomy, Hebei Medical University, Shijiazhuang 050017, Hebei, China; Hebei Research Center for Stem Cell Medical Translational Engineering, Shijiazhuang 050017, Hebei, China; International Cooperation Laboratory of Stem Cell Research, Shijiazhuang 050017, Hebei, China.
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Yammine L, Zablocki A, Baron W, Terzi F, Gallazzini M. Lipocalin-2 Regulates Epidermal Growth Factor Receptor Intracellular Trafficking. Cell Rep 2020; 29:2067-2077.e6. [PMID: 31722218 DOI: 10.1016/j.celrep.2019.10.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 08/02/2019] [Accepted: 10/03/2019] [Indexed: 11/27/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) activation and lipocalin-2 (Lcn2) expression are frequently observed in the same pathological contexts, such as cancers or chronic kidney disease (CKD). However, the significance of this association is unknown. Here, we describe the role of Lcn2 in regulating EGFR trafficking. We show that Lcn2 increases EGFR cell surface abundance and is required for transforming growth factor α (TGF-α)-induced EGFR recycling to the plasma membrane and sustained activation. Lcn2 binds to the intracellular domain of EGFR in late endosomal compartments and inhibits its lysosomal degradation. Consistently, Lcn2 enhances EGFR-induced cell migration after TGF-α stimulation. In vivo, Lcn2 gene inactivation prevents EGFR recycling to the plasma membrane in an experimental model of CKD. Remarkably, this is associated with a dramatic decrease of renal lesions. Together, our data identify Lcn2 as a key mediator of EGFR trafficking processes. Hence, therapeutic inhibition of Lcn2 may counteract the deleterious effect of EGFR activation.
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Affiliation(s)
- Lucie Yammine
- Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Institut Necker Enfants Malades, Département "Croissance et Signalisation," Hôpital Necker Enfants Malades, Université Paris Descartes, 149 Rue de Sèvres, Paris 75015, France
| | - Aniela Zablocki
- Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Institut Necker Enfants Malades, Département "Croissance et Signalisation," Hôpital Necker Enfants Malades, Université Paris Descartes, 149 Rue de Sèvres, Paris 75015, France
| | - William Baron
- Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Institut Necker Enfants Malades, Département "Croissance et Signalisation," Hôpital Necker Enfants Malades, Université Paris Descartes, 149 Rue de Sèvres, Paris 75015, France
| | - Fabiola Terzi
- Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Institut Necker Enfants Malades, Département "Croissance et Signalisation," Hôpital Necker Enfants Malades, Université Paris Descartes, 149 Rue de Sèvres, Paris 75015, France
| | - Morgan Gallazzini
- Mechanisms and Therapeutic Strategies of Chronic Kidney Disease, INSERM U1151-CNRS UMR 8253, Institut Necker Enfants Malades, Département "Croissance et Signalisation," Hôpital Necker Enfants Malades, Université Paris Descartes, 149 Rue de Sèvres, Paris 75015, France.
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Schröder SK, Asimakopoulou A, Tillmann S, Koschmieder S, Weiskirchen R. TNF-α controls Lipocalin-2 expression in PC-3 prostate cancer cells. Cytokine 2020; 135:155214. [PMID: 32712458 DOI: 10.1016/j.cyto.2020.155214] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/30/2020] [Accepted: 07/16/2020] [Indexed: 12/21/2022]
Abstract
Prostate cancer (PCa) is one of the most common and deadly cancers in men worldwide. The surrounding tumor microenvironment (TME) is important in tumor progression, as cytokines and soluble mediators including tumor necrosis factor (TNF-α) or lipocalin-2 (LCN2) can influence tumor growth and formation of metastasis. The exact mechanisms on how these pleiotropic factors affect PCa are still unknown. In this study, we showed for the first time that LCN2 mRNA and protein expression are strongly inducible by TNF-α in the highly metastatic human PCa cell line PC-3. In addition, we observed higher levels of secreted LCN2 in cell culture medium of TNF-α-treated PC-3 cells. We found that different signaling pathways such as p38, NF-κB or JNK were activated shortly after TNF-α treatment. Moreover, the mRNA levels of IL-1β and IL-8 were also significantly increased after 24 h stimulation. Mechanistically, the NF-κB pathway and the JNK signaling axis are directly responsible for LCN2 upregulation. This was shown by the fact that pretreatment with the JNK inhibitors SP600125 or JNK-IN-8 strongly downregulated phosphorylation of c-Jun protein and markedly reduced TNF-α-mediated LCN2 upregulation in PC-3 cells. Likewise, the NF-κB inhibitor QNZ was able to repress TNF-α-induced LCN2 expression in PC-3 cells. Taking into consideration that LCN2 has been described as a tumor promoting factor in PCa, our results indicate that JNK regulates LCN2 expression and unmasks the JNK signaling axis as a possible therapeutic target for patients with PCa.
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Affiliation(s)
- Sarah K Schröder
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany
| | - Anastasia Asimakopoulou
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany
| | - Stefan Tillmann
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | - Steffen Koschmieder
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany.
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Yang X, Ma L, Wei R, Ye T, Zhou J, Wen M, Men R, Aqeilan RI, Peng Y, Yang L. Twist1-induced miR-199a-3p promotes liver fibrosis by suppressing caveolin-2 and activating TGF-β pathway. Signal Transduct Target Ther 2020; 5:75. [PMID: 32499481 PMCID: PMC7272438 DOI: 10.1038/s41392-020-0169-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 01/07/2020] [Accepted: 01/07/2020] [Indexed: 02/05/2023] Open
Abstract
The activation of hepatic stellate cells (HSCs) participates in liver fibrosis, and emerging evidences indicate that microRNAs (miRNAs) are abnormally expressed during HSC activation. However, the potential roles of miRNAs in liver fibrosis still remain elusive. Therefore, this study aimed to investigate the role of miR-199a-3p in liver fibrosis and its underlying mechanism. We found that miR-199a-3p expression was dramatically upregulated during HSC activation in vitro, and during liver fibrogenesis in CCl4-treated rats, and its liver expression was increased in the patients with cirrhosis. By the luciferase assay and RT-qPCR, we revealed that the expression of miR-199a-3p in HSCs was driven by the transcription factor Twist1 which could be further induced by TGF-β treatment. Functional studies showed that inhibition of miR-199a-3p in both human LX2 cells and rat HSCs significantly decreased the expression of fibrotic markers, such as fibronectin and connective tissue growth factor (CTGF), whereas the forced expression of miR-199a-3p exhibited opposite effects, demonstrating the role of miR-199a-3p in promoting HSC activation. Mechanistically, miR-199a-3p plays an important role in TGF-β signalling pathway activation through targeting CAV2 that negatively regulates the expression of transforming growth factor-beta receptor type I (TGFβRI). Importantly, administration of antagomiR-199a-3p in the CCl4-treated mice significantly ameliorated hepatic fibrosis. In conclusion, Twist1-induced miR-199a-3p mediates the activation of HSCs by suppressing CAV2 expression and subsequently increasing TGFβRI expression to promote TGF-β pathway. Our findings highlight the therapeutic potential of miR-199a-3p for hepatic fibrosis.
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Affiliation(s)
- Xiaoxue Yang
- Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Liping Ma
- State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, and Collaborative Innovation Centre for Biotherapy, Chengdu, 610041, China.,School of Bioscience and Technology, Chengdu medical college, Chengdu, 610500, China
| | - Rong Wei
- State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, and Collaborative Innovation Centre for Biotherapy, Chengdu, 610041, China
| | - Tinghong Ye
- Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - JianKang Zhou
- State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, and Collaborative Innovation Centre for Biotherapy, Chengdu, 610041, China
| | - Maoyao Wen
- Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ruoting Men
- Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Rami I Aqeilan
- Department of Immunology & Cancer Research, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Yong Peng
- State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, and Collaborative Innovation Centre for Biotherapy, Chengdu, 610041, China.
| | - Li Yang
- Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Zhao W, Bendickson L, Nilsen-Hamilton M. The Lipocalin2 Gene is Regulated in Mammary Epithelial Cells by NFκB and C/EBP In Response to Mycoplasma. Sci Rep 2020; 10:7641. [PMID: 32376831 PMCID: PMC7203223 DOI: 10.1038/s41598-020-63393-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 03/25/2020] [Indexed: 02/02/2023] Open
Abstract
Lcn2 gene expression increases in response to cell stress signals, particularly in cells involved in the innate immune response. Human Lcn2 (NGAL) is increased in the blood and tissues in response to many stressors including microbial infection and in response to LPS in myeloid and epithelial cells. Here we extend the microbial activators of Lcn2 to mycoplasma and describe studies in which the mechanism of Lcn2 gene regulation by MALP-2 and mycoplasma infection was investigated in mouse mammary epithelial cells. As for the LPS response of myeloid cells, Lcn2 expression in epithelial cells is preceded by increased TNFα, IL-6 and IκBζ expression and selective reduction of IκBζ reduces Lcn2 promoter activity. Lcn2 promoter activation remains elevated well beyond the period of exposure to MALP-2 and is persistently elevated in mycoplasma infected cells. Activation of either the human or the mouse Lcn2 promoter requires both NFκB and C/EBP for activation. Thus, Lcn2 is strongly and enduringly activated by mycoplasma components that stimulate the innate immune response with the same basic regulatory mechanism for the human and mouse genes.
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Affiliation(s)
- Wei Zhao
- Roy J Carver Department of Biochemistry, Biophysics and Molecular Biology and the Interdepartmental Molecular, Cellular and Developmental Biology Program, Iowa State University, Ames, IA, 50011, USA
- Interdepartmental Molecular, Cellular and Developmental Biology Program, Iowa State University, Ames, IA, 50011, USA
- Bayview Physicians Group, Battlefield Medical association, 675 North Battlefield Boulevard, Chesapeake, VA, 23320, USA
| | - Lee Bendickson
- Roy J Carver Department of Biochemistry, Biophysics and Molecular Biology and the Interdepartmental Molecular, Cellular and Developmental Biology Program, Iowa State University, Ames, IA, 50011, USA
| | - Marit Nilsen-Hamilton
- Roy J Carver Department of Biochemistry, Biophysics and Molecular Biology and the Interdepartmental Molecular, Cellular and Developmental Biology Program, Iowa State University, Ames, IA, 50011, USA.
- Interdepartmental Molecular, Cellular and Developmental Biology Program, Iowa State University, Ames, IA, 50011, USA.
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Cheng J, Chen J, Zhao Y, Yang J, Xue K, Wang Z. MicroRNA-761 suppresses remodeling of nasal mucosa and epithelial-mesenchymal transition in mice with chronic rhinosinusitis through LCN2. Stem Cell Res Ther 2020; 11:151. [PMID: 32272958 PMCID: PMC7147028 DOI: 10.1186/s13287-020-01598-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 02/06/2020] [Accepted: 02/11/2020] [Indexed: 01/15/2023] Open
Abstract
Background Chronic rhinosinusitis (CRS) is characterized by persistent symptomatic inflammation of the nasal passage and sinus mucosa. Various microRNAs (miRs) have been implicated in CRS. Hence, the current study was conducted to explore the effect of microRNA-761 (miR-761) on remodeling of nasal mucosa and epithelial–mesenchymal transition (EMT). Methods Bioinformatics analysis was initially performed to predict the differentially expressed genes (DEGs) associated with CRS. Gene targeting relationship between miR-761 and lipocalin 2 (LCN2) was analyzed by bioinformatics analysis and verified using dual-luciferase reporter gene assay. Histopathological analyses of the nasal mucosa tissues were conducted via hematoxylin–eosin (HE) and alcian blue (AB)-periodic acid Schiff (PAS) staining. ELISA was employed to determine the IL-8 and MMP-9 levels. To define downstream pathway of miR-761, levels of proteins related to LCN2/Twist1 signaling pathway were assessed. Additionally, the effects of miR-761 on EMT, proliferation, and apoptosis were determined. Results LCN2 was highly expressed in CRS. LCN2 was a target of miR-761. miR-761 overexpression or LCN2 silencing decreased IL-8 and MMP-9 levels and morphological changes in nasal epithelial tissue from CRS mice. Overexpressed miR-761 or silenced LCN2 decreased the expression of LCN2 and Twist1, indicating LCN2/Twist1 signaling pathway was inactivated. Moreover, miR-761 overexpression or LCN2 silencing reduced the expression of N-cadherin and vimentin, while increased that of E-cadherin, suggesting inhibition of EMT. Furthermore, miR-761 overexpression or LCN2 silencing promoted cell proliferation and inhibited cell apoptosis in CRS. Conclusion Taken together, miR-761 suppressed the remodeling of nasal mucosa through inhibition of LCN2 and the LCN2/Twist1 signaling pathway.
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Affiliation(s)
- Jinzhang Cheng
- Department of Otolaryngology Head and Neck Surgery, the Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun, 130041, Jilin Province, People's Republic of China
| | - Junjun Chen
- Department of Pharmacy, the Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Yin Zhao
- Department of Otolaryngology Head and Neck Surgery, the Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun, 130041, Jilin Province, People's Republic of China
| | - Jingpu Yang
- Department of Otolaryngology Head and Neck Surgery, the Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun, 130041, Jilin Province, People's Republic of China
| | - Kai Xue
- Department of Otolaryngology Head and Neck Surgery, the Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun, 130041, Jilin Province, People's Republic of China
| | - Zonggui Wang
- Department of Otolaryngology Head and Neck Surgery, the Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun, 130041, Jilin Province, People's Republic of China.
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Aydoğdu Tığ G, Pekyardımcı Ş. An electrochemical sandwich-type aptasensor for determination of lipocalin-2 based on graphene oxide/polymer composite and gold nanoparticles. Talanta 2019; 210:120666. [PMID: 31987191 DOI: 10.1016/j.talanta.2019.120666] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 12/16/2019] [Accepted: 12/20/2019] [Indexed: 01/05/2023]
Abstract
In this work, we reported an electrochemical aptasensor based on the poly-3-amino-1,2,4-triazole-5-thiol/graphene oxide composite (P(ATT)-GO) and gold nanoparticles (AuNPs) modified graphite screen-printed electrode (GSPE) (GSPE/P(ATT)-GO/AuNPs) for determination of lipocalin-2 (LCN2) (neutrophil gelatinase-associated lipocalin). A sandwich based strategy was utilized to enhance the electrochemical signal. First, a thiol tethered DNA aptamer was immobilized onto the composite electrode. Then, the LCN2 solution was incubated with the aptamer modified GSPE/P(ATT)-GO/AuNPs. Secondary aptamer (Apt2) peculiar to the LCN2 and labeled with biotin was interacted with the LCN2. A streptavidin-alkaline phosphatase conjugate was then applied to the surface. The determination of LCN2 was performed by using the electroactive property of α-naphthol which is acquired the product from the interaction between alkaline phosphatase and α-naphthyl phosphate. The constructed electrode was characterized by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The aptamer modified GSPE/P(ATT)-GO/AuNPs showed the superior electrocatalytic performance towards the voltammetric determination of LCN2 with a wide linear range (1.0-1000.0 ng/mL) and a low limit of detection (LOD) (0.3 ng/mL). The proposed aptasensor revealed the excellent sensitivity, anti-interference ability and reproducibility which approved that the GSPE/P (ATT)-GO/AuNPs is a promising composite for the sensitive detection of LCN2. The fabricated aptasensor was applied for the determination of LCN2 in fetal bovine serum samples using the standard addition method and the recovery values were in the range of 99.2% and 103.22%.
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Affiliation(s)
- Gözde Aydoğdu Tığ
- Ankara University, Faculty of Science, Department of Chemistry, Ankara, 06100, Turkey.
| | - Şule Pekyardımcı
- Ankara University, Faculty of Science, Department of Chemistry, Ankara, 06100, Turkey
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Kurozumi S, Alsaeed S, Orah N, Miligy IM, Joseph C, Aljohani A, Toss MS, Fujii T, Shirabe K, Green AR, Aleskandarany MA, Rakha EA. Clinicopathological significance of lipocalin 2 nuclear expression in invasive breast cancer. Breast Cancer Res Treat 2019; 179:557-564. [PMID: 31707510 DOI: 10.1007/s10549-019-05488-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 10/29/2019] [Indexed: 12/12/2022]
Abstract
PURPOSE The epithelial-mesenchymal transition (EMT) plays a key role in breast cancer progression and metastasis. Lipocalin 2 (LCN2) is involved in the regulation of EMT. The aim of this study was to investigate the clinicopathological significance of LCN2 expression in breast cancer. METHODS The expression of LCN2 protein was immunohistochemically assessed in two well-characterised annotated cohorts of breast cancer (discovery cohort, n = 612; validation cohort, n = 1363). The relationship of LCN2 expression and subcellular location with the clinicopathological factors and outcomes of patients was analysed. RESULTS Absent or reduced nuclear LCN2 expression was associated with features of aggressive behaviour, including high histological grade, high Nottingham Prognostic Index, high Ki67 labelling index, hormone receptor negativity and human epidermal growth factor receptor 2 positivity. The high cytoplasmic expression of LCN2 was correlated with lymph node positivity. The nuclear downregulation of LCN2 was correlated with the overexpression of EMT associated proteins (N-cadherin and Twist-related protein 2) and basal biomarkers (cytokeratin 5/6 and epidermal growth factor receptor). Unlike the cytoplasmic expression of LCN2, the loss of nuclear expression was a significant predictor of poor outcome. The combinatorial expression tumours with high cytoplasmic and low nuclear expression were associated with the worst prognosis. CONCLUSIONS Tumour cell expression of LCN2 plays a role in breast cancer progression with loss of its nuclear expression which is associated with aggressive features and poor outcome. Further functional analysis is warranted to confirm the relationship between the subcellular localisation LCN2 and behaviour of breast cancer.
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Affiliation(s)
- Sasagu Kurozumi
- Division of Cancer and Stem Cells, School of Medicine, Nottingham Breast Cancer Research Centre, University of Nottingham, Nottingham, UK
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Sami Alsaeed
- Division of Cancer and Stem Cells, School of Medicine, Nottingham Breast Cancer Research Centre, University of Nottingham, Nottingham, UK
| | - Nnamdi Orah
- Division of Cancer and Stem Cells, School of Medicine, Nottingham Breast Cancer Research Centre, University of Nottingham, Nottingham, UK
| | - Islam M Miligy
- Division of Cancer and Stem Cells, School of Medicine, Nottingham Breast Cancer Research Centre, University of Nottingham, Nottingham, UK
| | - Chitra Joseph
- Division of Cancer and Stem Cells, School of Medicine, Nottingham Breast Cancer Research Centre, University of Nottingham, Nottingham, UK
| | - Abrar Aljohani
- Division of Cancer and Stem Cells, School of Medicine, Nottingham Breast Cancer Research Centre, University of Nottingham, Nottingham, UK
| | - Michael S Toss
- Division of Cancer and Stem Cells, School of Medicine, Nottingham Breast Cancer Research Centre, University of Nottingham, Nottingham, UK
| | - Takaaki Fujii
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Ken Shirabe
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Andrew R Green
- Division of Cancer and Stem Cells, School of Medicine, Nottingham Breast Cancer Research Centre, University of Nottingham, Nottingham, UK
| | - Mohammed A Aleskandarany
- Division of Cancer and Stem Cells, School of Medicine, Nottingham Breast Cancer Research Centre, University of Nottingham, Nottingham, UK
| | - Emad A Rakha
- Division of Cancer and Stem Cells, School of Medicine, Nottingham Breast Cancer Research Centre, University of Nottingham, Nottingham, UK.
- Department of Histopathology, Division of Cancer and Stem Cells, School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, NG5 1PB, UK.
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El-Kady DS, Ali NA, Sayed AH, Abdelhaliem MM, Elmegeed GA, Ahmed HH. Assessment of the Antitumor Potentiality of Newly Designed Steroid Derivatives: Pre-Clinical Study. Asian Pac J Cancer Prev 2019; 20:3057-3070. [PMID: 31653155 PMCID: PMC6982653 DOI: 10.31557/apjcp.2019.20.10.3057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Indexed: 12/03/2022] Open
Abstract
Cancer is recognized as one of the most prevalent contributors to mortality in several nations and it remains one of the common health issues globally. In particular, hepatocellular carcinoma (HCC) has become a public health problem along with the increase of hepatitis B (HBV) and hepatitis C (HCV) virus infections. Based on this fact, our study goaled to synthesize newly hybrid drugs containing heterocyclic rings incorporated to steroid moiety and to examine the potential antitumor activity of the newly designed heterosteroid derivatives against HCC induced in animal model. Several heterocyclic steroids were synthesized 2-7 and confirmed via the analytical and spectral data (IR, 1H NMR13C NMR and Mass spectroscopy). Compounds 3, 4, and 5 were chosen to be investigated as anticancer agents in HCC rat model by means of validated biomarkers (alfa –fetoprotein, endoglin, lipocali-2 and heat shock protein-70). Following administration of compounds 3, 4 or 5, availability of the active tumor marker molecules was significantly dropped and a substantial decrease of the angiogenic and inflammatory mediators was also evident. These findings were supported by the histological examination of liver tissue. Taken together, this study indicates the potential anticancer activity of the newly synthesized heterosteroid derivatives against HCC in vivo. The antitumor activity of these compounds was likely attributable to modulating some signal transduction pathways involved in tumorigenesis, angiogenesis and inflammation.
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Affiliation(s)
- Dina S El-Kady
- Department of Hormones, Medical Research Division, National Research Centre, Dokki, Giza, Egypt
| | - Naglaa A Ali
- Department of Hormones, Medical Research Division, National Research Centre, Dokki, Giza, Egypt
| | - Alaa H Sayed
- Department of Hormones, Medical Research Division, National Research Centre, Dokki, Giza, Egypt.,Department of Applied Medical Sciences, Community College in Al-Qurayyat, Al-Jouf University, KSA
| | - Mervat M Abdelhaliem
- Department of Hormones, Medical Research Division, National Research Centre, Dokki, Giza, Egypt
| | - Gamal A Elmegeed
- Department of Hormones, Medical Research Division, National Research Centre, Dokki, Giza, Egypt
| | - Hanaa H Ahmed
- Department of Hormones, Medical Research Division, National Research Centre, Dokki, Giza, Egypt
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Intergrated analysis of ELMO1, serves as a link between tumour mutation burden and epithelial-mesenchymal transition in hepatocellular carcinoma. EBioMedicine 2019; 46:105-118. [PMID: 31324602 PMCID: PMC6710851 DOI: 10.1016/j.ebiom.2019.07.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Revised: 06/23/2019] [Accepted: 07/01/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Epithelial-mesenchymal transition (EMT) is critical for cancer cell metastasis. Recently, EMT was reported to be associated with the inflammatory tumour microenvironment and, therefore, might be a predictive biomarker for immune checkpoint blockade agents. However, the underlying mechanism is still unclear. METHODS Patient survival data for our HCC cohort, TCGA and GEO datasets were determined by Kaplan-Meier analysis. The functional roles of ELMO1 in HCC were demonstrated by a series of in vitro and in vivo experiments. Gene microarray analysis was used to demonstrate potential mechanisms of ELMO1. Data retrieved from the TCGA datasets were used to determine the relationships of ELMO1, EMT and TMB. FINDINGS Here, we report an indispensable role for ELMO1 in linking EMT with tumour mutation burden (TMB), which is a promising biomarker for the immune checkpoint blockade agent response. Upregulated ELMO1 expression is associated with a poor prognosis in hepatocellular carcinoma (HCC), as well as increased cell growth, invasion, migration, angiogenesis and EMT in vitro and in vivo. Mechanistically, we provide evidence that ELMO1 regulates SOX10 expression and induces EMT through PI3K/Akt signalling. Moreover, ELMO1 is negatively associated with TMB, indicating a negative relationship between EMT and TMB. INTERPRETATION ELMO1 serves as a link between EMT and TMB, providing a mechanistic basis for the further development of ELMO1 as a therapeutic target against HCC and potentially a promising biomarker of the immune checkpoint blockade agent response. FUND: National Natural Science Foundation of China; Natural Science Foundation of Guangdong Province; Young Teacher Training Program of Sun Yat-sen University; Science and Technology Plan of Guangdong Province; Special Support Program of Guangdong Province, Science and Technology Innovation Youth Talent Support Program; the Pearl River Science and Technology New Talent of Guangzhou City; Medical Scientific Research Foundation of Guangdong Province.
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Xia Q, Li Z, Zheng J, Zhang X, Di Y, Ding J, Yu D, Yan L, Shen L, Yan D, Jia N, Chen W, Feng Y, Wang J. Identification of novel biomarkers for hepatocellular carcinoma using transcriptome analysis. J Cell Physiol 2019; 234:4851-4863. [PMID: 30272824 DOI: 10.1002/jcp.27283] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 07/26/2018] [Indexed: 01/01/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer in the world. To comprehensively investigate the utility of microRNAs (miRNAs) and protein-encoding transcripts (messenger RNAs [mRNAs]) in HCC as potential biomarkers for early detection and diagnosis, we exhaustively mined genomic data from three available omics datasets (GEO, Oncomine, and TCGA), analyzed the overlaps among gene expression studies from 920 hepatocellular carcinoma samples and 508 healthy (or adjacent normal) liver tissue samples available from six laboratories, and identified 178 differentially expressed genes (DEGs) associated with HCC. Paired with miRNA and lncRNA data, we identified 23 core genes that were targeted by nine differentially expressed miRNAs and 21 HCC-specific lncRNAs. We further demonstrated that alterations in these 23 genes were quite frequent, with five genes altered in over 5% of the population. Patients with high levels of YWHAZ, ENAH, and HMGN4 tended to have high-grade tumors and shorter overall survival, suggesting that these genes could be promising candidate biomarkers for disease and poor prognosis in patients with HCC. Our comprehensive mRNA, miRNA, and lncRNA omics analyses from multiple independent datasets identified robust molecules that may be used as biomarkers for early HCC detection and diagnosis.
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Affiliation(s)
- Qianlin Xia
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai, China
| | - Zehuan Li
- Department of General Surgery, Zhong Shan Hospital, Fudan University, Shanghai, China
| | - Jianghua Zheng
- Department of Laboratory Medicine, Zhoupu Hospital Affiliated to Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Xu Zhang
- National Center for Liver Cancer, Shanghai, China
| | - Yang Di
- Department of Pancreatic Surgery, Pancreatic Disease Institute, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jin Ding
- Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Die Yu
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai, China
| | - Li Yan
- Department of Severe Hepatology, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai, China
| | - Longqiang Shen
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai, China
| | - Dong Yan
- Department of Medical Oncology, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China
| | - Ning Jia
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai, China
- Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui, China
| | - Weiping Chen
- Microarray Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, USA
| | - Yanling Feng
- Department of Pathology, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai, China
| | - Jin Wang
- Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Jinshan District, Shanghai, China
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Perilipin 5 and Lipocalin 2 Expression in Hepatocellular Carcinoma. Cancers (Basel) 2019; 11:cancers11030385. [PMID: 30893876 PMCID: PMC6468921 DOI: 10.3390/cancers11030385] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 03/13/2019] [Accepted: 03/15/2019] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent and deadly cancers worldwide. Therefore, current global research focuses on molecular tools for early diagnosis of HCC, which can lead to effective treatment at an early stage. Perilipin 5 (PLIN5) has been studied as one of the main proteins of the perilipin family, whose role is to maintain lipid homeostasis by inhibiting lipolysis. In this study, we show for the first time that PLIN5 is strongly expressed in tumors of human patients with HCC as well as in mouse livers, in which HCC was genetically or experimentally induced by treatment with the genotoxic agent diethylnitrosamine. Moreover, the secreted acute phase glycoprotein Lipocalin 2 (LCN2) established as a biomarker of acute kidney injury, is also proven to indicate liver injury with upregulated expression in numerous cases of hepatic damage, including steatohepatitis. LCN2 has been studied in various cancers, and it has been assigned roles in multiple cellular processes such as the suppression of the invasion of HCC cells and their metastatic abilities. The presence of this protein in blood and urine, in combination with the presence of α-Fetoprotein (AFP), is hypothesized to serve as a biomarker of early stages of HCC. In the current study, we show in humans and mice that LCN2 is secreted into the serum from liver cancer tissue. We also show that AFP-positive hepatocytes represent the main source for the massive expression of LCN2 in tumoral tissue. Thus, the strong presence of PLIN5 and LCN2 in HCC and understanding their roles could establish them as markers for diagnosis or as treatment targets against HCC.
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Zhuang R, Zhang X, Lu D, Wang J, Zhuo J, Wei X, Ling Q, Xie H, Zheng S, Xu X. lncRNA DRHC inhibits proliferation and invasion in hepatocellular carcinoma via c-Myb-regulated MEK/ERK signaling. Mol Carcinog 2019; 58:366-375. [PMID: 30362626 DOI: 10.1002/mc.22934] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Revised: 09/27/2018] [Accepted: 10/23/2018] [Indexed: 12/26/2022]
Abstract
Accumulating evidence indicates that long non-coding RNAs (lncRNAs) play a crucial role in hepatocellular carcinoma (HCC). Here, we reported a novel lncRNA, CTC-505O3 (lncRNA DRHC), that was downregulated in HCC and its low expression was associated with dismal survival. Gain-of-function studies indicated that it inhibited proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in HCC cell lines in vitro. lncRNA DRHC also inhibited tumorigenicity in vivo. In mechanistic experiments, GO analysis based on NGS indicated that MAPK signaling was most affected. The result was confirmed by Western blot and this effect was abolished either by MEK1/2 specific inhibitor Trametinib or ERK1/2 inhibitor SCH772984. In addition, differences in proliferation and invasion were abrogated by Trametinib. Moreover, we found that lncRNA DRHC interacted with MYBBP1A and modulated MEK/ERK signaling via c-Myb. Taken together, our findings indicate that the lncRNA DRHC play a key role in HCC progression and may serve as a novel therapeutic target.
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MESH Headings
- Animals
- Apoptosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Proliferation
- DNA-Binding Proteins
- Epithelial-Mesenchymal Transition
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- MAP Kinase Kinase 1/genetics
- MAP Kinase Kinase 1/metabolism
- MAP Kinase Kinase 2/genetics
- MAP Kinase Kinase 2/metabolism
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Middle Aged
- Mitogen-Activated Protein Kinase 1/genetics
- Mitogen-Activated Protein Kinase 1/metabolism
- Mitogen-Activated Protein Kinase 3/genetics
- Mitogen-Activated Protein Kinase 3/metabolism
- Neoplasm Invasiveness
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism
- Nucleocytoplasmic Transport Proteins/genetics
- Nucleocytoplasmic Transport Proteins/metabolism
- Prognosis
- Proto-Oncogene Proteins c-myb/genetics
- Proto-Oncogene Proteins c-myb/metabolism
- RNA, Long Noncoding/genetics
- RNA-Binding Proteins
- Signal Transduction
- Survival Rate
- Transcription Factors
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Runzhou Zhuang
- Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHFPC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, China
| | - Xuanyu Zhang
- Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHFPC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, China
| | - Di Lu
- Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHFPC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, China
| | - Jianguo Wang
- Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHFPC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, China
| | - Jianyong Zhuo
- Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHFPC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, China
| | - Xuyong Wei
- Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHFPC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, China
| | - Qi Ling
- Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHFPC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, China
| | - Haiyang Xie
- Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHFPC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, China
| | - Shusen Zheng
- Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHFPC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, China
| | - Xiao Xu
- Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- NHFPC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, China
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Li HM. Liver regeneration microenvironment in liver cancer: Research progress and prospect. Shijie Huaren Xiaohua Zazhi 2018; 26:1529-1536. [DOI: 10.11569/wcjd.v26.i26.1529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The proposal of the new concept of liver regeneration microenvironment in liver cancer (LC) contributes to the overall understanding of how LC microenvironment influences the occurrence and development of LC through liver regeneration microenvironment, inflammatory microenvironment, immune microenvironment, and angiogenesis microenvironment, and helps explore more comprehensive and effective preventive and therapeutic measures for LC to improve the capability of LC prevention and cure. On the basis of eliminating hepatocellular carcinoma cells or tissues, the maintenance of normal liver regeneration and improvement of liver regeneration microenvironment in LC is an important strategy for LC prevention and treatment. Improving liver regeneration microenvironment to prevent or reverse the occurrence, development, and metastasis of LC should be an important research direction of LC prevention and treatment research. In recent years, traditional Chinese medicine research and application have made some progress in improving liver regeneration microenvironment to prevent or reverse the occurrence, development, recurrence, and metastasis of LC. However, it remains to be solved on how to accurately reveal the comprehensive network mechanism and how to provide advanced evidence-based medical evidence, which needs further extensive research.
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Affiliation(s)
- Han-Min Li
- Institute of Liver Diseases and Institute of Traditional Chinese Medicine Basic Theory, Hubei Provincial Hospital of Traditional Chinese Medicine (Affiliated Hospital of Hubei University of Chinese Medicine, Hubei Province Academy of Traditional Chinese Medicine), Wuhan 430061, Hubei Province, China
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Molina L, Bell D, Tao J, Preziosi M, Pradhan-Sundd T, Singh S, Poddar M, Luo J, Ranganathan S, Chikina M, Monga SP. Hepatocyte-Derived Lipocalin 2 Is a Potential Serum Biomarker Reflecting Tumor Burden in Hepatoblastoma. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:1895-1909. [PMID: 29920228 DOI: 10.1016/j.ajpath.2018.05.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Revised: 05/01/2018] [Accepted: 05/03/2018] [Indexed: 12/24/2022]
Abstract
Hepatoblastoma (HB) is the most common pediatric liver malignant tumor. Previously, we reported co-activation of β-catenin and Yes-associated protein-1 (YAP1) in 80% of HB. Hepatic co-expression of active β-catenin and YAP1 via sleeping beauty transposon/transposase and hydrodynamic tail vein injection led to HB development in mice. Here, we identify lipocalin 2 (Lcn2) as a target of β-catenin and YAP1 in HB and show that serum Lcn2 values positively correlated with tumor burden. Lcn2 was strongly expressed in HB tumor cells in our mouse model. A tissue array of 62 HB cases showed highest LCN2 expression in embryonal and lowest in fetal, blastemal, and small cell undifferentiated forms of HB. Knockdown of LCN2 in HB cells had no effect on cell proliferation but reduced NF-κB reporter activity. Next, liver-specific Lcn2 knockout (KO) mice were generated. No difference in tumor burden was observed between Lcn2 KO mice and wild-type littermate controls after sleeping beauty transposon/transposase and hydrodynamic tail vein injection delivery of active YAP1 and β-catenin, although Lcn2 KO mice with HB lacked any serum Lcn2 elevation, demonstrating that transformed hepatocytes are the source of serum Lcn2. More blastemal areas and inflammation were observed within HB in Lcn2 KO compared with wild-type tumors. In conclusion, Lcn2 expressed in hepatocytes appears to be dispensable for the pathogenesis of HB. However, transformed hepatocytes secrete serum Lcn2, making Lcn2 a valuable biomarker for HB.
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Affiliation(s)
- Laura Molina
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Danielle Bell
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Division of Hematology-Oncology, Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | - Junyan Tao
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Morgan Preziosi
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Tirthadipa Pradhan-Sundd
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Sucha Singh
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Minakshi Poddar
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Jianhua Luo
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Sarangarajan Ranganathan
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Division of Pediatric Pathology, Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | - Maria Chikina
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Satdarshan P Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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Zhang T, Liu W, Meng W, Zhao H, Yang Q, Gu SJ, Xiao CC, Jia CC, Fu BS. Downregulation of miR-542-3p promotes cancer metastasis through activating TGF-β/Smad signaling in hepatocellular carcinoma. Onco Targets Ther 2018; 11:1929-1939. [PMID: 29670368 PMCID: PMC5896681 DOI: 10.2147/ott.s154416] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) accounts for more than 90% of primary liver cancer. Although great progress has been made on HCC molecular mechanism and therapy techniques, the prognosis of HCC patient is poor due to high metastasis and recurrence. Materials and methods Expression of miR-542-3p was quantified by quantitative real-time PCR (qRT-PCR). The role of miR-542-3p in HCC metastasis was examined using transwell and 3D-culture assay. qRT-PCR, Western blotting and luciferase reporter assay were used to elucidate the mechanisms of miR-542-3p-mediated cancer metastasis. Results and Conclusion In the research, we found that miR-542-3p is decreased in HCC cell lines and tissues, and downregulation of miR-542-3p enhances, while upregulation suppresses HCC cell invasion ability. Further assay demonstrated that miR-542-3p can directly target TGF-β1 3′ untranslated region (3′UTR) to influence TGF-β/Smad signaling pathway, and suppression of miR-542-3p can hyperactivate TGF-β/Smad pathway and further to promote Epithelial-Mesenchyme Transition (EMT) and induce poor prognosis. Lastly, the clinical correlation analysis illustrated that miR-542-3p is negatively related with the activity of TGF-β1. In summary, our results find that miR-542-3p takes an important role on HCC progression and provide more evidence of microRNAs (miRNAs) for cancer therapy.
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Affiliation(s)
- Tong Zhang
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Institute of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, People's Republic of China
| | - Wei Liu
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Wei Meng
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Institute of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, People's Republic of China
| | - Hui Zhao
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Institute of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, People's Republic of China
| | - Qing Yang
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Institute of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, People's Republic of China
| | - Shi-Jie Gu
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Institute of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, People's Republic of China
| | - Cui-Cui Xiao
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Chang-Chang Jia
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Bin-Sheng Fu
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Institute of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, People's Republic of China
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Wang JL, Yang MY, Xiao S, Sun B, Li YM, Yang LY. Downregulation of castor zinc finger 1 predicts poor prognosis and facilitates hepatocellular carcinoma progression via MAPK/ERK signaling. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:45. [PMID: 29506567 PMCID: PMC5836448 DOI: 10.1186/s13046-018-0720-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/16/2017] [Accepted: 02/22/2018] [Indexed: 12/15/2022]
Abstract
Background Castor zinc finger 1 (CASZ1) plays critical roles in various biological processes and pathologic conditions, including cancer. However, the prognostic importance and biologic functions of CASZ1 in hepatocellular carcinoma (HCC) are still unclear. Methods qRT-PCR, western blot and immunohistochemistry analyses were used to determine CASZ1 expression in HCC samples and cell lines. The clinical significance of CASZ1 was assessed in two independent study cohorts containing 232 patients with HCC. A series of in vitro and in vivo experiments were performed to explore the role and molecular mechanism of CASZ1 in HCC progression. Results Here we report that CASZ1 expression was downregulated in HCC tissues and cell lines. Low CASZ1 expression was closely correlated with aggressive clinicopathological features, poor clinical outcomes and early recurrence of HCC patients. Moreover, overexpression of CASZ1 in HCCLM3 cells significantly inhibited cell proliferation, migration, invasion in vitro and tumor growth and metastasis in vivo, whereas silencing CASZ1 significantly enhanced the above abilities of PLC/PRF/5 cells. Further mechanism study indicated that these phenotypic changes were mediated by MAPK/ERK signaling pathway and involved altered expression of MMP2, MMP9 and cyclinD1. Finally, we proved that CASZ1 exerted its tumor-suppressive effect by directly interacting with RAF1 and reducing the protein stability of RAF1. Conclusions Our study for the first time demonstrated that CASZ1 is a tumor suppressor in HCC, which may serve as a novel prognostic predictor and therapeutic target for HCC patients. Electronic supplementary material The online version of this article (10.1186/s13046-018-0720-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ji-Long Wang
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, Hunan, 410008, China
| | - Meng-Yuan Yang
- Department of Obstetrics and Gynecology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Shuai Xiao
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, Hunan, 410008, China.,Department of Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Bo Sun
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, Hunan, 410008, China
| | - Yi-Ming Li
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, Hunan, 410008, China
| | - Lian-Yue Yang
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, Hunan, 410008, China. .,Department of Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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45
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Li T, Yu L, Wen J, Liao Q, Liu Z. An early-screening biomarker of endometrial carcinoma: NGAL is associated with epithelio-mesenchymal transition. Oncotarget 2018; 7:86064-86074. [PMID: 27863382 PMCID: PMC5349897 DOI: 10.18632/oncotarget.13340] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 11/07/2016] [Indexed: 12/11/2022] Open
Abstract
neutrophilgelatinase-associated lipocalin is currently one of the most interesting and enigmatic proteins involved in the development of malignancies. In this study, we found that the expression of neutrophilgelatinase-associated lipocalin was up-regulated in endometrial cancer tissues and cell lines, significantly increased in early-grade ones, suggesting it may serve as a biomarker for early-stage screening for endometrial carcinoma. Moreover, neutrophilgelatinase-associated lipocalin was up-regulated in Ishikawa cells under going epithelio-mesenchymal transition induced by epidermal growth factor (5 ng/ml). Up-regulation of neutrophilgelatinase-associated lipocalin may correlate with the down-regulation of E-cadherin expression, up-regulation of Vimentin expression, enhanced cell migration, invasion and proliferation, which are the typical hallmarks of epithelio-mesenchymal transition processes. neutrophilgelatinase-associated lipocalin may play a dual role during tumorigenetic and developmental processes of endometrial carcinoma. These results suggested neutrophilgelatinase-associated lipocalin to be a potential molecular target in the early diagnosis and treatment of endometrial carcinoma. Further studies are warranted to clarify the molecular mechanisms behind the expression and function of neutrophilgelatinase-associated lipocalin and epithelio-mesenchymal transition.
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Affiliation(s)
- Ting Li
- Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China
| | - Li Yu
- Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China
| | - Jia Wen
- Department of Obstetrics and Gynecology, Tsinghua Changgung Hospital, Beijing, China
| | - Qinping Liao
- Department of Obstetrics and Gynecology, Tsinghua Changgung Hospital, Beijing, China
| | - Zhaohui Liu
- Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China
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Abstract
Fibrosis of the liver is an inherent wound healing response to chronic liver injury. Regeneration of liver epithelium and restoration of normal liver structure were generally involved in this process. Although the liver has a striking capacity to adapt to damage through tissue repair, excessive accumulation of extracellular matrix during this process often leads to scar tissue formation and subsequent fibrosis. Epithelial to mesenchymal transition (EMT) enables a polarized epithelial cell to undergo multiple changes biochemically and to bear a mesenchymal cell phenotype. EMT plays a critical role in tissue and organ development and embryogenesis. In the liver, it is proposed that epithelial cells can acquire fibroblastic phonotype via EMT and contribute to fibrogenesis. This made EMT a potential target for antifibrotic strategies. Following an original passion, many investigators devote themselves to exploring this mechanism in liver fibrosis. However, as research continues, this hypothesis became highly controversial. The exact contribution of EMT to fibrogenesis was challenged due to the contradictory results from related studies. In this review, we summarized the recent advances regarding EMT in hepatic fibrosis and discussed the potentially involved liver cell types and pathways in order to reach rational and helpful conclusions.
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Affiliation(s)
- Kangkang Yu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Qian Li
- Department of General Surgery, Qingdao Municipal Hospital, Qingdao, People's Republic of China
| | - Guangfeng Shi
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Ning Li
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People's Republic of China,Address for correspondence: Dr. Ning Li, Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai – 200040, People's Republic of China. E-mail:
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47
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Sun X, Wang SC, Wei Y, Luo X, Jia Y, Li L, Gopal P, Zhu M, Nassour I, Chuang JC, Maples T, Celen C, Nguyen LH, Wu L, Fu S, Li W, Hui L, Tian F, Ji Y, Zhang S, Sorouri M, Hwang TH, Letzig L, James L, Wang Z, Yopp AC, Singal AG, Zhu H. Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer. Cancer Cell 2017; 32:574-589.e6. [PMID: 29136504 PMCID: PMC5728182 DOI: 10.1016/j.ccell.2017.10.007] [Citation(s) in RCA: 166] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 08/10/2017] [Accepted: 10/11/2017] [Indexed: 12/11/2022]
Abstract
ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be tumor suppressive. In some hepatocellular carcinoma patients, ARID1A was highly expressed in primary tumors but not in metastatic lesions, suggesting that ARID1A can be lost after initiation. Mice with liver-specific homozygous or heterozygous Arid1a loss were resistant to tumor initiation while ARID1A overexpression accelerated initiation. In contrast, homozygous or heterozygous Arid1a loss in established tumors accelerated progression and metastasis. Mechanistically, gain of Arid1a function promoted initiation by increasing CYP450-mediated oxidative stress, while loss of Arid1a within tumors decreased chromatin accessibility and reduced transcription of genes associated with migration, invasion, and metastasis. In summary, ARID1A has context-dependent tumor-suppressive and oncogenic roles in cancer.
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MESH Headings
- Animals
- Blotting, Western
- Carcinogenesis/genetics
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Line, Tumor
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/metabolism
- Gene Expression Profiling/methods
- Gene Expression Regulation, Neoplastic
- Genes, Tumor Suppressor
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Mice, 129 Strain
- Mice, Inbred C57BL
- Mice, Inbred NOD
- Mice, Knockout
- Mice, SCID
- Neoplasm Metastasis
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism
- Oncogenes/genetics
- RNA Interference
- Transcription Factors
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Affiliation(s)
- Xuxu Sun
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Sam C Wang
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yonglong Wei
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Xin Luo
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yuemeng Jia
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Lin Li
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Purva Gopal
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Min Zhu
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Ibrahim Nassour
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jen-Chieh Chuang
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Thomas Maples
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Cemre Celen
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Liem H Nguyen
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Linwei Wu
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Organ Transplant Center, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Shunjun Fu
- Organ Transplant Center, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Weiping Li
- State Key Laboratory of Cell Biology, Innovation Center for Cell Signaling Network, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Lijian Hui
- State Key Laboratory of Cell Biology, Innovation Center for Cell Signaling Network, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Feng Tian
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Shuyuan Zhang
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Mahsa Sorouri
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Tae Hyun Hwang
- Lerner Research Institute, Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Lynda Letzig
- Clinical Pharmacology and Toxicology, Arkansas Children's Hospital and Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
| | - Laura James
- Clinical Pharmacology and Toxicology, Arkansas Children's Hospital and Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
| | - Zixi Wang
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Adam C Yopp
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Hao Zhu
- Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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Kim SL, Lee ST, Min IS, Park YR, Lee JH, Kim DG, Kim SW. Lipocalin 2 negatively regulates cell proliferation and epithelial to mesenchymal transition through changing metabolic gene expression in colorectal cancer. Cancer Sci 2017; 108:2176-2186. [PMID: 28859238 PMCID: PMC5666039 DOI: 10.1111/cas.13389] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 08/20/2017] [Accepted: 08/25/2017] [Indexed: 12/17/2022] Open
Abstract
Lipocalin 2 (LCN2), a member of the lipocalin superfamily, plays an important role in oncogenesis and progression in various types of cancer. However, the expression pattern and functional role of LCN2 in colorectal cancer (CRC) is still poorly understood. The purpose of the present study was to investigate whether LCN2 is associated with proliferation and the epithelial-mesenchymal transition (EMT) in CRC and to elucidate the underlying signaling pathways. LCN2 was preferentially expressed in CRC cells compared to normal tissues. However, LCN2 expression was significantly lower in metastatic or advanced-stage CRC than in non-metastatic or early stage CRC. Knockdown of LCN2 using small interfering RNA (siRNA) in CRC cells expressing a high level of LCN2 induced cell proliferation and a morphological switch from an epithelial to mesenchymal state. Furthermore, downregulation of LCN2 in CRC cells increased cell migration and invasion involved in the regulation of EMT markers. Knockdown of LCN2 also induced glucose consumption and lactate production, accompanied by an increase in energy metabolism-related genes. Taken together, our findings indicated that LCN2 negatively modulated proliferation, EMT and energy metabolism in CRC cells. Accordingly, LCN2 may be a candidate metastasis suppressor and potential therapeutic target in CRC.
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Affiliation(s)
- Se-Lim Kim
- Department of Internal Medicine Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea.,Biomedical Research Institute, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Soo Teik Lee
- Department of Internal Medicine Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea.,Biomedical Research Institute, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - In Suk Min
- Department of Internal Medicine Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea.,Biomedical Research Institute, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Young Ran Park
- Department of Internal Medicine Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea.,Biomedical Research Institute, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Ju Hyung Lee
- Department of Preventive Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Dae-Ghon Kim
- Department of Internal Medicine Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea.,Biomedical Research Institute, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Sang-Wook Kim
- Department of Internal Medicine Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea.,Biomedical Research Institute, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
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49
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OIP5, a target of miR-15b-5p, regulates hepatocellular carcinoma growth and metastasis through the AKT/mTORC1 and β-catenin signaling pathways. Oncotarget 2017; 8:18129-18144. [PMID: 28184024 PMCID: PMC5392313 DOI: 10.18632/oncotarget.15185] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 01/16/2017] [Indexed: 12/12/2022] Open
Abstract
Opa interacting protein 5 (OIP5) is upregulated in some types of human cancers, but the biological implications of its upregulation have not yet been clarified in human hepatocellular carcinoma (HCC). In this study, the signaling pathway downstream of OIP5 was analyzed by proteome kinase profiling. A putative microRNA targeting OIP5 was identified using a miRNA PCR array. Tumorigenicity and metastatic ability were examined in an orthotopic animal model. OIP5 expression was strongly detected in early and advanced tumors via gene expression profiling and immunohistochemical staining analyses. Cells with knockdown of OIP5 via target shRNA exhibited reduced hepatic mass formation and metastatic tumor nodules in an orthotopic mouse model. OIP5-induced AKT activation was mediated by both mTORC2 and p38/PTEN activation. AKT activation was linked to mTORC1 and GSK-3β/β-catenin signaling, which are primarily associated with tumor cell growth and metastasis, respectively. miR-15b-5p, which targets OIP5, efficiently inhibited OIP5-mediated mTORC1 and GSK-3β/β-catenin signaling. These findings suggest that OIP5 may be involved in HCC growth and metastasis and that miR-15b-5p inhibits OIP5-mediated oncogenic signaling in HCC.
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50
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Yeh HW, Lee SS, Chang CY, Hu CM, Jou YS. Pyrimidine metabolic rate limiting enzymes in poorly-differentiated hepatocellular carcinoma are signature genes of cancer stemness and associated with poor prognosis. Oncotarget 2017; 8:77734-77751. [PMID: 29100421 PMCID: PMC5652811 DOI: 10.18632/oncotarget.20774] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 07/29/2017] [Indexed: 12/18/2022] Open
Abstract
Cellular metabolism of cancer cell is generally recognized to provide energy for facilitating tumor growth, but little is known about the aberrant metabolism in tumor progression and its prognostic value. Here, we applied integrated genomic approach to uncover the aberrant expression of metabolic enzymes in poorly-differentiated human hepatocellular carcinoma (HCC) for revealing targets against HCC malignancy. A total of 135 upregulated (22 are rate-limiting enzymes (RLEs)) and 362 down-regulated (77 are RLEs) metabolic genes were identified and associated with poor patient survival in large-cohorts of HCC patients in TCGA-LIHC and two other independent transcriptomic studies. Ten out of 22 upregulated RLEs in poorly-differentiated HCC are critical enzymes in pyrimidine metabolism pathways in association with stemness features by gene enrichment analysis and upregulated in ALDH1+ stem-like HCC subpopulations. By focusing on three RLEs including TK1, TYMS and DTYMK of dTTP biosynthesis pathway, expression of 3 RLEs in well-differentiated HCC cells increased ALDH1+ and spheroid stemness population but reversed by knockdown in poorly-differentiated HCC cells. Up-regulated 3 RLEs in HCC were associated with poor patient survival in multiple cohorts. Together, we identified aberrant pyrimidine pathway in poorly-differentiated HCC promotes cancer stemness served as potential theranostic target for battling HCC tumor progression.
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Affiliation(s)
- Hsi-Wen Yeh
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.,Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Szu-Shuo Lee
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.,Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan
| | - Chieh-Yu Chang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.,Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan
| | - Chun-Mei Hu
- Genomic Research Center, Academia Sinica, Taipei, Taiwan
| | - Yuh-Shan Jou
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.,Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.,Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan.,Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan
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