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1
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Kojima K, Sakurai K, Ando T, Sakai Y, Ochiai M, Kato T, Ito H. Immunohistochemical investigation of the transcription factor PROX1 emphasizing on neuroendocrine neoplasms. Med Mol Morphol 2025:10.1007/s00795-025-00437-z. [PMID: 40234276 DOI: 10.1007/s00795-025-00437-z] [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: 03/04/2025] [Accepted: 04/06/2025] [Indexed: 04/17/2025]
Abstract
Prospero homeobox protein 1 (PROX1) is aberrantly expressed in tumors, including neuroendocrine neoplasms (NENs); however, the detailed expression pattern remains elusive. This study aimed to immunohistochemically assess PROX1 expression. Immunohistochemistry (IHC) for PROX1 was performed on tissue microarrays of normal tissues (n = 107), NENs (n = 152) (small cell lung carcinoma [SCLC], lung carcinoid [LC], gastroenteropancreatic-NEN [GEP-NEN], esophageal neuroendocrine carcinoma [ENEC], medullary thyroid carcinoma [MTC], neuroblastoma [NB], and pheochromocytoma [PHEO]), and non-NENs (n = 469). In normal tissues, PROX1 was expressed in lymphatic endothelial cells and a subset of epithelial cells in the gastrointestinal tract and the distal convoluted tubules. In NENs, the positive expression was observed in the nucleus of tumor cells in 19/26 SCLC (73.1%), 13/16 LC (81.3%), 10/15 GEP-NEN (66.7%), 2/2 ENEC (100%), 17/43 MTC (39.5%), 1/25 NB (4.0%), and 0/25 PHEO (0%). Although PROX1 was negative in many non-NENs, our analysis revealed high expression in certain cases with medulloblastoma and one case with juvenile granulosa cell tumor. PROX1 was expressed in specific cases with epithelial NENs and some cases with non-NENs. Analysis of PROX1 should provide insights into the molecular characteristics of distinct tumors.
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Affiliation(s)
- Kanata Kojima
- Department of Clinical Laboratory, Fujita Health University Hospital, Toyoake, Aichi, 470-1192, Japan
- Department of Joint Research Laboratory of Clinical Medicine, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Kouhei Sakurai
- Department of Joint Research Laboratory of Clinical Medicine, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.
| | - Tatsuya Ando
- Department of Joint Research Laboratory of Clinical Medicine, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Yasuhiro Sakai
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Mako Ochiai
- Department of Clinical Laboratory, Fujita Health University Hospital, Toyoake, Aichi, 470-1192, Japan
- Department of Joint Research Laboratory of Clinical Medicine, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Taku Kato
- Department of Joint Research Laboratory of Clinical Medicine, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
| | - Hiroyasu Ito
- Department of Clinical Laboratory, Fujita Health University Hospital, Toyoake, Aichi, 470-1192, Japan
- Department of Joint Research Laboratory of Clinical Medicine, School of Medicine, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
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2
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Lim B, Kamal A, Gomez Ramos B, Adrian Segarra JM, Ibarra IL, Dignas L, Kindinger T, Volz K, Rahbari M, Rahbari N, Poisel E, Kafetzopoulou K, Böse L, Breinig M, Heide D, Gallage S, Barragan Avila JE, Wiethoff H, Berest I, Schnabellehner S, Schneider M, Becker J, Helm D, Grimm D, Mäkinen T, Tschaharganeh DF, Heikenwalder M, Zaugg JB, Mall M. Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis. Nat Genet 2025; 57:668-679. [PMID: 39948437 PMCID: PMC11906372 DOI: 10.1038/s41588-025-02081-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: 10/08/2023] [Accepted: 01/08/2025] [Indexed: 02/20/2025]
Abstract
Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. While transcription master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether plasticity is actively suppressed by lineage-specific repressors. Here we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternative fate master regulators. In mice, Prox1 was required for efficient hepatocyte regeneration after injury and was sufficient to prevent liver tumorigenesis. In line with patient data, Prox1 depletion caused hepatocyte fate loss in vivo and enabled the transition of hepatocellular carcinoma to cholangiocarcinoma. Conversely, overexpression promoted cholangiocarcinoma to hepatocellular carcinoma transdifferentiation. Our findings provide evidence for PROX1 as a hepatocyte-specific safeguard and support a model where cell-type-specific repressors actively suppress plasticity throughout life to safeguard lineage identity and thus prevent disease.
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Affiliation(s)
- Bryce Lim
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Aryan Kamal
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
- European Molecular Biology Laboratory, Molecular Systems Biology Unit, Heidelberg, Germany
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Borja Gomez Ramos
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Juan M Adrian Segarra
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Ignacio L Ibarra
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
- European Molecular Biology Laboratory, Molecular Systems Biology Unit, Heidelberg, Germany
| | - Lennart Dignas
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Tim Kindinger
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Kai Volz
- Cell Plasticity and Epigenetic Remodeling Helmholtz Group, DKFZ, Heidelberg, Germany
- Institute of Pathology, University Hospital, Heidelberg, Germany
| | - Mohammad Rahbari
- Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany
- Department of Surgery, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Nuh Rahbari
- Department of Surgery, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Department of General and Visceral Surgery, University of Ulm, Ulm, Germany
| | - Eric Poisel
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Kanela Kafetzopoulou
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Lio Böse
- Cell Plasticity and Epigenetic Remodeling Helmholtz Group, DKFZ, Heidelberg, Germany
- Institute of Pathology, University Hospital, Heidelberg, Germany
| | - Marco Breinig
- Cell Plasticity and Epigenetic Remodeling Helmholtz Group, DKFZ, Heidelberg, Germany
- Institute of Pathology, University Hospital, Heidelberg, Germany
| | - Danijela Heide
- Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany
| | - Suchira Gallage
- Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany
- Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Faculty of Medicine, University Tuebingen, Tübingen, Germany
| | | | - Hendrik Wiethoff
- Institute of Pathology, University Hospital, Heidelberg, Germany
| | - Ivan Berest
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
- European Molecular Biology Laboratory, Molecular Systems Biology Unit, Heidelberg, Germany
| | - Sarah Schnabellehner
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | | | - Jonas Becker
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
- Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Medical Faculty and Faculty of Engineering Sciences, Heidelberg University, Center for Integrative Infectious Diseases Research (CIID), BioQuant, Heidelberg, Germany
| | - Dominic Helm
- Proteomics Core Facility, DKFZ, Heidelberg, Germany
| | - Dirk Grimm
- Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Medical Faculty and Faculty of Engineering Sciences, Heidelberg University, Center for Integrative Infectious Diseases Research (CIID), BioQuant, Heidelberg, Germany
- German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Heidelberg, Heidelberg, Germany
| | - Taija Mäkinen
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Translational Cancer Medicine Program and Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland
- Wihuri Research Institute, Helsinki, Finland
| | - Darjus F Tschaharganeh
- Cell Plasticity and Epigenetic Remodeling Helmholtz Group, DKFZ, Heidelberg, Germany
- Institute of Pathology, University Hospital, Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany
- Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Faculty of Medicine, University Tuebingen, Tübingen, Germany
| | - Judith B Zaugg
- European Molecular Biology Laboratory, Molecular Systems Biology Unit, Heidelberg, Germany.
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
| | - Moritz Mall
- Cell Fate Engineering and Disease Modeling Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany.
- HITBR Hector Institute for Translational Brain Research gGmbH, Heidelberg, Germany.
- Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
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Wang C, Ma X. The role of acetylation and deacetylation in cancer metabolism. Clin Transl Med 2025; 15:e70145. [PMID: 39778006 PMCID: PMC11706801 DOI: 10.1002/ctm2.70145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 12/02/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
As a hallmark of cancer, metabolic reprogramming adjusts macromolecular synthesis, energy metabolism and redox homeostasis processes to adapt to and promote the complex biological processes of abnormal growth and proliferation. The complexity of metabolic reprogramming lies in its precise regulation by multiple levels and factors, including the interplay of multiple signalling pathways, precise regulation of transcription factors and dynamic adjustments in metabolic enzyme activity. In this complex regulatory network, acetylation and deacetylation, which are important post-translational modifications, regulate key molecules and processes related to metabolic reprogramming by affecting protein function and stability. Dysregulation of acetylation and deacetylation may alter cancer cell metabolic patterns by affecting signalling pathways, transcription factors and metabolic enzyme activity related to metabolic reprogramming, increasing the susceptibility to rapid proliferation and survival. In this review, we focus on discussing how acetylation and deacetylation regulate cancer metabolism, thereby highlighting the central role of these post-translational modifications in metabolic reprogramming, and hoping to provide strong support for the development of novel cancer treatment strategies. KEY POINTS: Protein acetylation and deacetylation are key regulators of metabolic reprogramming in tumour cells. These modifications influence signalling pathways critical for tumour metabolism. They modulate the activity of transcription factors that drive gene expression changes. Metabolic enzymes are also affected, altering cellular metabolism to support tumour growth.
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Affiliation(s)
- Cuicui Wang
- Department of Obstetrics and GynecologyShengjing Hospital of China Medical UniversityShenyang CityLiaoning ProvinceChina
- Key Laboratory of Gynecological Oncology of Liaoning ProvinceDepartment of Obstetrics and GynecologyShengjing Hospital of China Medical UniversityShenyangLiaoning ProvinceChina
| | - Xiaoxin Ma
- Department of Obstetrics and GynecologyShengjing Hospital of China Medical UniversityShenyang CityLiaoning ProvinceChina
- Key Laboratory of Gynecological Oncology of Liaoning ProvinceDepartment of Obstetrics and GynecologyShengjing Hospital of China Medical UniversityShenyangLiaoning ProvinceChina
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4
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Liu C, Chen J, Cong Y, Chen K, Li H, He Q, Chen L, Song Y, Xing Y. PROX1 drives neuroendocrine plasticity and liver metastases in prostate cancer. Cancer Lett 2024; 597:217068. [PMID: 38901665 DOI: 10.1016/j.canlet.2024.217068] [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: 03/16/2024] [Revised: 06/11/2024] [Accepted: 06/12/2024] [Indexed: 06/22/2024]
Abstract
With the widespread use of anti-androgen therapy, such as abiraterone and enzalutamide, the incidence of neuroendocrine prostate cancer (NEPC) is increasing. NEPC is a lethal form of prostate cancer (PCa), with a median overall survival of less than one year after diagnosis. In addition to the common bone metastases seen in PCa, NEPC exhibits characteristics of visceral metastases, notably liver metastasis, which serves as an indicator of a poor prognosis clinically. Key factors driving the neuroendocrine plasticity of PCa have been identified, yet the underlying mechanism behind liver metastasis remains unclear. In this study, we identified PROX1 as a driver of neuroendocrine plasticity in PCa, responsible for promoting liver metastases. Mechanistically, anti-androgen therapy alleviates transcriptional inhibition of PROX1. Subsequently, elevated PROX1 levels drive both neuroendocrine plasticity and liver-specific transcriptional reprogramming, promoting liver metastases. Moreover, liver metastases in PCa induced by PROX1 depend on reprogrammed lipid metabolism, a disruption that effectively reduces the formation of liver metastases.
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Affiliation(s)
- Chunyu Liu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Jiawei Chen
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Yukun Cong
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Kang Chen
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Haoran Li
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Qingliu He
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Liang Chen
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
| | - Yarong Song
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
| | - Yifei Xing
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
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5
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Liu Y, Wang F, Yan G, Tong Y, Guo W, Li S, Qian Y, Li Q, Shu Y, Zhang L, Zhang Y, Xia Q. CPT1A loss disrupts BCAA metabolism to confer therapeutic vulnerability in TP53-mutated liver cancer. Cancer Lett 2024; 595:217006. [PMID: 38823763 DOI: 10.1016/j.canlet.2024.217006] [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: 03/21/2024] [Revised: 05/12/2024] [Accepted: 05/28/2024] [Indexed: 06/03/2024]
Abstract
Driver genomic mutations in tumors define specific molecular subtypes that display distinct malignancy competence, therapeutic resistance and clinical outcome. Although TP53 mutation has been identified as the most common mutation in hepatocellular carcinoma (HCC), current understanding on the biological traits and therapeutic strategies of this subtype has been largely unknown. Here, we reveal that fatty acid β oxidation (FAO) is remarkable repressed in TP53 mutant HCC and which links to poor prognosis in HCC patients. We further demonstrate that carnitine palmitoyltransferase 1 (CPT1A), the rate-limiting enzyme of FAO, is universally downregulated in liver tumor tissues, and which correlates with poor prognosis in HCC and promotes HCC progression in the de novo liver tumor and xenograft tumor models. Mechanically, hepatic Cpt1a loss disrupts lipid metabolism and acetyl-CoA production. Such reduction in acetyl-CoA reduced histone acetylation and epigenetically reprograms branched-chain amino acids (BCAA) catabolism, and leads to the accumulation of cellular BCAAs and hyperactivation of mTOR signaling. Importantly, we reveal that genetic ablation of CPT1A renders TP53 mutant liver cancer mTOR-addicted and sensitivity to mTOR inhibitor AZD-8055 treatment. Consistently, Cpt1a loss in HCC directs tumor cell therapeutic response to AZD-8055. CONCLUSION: Our results show genetic evidence for CPT1A as a metabolic tumor suppressor in HCC and provide a therapeutic approach for TP53 mutant HCC patients.
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Affiliation(s)
- Yanfeng Liu
- Department of Liver Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China; Shanghai Institute of Transplantation, Shanghai, China.
| | - Fan Wang
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guoquan Yan
- Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yu Tong
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenyun Guo
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Songling Li
- School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Yifei Qian
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qianyu Li
- Department of Liver Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Shu
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Zhang
- Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Yonglong Zhang
- Central Laboratory, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China.
| | - Qiang Xia
- Department of Liver Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China; Shanghai Institute of Transplantation, Shanghai, China.
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6
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Ghosal K, Pani A, Chowdhury T, Kundu A, Thomas S. Multi-vesicular Liposome and its Applications: A Novel Chemically Modified Approach for Drug Delivery Application. Mini Rev Med Chem 2024; 24:26-38. [PMID: 37312447 DOI: 10.2174/1389557523666230613162512] [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: 11/13/2022] [Revised: 01/16/2023] [Accepted: 02/08/2023] [Indexed: 06/15/2023]
Abstract
BACKGROUND This study aimed to elaborate on all the aspects of multivesicular liposomes, including structure, function, topology, etc. Liposomes are a unique drug delivery system, in which both hydrophilic and hydrophobic drug molecules can be incorporated. Particularly, multivesicular liposomes have more advantages than other liposomes because of their unique structure. This study provides an overview of several works already performed by various researchers in this field. Numerous studies have reported on preparing and evaluating multivesicular liposomes for drug delivery applications. This study summarizes the process of formulating multivesicular liposomes and their application in drug delivery systems and provides details about how to resolve the problem of limited solubility and stability of biomolecules, along with controlled drug release kinetics, with the possibility of loading various drugs. There is no doubt that multivesicular liposome opens new avenues to develop novel drug delivery system for achieving the desired functional performances and expanding the applications in the drug delivery area.
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Affiliation(s)
- Kajal Ghosal
- Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, India
| | - Ayan Pani
- Department of Pharmaceutics, Haldia Institute of Pharmacy, Hatiberia, Haldia, Purba Medinipur, West Bengal, 721657, India
| | - Totan Chowdhury
- Dr. B.C. Roy College of Pharmacy and AHS, Durgapur, 713206, India
| | - Abhijeet Kundu
- Dr. B.C. Roy College of Pharmacy and AHS, Durgapur, 713206, India
| | - Sabu Thomas
- Department of Chemical Science, International and Inter University Center for Nanoscience and Nanotechnology (IIUCNN), Mahatma Gandhi University, Priyadarshini Hill, Kottayam, 686560, Kerala, India
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7
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Zhang R, Luo D, Shan Z, Yang Y, Qin Y, Li Q, Li X. PROX1 restrains ferroptosis via SCD transcription activation in colorectal cancer. Acta Biochim Biophys Sin (Shanghai) 2023; 55:691-694. [PMID: 36815375 DOI: 10.3724/abbs.2023027] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023] Open
Affiliation(s)
- Ruoxin Zhang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Dakui Luo
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Zezhi Shan
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yufei Yang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yi Qin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Qingguo Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xinxiang Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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8
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Jeong M, Jung E, Oh S, Shin SY. Homeobox Protein PROX1 Expression is Negatively Regulated by Histone Deacetylase 1 and c-JUN Complex in MDA-MB-231 Human Breast Cancer Cells. Folia Biol (Praha) 2023; 69:81-90. [PMID: 38206773 DOI: 10.14712/fb2023069030081] [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] [Indexed: 01/13/2024]
Abstract
Prospero homeobox 1 (PROX1) is a member of the homeobox transcription factor family that plays a critical role in the development of multiple tissues and specification of cell fate. PROX1 expression is differentially regulated based on the cellular context and plays an antagonistic role as a tumour promoter or suppressor in different tumour types. In human breast cancer, PROX1 expression is suppress-ed; however, the molecular mechanism by which it is down-regulated remains poorly understood. Here, we show that ectopic expression of PROX1 reduces the motility and invasiveness of MDA-MB-231 human breast cancer cells, suggesting that PROX1 functions as a negative regulator of tumour invasion in MDA-MB-231 cells. Treatment with histone deacetylase (HDAC) inhibitors up-regulates PROX1 mRNA and protein expression levels. Knockdown of HDAC1 using short hairpin RNA also up-regulates PROX1 mRNA and protein expression levels. We found that HDAC1 interacted with c-JUN at the activator protein (AP)-1-binding site located at -734 to -710 in the PROX1 promoter region to suppress PROX1 expression. In addition, c-JUN N-terminal kinase-mediated c-JUN phosphorylation was found to be crucial for silencing PROX1 expression. In conclusion, PROX1 expression can be silenced by the epigenetic mechanism involved in the complex formation of HDAC1 and c-JUN at the AP-1 site in the PROX1 promoter region in MDA-MB-231 human breast cancer cells. Therefore, this study revealed the epigenetic regulatory mechanism involved in the suppression of PROX1 expression in breast cancer cells.
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Affiliation(s)
- Munki Jeong
- Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, Seoul 05029, Republic of Korea
| | - Euitaek Jung
- Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, Seoul 05029, Republic of Korea
| | - Sukjin Oh
- Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, Seoul 05029, Republic of Korea
| | - Soon Young Shin
- Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, Seoul 05029, Republic of Korea.
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9
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MKL-1-induced PINK1-AS overexpression contributes to the malignant progression of hepatocellular carcinoma via ALDOA-mediated glycolysis. Sci Rep 2022; 12:21283. [PMID: 36494481 PMCID: PMC9734095 DOI: 10.1038/s41598-022-24023-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 11/08/2022] [Indexed: 12/13/2022] Open
Abstract
Aldolase A (ALDOA), an important metabolic enzyme in the glycolytic pathway, plays an important role in regulating tumour metabolism. In this study, we investigated the expression pattern of ALDOA in hepatocellular carcinoma (HCC) and its biological role in tumour progression. Bioinformatics analysis, western blot (WB) and RT-qPCR were performed to detect the relative expression of ALDOA in HCC tissues and cell lines. A loss-of-function approach was used to investigate the biological function of ALDOA. The role of ALDOA on glycolysis was assessed by WB, glucose and lactate assay kits and a nude mouse xenograft model. Luciferase reporter experiment, chromatin immunoprecipitation and WB were performed to elucidate the underlying molecular. The expression level of ALODA was up-regulated in HCC tissues and cell lines. High ALDOA levels were associated with poorer patient overall survival. Mechanistic studies suggest that ALDOA is a direct target of miR-34a-5p, which can inhibit glycolysis in hepatocellular carcinoma cells by targeting the 3'UTR of ALDOA. PINK1 antisense RNA (PINK1-AS) competitively sponged miR-34a-5p to increase ALDOA expression by antagonizing miR-34a-5p-mediated ALDOA inhibition. MKL-1 acted as a transcription factor to promote the expression of PINK1-AS and ALDOA, thus promoting the deterioration of HCC cells. This study shows that high expression of ALDOA contributes to the development and poor prognosis of hepatocellular carcinoma and will be a target and potential prognostic biomarker for the treatment of HCC.
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10
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Hymel E, Fisher KW, Farazi PA. Differential methylation patterns in lean and obese non-alcoholic steatohepatitis-associated hepatocellular carcinoma. BMC Cancer 2022; 22:1276. [PMID: 36474183 PMCID: PMC9727966 DOI: 10.1186/s12885-022-10389-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease affects about 24% of the world's population and may progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). While more common in those that are obese, NASH-HCC can develop in lean individuals. The mechanisms by which HCC develops and the role of epigenetic changes in the context of obesity and normal weight are not well understood. METHODS In this study, we used previously generated mouse models of lean and obese HCC using a choline deficient/high trans-fat/fructose/cholesterol diet and a choline supplemented/high trans-fat/fructose/cholesterol diet, respectively, to evaluate methylation differences in HCC progression in lean versus obese mice. Differentially methylated regions were determined using reduced representation bisulfite sequencing. RESULTS A larger number of differentially methylated regions (DMRs) were seen in NASH-HCC progression in the obese mice compared to the non-obese mice. No overlap existed in the DMRs with the largest methylation differences between the two models. In lean NASH-HCC, methylation differences were seen in genes involved with cancer progression and prognosis (including HCC), such as CHCHD2, FSCN1, and ZDHHC12, and lipid metabolism, including PNPLA6 and LDLRAP1. In obese NASH- HCC, methylation differences were seen in genes known to be associated with HCC, including RNF217, GJA8, PTPRE, PSAPL1, and LRRC8D. Genes involved in Wnt-signaling pathways were enriched in hypomethylated DMRs in the obese NASH-HCC. CONCLUSIONS These data suggest that differential methylation may play a role in hepatocarcinogenesis in lean versus obese NASH. Hypomethylation of Wnt signaling pathway-related genes in obese mice may drive progression of HCC, while progression of HCC in lean mice may be driven through other signaling pathways, including lipid metabolism.
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Affiliation(s)
- Emma Hymel
- grid.266813.80000 0001 0666 4105Department of Epidemiology, University of Nebraska Medical Center, 984395 Nebraska Medical Center, Omaha, NE 68198-4395 USA
| | - Kurt W. Fisher
- grid.266813.80000 0001 0666 4105Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE USA
| | - Paraskevi A. Farazi
- grid.266813.80000 0001 0666 4105Department of Epidemiology, University of Nebraska Medical Center, 984395 Nebraska Medical Center, Omaha, NE 68198-4395 USA
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11
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Wang Y, Luo M, Wang F, Tong Y, Li L, Shu Y, Qiao K, Zhang L, Yan G, Liu J, Ji H, Xie Y, Zhang Y, Gao WQ, Liu Y. AMPK induces degradation of the transcriptional repressor PROX1 impairing branched amino acid metabolism and tumourigenesis. Nat Commun 2022; 13:7215. [PMID: 36433955 PMCID: PMC9700865 DOI: 10.1038/s41467-022-34747-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 11/04/2022] [Indexed: 11/26/2022] Open
Abstract
Tumour cell metabolic plasticity is essential for tumour progression and therapeutic responses, yet the underlying mechanisms remain poorly understood. Here, we identify Prospero-related homeobox 1 (PROX1) as a crucial factor for tumour metabolic plasticity. Notably, PROX1 is reduced by glucose starvation or AMP-activated protein kinase (AMPK) activation and is elevated in liver kinase B1 (LKB1)-deficient tumours. Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation. Downregulation of PROX1 activates branched-chain amino acids (BCAA) degradation through mediating epigenetic modifications and inhibits mammalian target-of-rapamycin (mTOR) signalling. Importantly, PROX1 deficiency or Ser79 phosphorylation in liver tumour shows therapeutic resistance to metformin. Clinically, the AMPK-PROX1 axis in human cancers is important for patient clinical outcomes. Collectively, our results demonstrate that deficiency of the LKB1-AMPK axis in cancers reactivates PROX1 to sustain intracellular BCAA pools, resulting in enhanced mTOR signalling, and facilitating tumourigenesis and aggressiveness.
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Affiliation(s)
- Yanan Wang
- Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Mengjun Luo
- Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fan Wang
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yu Tong
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Linfeng Li
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yu Shu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ke Qiao
- Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lei Zhang
- Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Guoquan Yan
- Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jing Liu
- Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hongbin Ji
- Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Youhua Xie
- Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
- Children's Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Yonglong Zhang
- Central Laboratory, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
| | - Wei-Qiang Gao
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
- School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
| | - Yanfeng Liu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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12
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Feng X, Yang G, Zhang L, Tao S, SHIM JS, Chen L, Wu Q. TRIM59 guards ER proteostasis and prevents Bortezomib-mediated colorectal cancer (CRC) cells’ killing. Invest New Drugs 2022; 40:1244-1253. [DOI: 10.1007/s10637-022-01306-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 09/19/2022] [Indexed: 12/24/2022]
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13
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Xia JK, Qin XQ, Zhang L, Liu SJ, Shi XL, Ren HZ. Roles and regulation of histone acetylation in hepatocellular carcinoma. Front Genet 2022; 13:982222. [PMID: 36092874 PMCID: PMC9452893 DOI: 10.3389/fgene.2022.982222] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 08/03/2022] [Indexed: 11/13/2022] Open
Abstract
Hepatocellular Carcinoma (HCC) is the most frequent malignant tumor of the liver, but its prognosis is poor. Histone acetylation is an important epigenetic regulatory mode that modulates chromatin structure and transcriptional status to control gene expression in eukaryotic cells. Generally, histone acetylation and deacetylation processes are controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Dysregulation of histone modification is reported to drive aberrant transcriptional programmes that facilitate liver cancer onset and progression. Emerging studies have demonstrated that several HDAC inhibitors exert tumor-suppressive properties via activation of various cell death molecular pathways in HCC. However, the complexity involved in the epigenetic transcription modifications and non-epigenetic cellular signaling processes limit their potential clinical applications. This review brings an in-depth view of the oncogenic mechanisms reported to be related to aberrant HCC-associated histone acetylation, which might provide new insights into the effective therapeutic strategies to prevent and treat HCC.
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Affiliation(s)
- Jin-kun Xia
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
- Hepatobiliary Institute Nanjing University, Nanjing, China
| | - Xue-qian Qin
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Lu Zhang
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Shu-jun Liu
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Xiao-lei Shi
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
- Hepatobiliary Institute Nanjing University, Nanjing, China
| | - Hao-zhen Ren
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
- Hepatobiliary Institute Nanjing University, Nanjing, China
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14
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Deldar Abad Paskeh M, Mirzaei S, Ashrafizadeh M, Zarrabi A, Sethi G. Wnt/β-Catenin Signaling as a Driver of Hepatocellular Carcinoma Progression: An Emphasis on Molecular Pathways. J Hepatocell Carcinoma 2021; 8:1415-1444. [PMID: 34858888 PMCID: PMC8630469 DOI: 10.2147/jhc.s336858] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/05/2021] [Indexed: 12/14/2022] Open
Abstract
Liver cancers cause a high rate of death worldwide and hepatocellular carcinoma (HCC) is considered as the most common primary liver cancer. HCC remains a challenging disease to treat. Wnt/β-catenin signaling pathway is considered a tumor-promoting factor in various cancers; hence, the present review focused on the role of Wnt signaling in HCC, and its association with progression and therapy response based on pre-clinical and clinical evidence. The nuclear translocation of β-catenin enhances expression level of genes such as c-Myc and MMPs in increasing cancer progression. The mutation of CTNNB1 gene encoding β-catenin and its overexpression can lead to HCC progression. β-catenin signaling enhances cancer stem cell features of HCC and promotes their growth rate. Furthermore, β-catenin prevents apoptosis in HCC cells and increases their migration via triggering EMT and upregulating MMP levels. It is suggested that β-catenin signaling participates in mediating drug resistance and immuno-resistance in HCC. Upstream mediators including ncRNAs can regulate β-catenin signaling in HCC. Anti-cancer agents inhibit β-catenin signaling and mediate its proteasomal degradation in HCC therapy. Furthermore, clinical studies have revealed the role of β-catenin and its gene mutation (CTNBB1) in HCC progression. Based on these subjects, future experiments can focus on developing novel therapeutics targeting Wnt/β-catenin signaling in HCC therapy.
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Affiliation(s)
- Mahshid Deldar Abad Paskeh
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, Istanbul, Turkey
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul, Turkey
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul, Turkey
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Sariyer, Istanbul, 34396, Turkey
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Cancer Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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15
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Liu XY, Guo CH, Xi ZY, Xu XQ, Zhao QY, Li LS, Wang Y. Histone methylation in pancreatic cancer and its clinical implications. World J Gastroenterol 2021; 27:6004-6024. [PMID: 34629816 PMCID: PMC8476335 DOI: 10.3748/wjg.v27.i36.6004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/12/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is an aggressive human cancer. Appropriate methods for the diagnosis and treatment of PC have not been found at the genetic level, thus making epigenetics a promising research path in studies of PC. Histone methylation is one of the most complicated types of epigenetic modifications and has proved crucial in the development of PC. Histone methylation is a reversible process regulated by readers, writers, and erasers. Some writers and erasers can be recognized as potential biomarkers and candidate therapeutic targets in PC because of their unusual expression in PC cells compared with normal pancreatic cells. Based on the impact that writers have on the development of PC, some inhibitors of writers have been developed. However, few inhibitors of erasers have been developed and put to clinical use. Meanwhile, there is not enough research on the reader domains. Therefore, the study of erasers and readers is still a promising area. This review focuses on the regulatory mechanism of histone methylation, and the diagnosis and chemotherapy of PC based on it. The future of epigenetic modification in PC research is also discussed.
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Affiliation(s)
- Xing-Yu Liu
- The First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
| | - Chuan-Hao Guo
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin Province, China
| | - Zhi-Yuan Xi
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin Province, China
| | - Xin-Qi Xu
- The First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
| | - Qing-Yang Zhao
- The First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Sha Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin Province, China
| | - Ying Wang
- The First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
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16
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Hao X, Luo W, Qiu X. The association of transcription factor Prox1 with the proliferation, migration, and invasion of lung cancer. Open Life Sci 2021; 16:602-610. [PMID: 34183992 PMCID: PMC8218550 DOI: 10.1515/biol-2021-0056] [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: 12/01/2020] [Revised: 03/10/2021] [Accepted: 03/11/2021] [Indexed: 12/15/2022] Open
Abstract
Background The current study investigates the effect of transcription factor Prox1 on the proliferation, migration, and invasion ability of lung cancer. Methods Lung cancer cell lines (A549 and H446 cells) were transfected with Prox1NAD and siRNA, respectively. Thus, the A549 and H446 cells overexpressed Prox1 after transfection of Prox1NAD plasmids, and A549 and H446 cells have low expression of Prox1 after transfection with siRNA. Reverse transcriptase quantitative PCR and western blot analyses were used to detect Prox1 mRNA and protein expression in cells. Plate clone formation experiments and MTT experiments were used to detect cell proliferation. Western blot was used to detect the expression of Rho family-related proteins in cells. Results Compared to untransfected wild-type A549 and H446 that served as blank controls, the expression level of Prox1mRNA and protein in A549 and H446 cells overexpressing Prox1 after plasmid transfection was high, while the expression level of Prox1mRNA and protein in A549 and H446 cells with low expression of Prox1 after siRNA transfection was low. With the increase of Prox1 expression, the expression of RhoA and RhoC increased, while the expression of RhoB decreased. Conclusion The finding of this study may provide a new approach for the treatment of lung cancer using targeted gene therapy.
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Affiliation(s)
- Xinxin Hao
- Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang 110001, China.,Department of Blood Transfusion, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Wenting Luo
- Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Xueshan Qiu
- Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang 110001, China
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17
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Papanikolaou S, Vourda A, Syggelos S, Gyftopoulos K. Cell Plasticity and Prostate Cancer: The Role of Epithelial-Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance. Cancers (Basel) 2021; 13:cancers13112795. [PMID: 34199763 PMCID: PMC8199975 DOI: 10.3390/cancers13112795] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 05/28/2021] [Accepted: 06/01/2021] [Indexed: 12/23/2022] Open
Abstract
Simple Summary Although epithelial-to-mesenchymal transition (EMT) is a well-known cellular process involved during normal embryogenesis and wound healing, it also has a dark side; it is a complex process that provides tumor cells with a more aggressive phenotype, facilitating tumor metastasis and even resistance to therapy. This review focuses on the key pathways of EMT in the pathogenesis of prostate cancer and the development of metastases and evasion of currently available treatments. Abstract Prostate cancer, the second most common malignancy in men, is characterized by high heterogeneity that poses several therapeutic challenges. Epithelial–mesenchymal transition (EMT) is a dynamic, reversible cellular process which is essential in normal embryonic morphogenesis and wound healing. However, the cellular changes that are induced by EMT suggest that it may also play a central role in tumor progression, invasion, metastasis, and resistance to current therapeutic options. These changes include enhanced motility and loss of cell–cell adhesion that form a more aggressive cellular phenotype. Moreover, the reverse process (MET) is a necessary element of the metastatic tumor process. It is highly probable that this cell plasticity reflects a hybrid state between epithelial and mesenchymal status. In this review, we describe the underlying key mechanisms of the EMT-induced phenotype modulation that contribute to prostate tumor aggressiveness and cancer therapy resistance, in an effort to provide a framework of this complex cellular process.
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18
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Ding ZN, Dong ZR, Chen ZQ, Yang YF, Yan LJ, Li HC, Liu KX, Yao CY, Yan YC, Yang CC, Li T. Effects of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α overexpression on hepatocellular carcinoma survival: A systematic review with meta-analysis. J Gastroenterol Hepatol 2021; 36:1487-1496. [PMID: 33393670 DOI: 10.1111/jgh.15395] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 12/08/2020] [Accepted: 12/28/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM The role of hypoxia-inducible factor-1α (HIF-1α) and hypoxia-inducible factor-2α (HIF-2α) has been implicated in the clinical prognosis of hepatocellular carcinoma (HCC), but the results remain controversial. We aim to investigate the association of HIF-1α and HIF-2α overexpression with the prognosis and clinicopathological features of HCC. METHODS A systematic search was conducted in PubMed, Embase, Scopus, Web of Science, and Cochrane Library until June 20, 2020. Meta-analysis was conducted to generate combined HRs with 95% confidence intervals (CI) for overall survival (OS) and disease-free survival (DFS). Odds ratios (ORs) with 95% CI were also derived by fixed or random effect model. RESULTS Twenty-two studies involving 3238 patients were included. Combined data suggested that overexpression of HIF-1α in HCC was not only correlated with poorer OS [HR = 1.75 (95% CI: 1.53-2.00)] and DFS [HR = 1.64 (95% CI: 1.34-2.00)] but was also positively associated with vascular invasion [OR = 1.83 (95% CI: 1.36-2.48)], tumor size [OR = 1.36 (95% CI: 1.12-1.66)], and tumor number [1.74 (95% CI: 1.34-2.25)]. In contrast, HIF-2α overexpression was not associated with the prognosis and clinicopathological features of HCC. CONCLUSION Our data provided compelling evidence of a worse prognosis of HCC in HIF-1α overexpression patients but not HIF-2α overexpression ones.
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Affiliation(s)
- Zi-Niu Ding
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Zhao-Ru Dong
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Zhi-Qiang Chen
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Ya-Fei Yang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Lun-Jie Yan
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Hai-Chao Li
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Kai-Xuan Liu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Cheng-Yu Yao
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Yu-Chuan Yan
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Chun-Cheng Yang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Tao Li
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
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Kaltezioti V, Foskolou IP, Lavigne MD, Ninou E, Tsampoula M, Fousteri M, Margarity M, Politis PK. Prox1 inhibits neurite outgrowth during central nervous system development. Cell Mol Life Sci 2021; 78:3443-3465. [PMID: 33247761 PMCID: PMC11072475 DOI: 10.1007/s00018-020-03709-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 11/06/2020] [Accepted: 11/11/2020] [Indexed: 12/24/2022]
Abstract
During central nervous system (CNS) development, proper and timely induction of neurite elongation is critical for generating functional, mature neurons, and neuronal networks. Despite the wealth of information on the action of extracellular cues, little is known about the intrinsic gene regulatory factors that control this developmental decision. Here, we report the identification of Prox1, a homeobox transcription factor, as a key player in inhibiting neurite elongation. Although Prox1 promotes acquisition of early neuronal identity and is expressed in nascent post-mitotic neurons, it is heavily down-regulated in the majority of terminally differentiated neurons, indicating a regulatory role in delaying neurite outgrowth in newly formed neurons. Consistently, we show that Prox1 is sufficient to inhibit neurite extension in mouse and human neuroblastoma cell lines. More importantly, Prox1 overexpression suppresses neurite elongation in primary neuronal cultures as well as in the developing mouse brain, while Prox1 knock-down promotes neurite outgrowth. Mechanistically, RNA-Seq analysis reveals that Prox1 affects critical pathways for neuronal maturation and neurite extension. Interestingly, Prox1 strongly inhibits many components of Ca2+ signaling pathway, an important mediator of neurite extension and neuronal maturation. In accordance, Prox1 represses Ca2+ entry upon KCl-mediated depolarization and reduces CREB phosphorylation. These observations suggest that Prox1 acts as a potent suppressor of neurite outgrowth by inhibiting Ca2+ signaling pathway. This action may provide the appropriate time window for nascent neurons to find the correct position in the CNS prior to initiation of neurites and axon elongation.
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Affiliation(s)
- Valeria Kaltezioti
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Street, 115 27, Athens, Greece
| | - Iosifina P Foskolou
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Street, 115 27, Athens, Greece
| | - Matthieu D Lavigne
- Institute for Fundamental Biomedical Research, BSRC 'Alexander Fleming', 34 Fleming Street, Vari, 16672, Athens, Greece
| | - Elpinickie Ninou
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Street, 115 27, Athens, Greece
| | - Matina Tsampoula
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Street, 115 27, Athens, Greece
| | - Maria Fousteri
- Institute for Fundamental Biomedical Research, BSRC 'Alexander Fleming', 34 Fleming Street, Vari, 16672, Athens, Greece
| | - Marigoula Margarity
- Laboratory of Human and Animal Physiology, Department of Biology, School of Natural Sciences, University of Patras, 26500, Rio Achaias, Greece
| | - Panagiotis K Politis
- Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Street, 115 27, Athens, Greece.
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20
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Zheng Y, Huang C, Lu L, Yu K, Zhao J, Chen M, Liu L, Sun Q, Lin Z, Zheng J, Chen J, Zhang J. STOML2 potentiates metastasis of hepatocellular carcinoma by promoting PINK1-mediated mitophagy and regulates sensitivity to lenvatinib. J Hematol Oncol 2021; 14:16. [PMID: 33446239 PMCID: PMC7807703 DOI: 10.1186/s13045-020-01029-3] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Accepted: 12/25/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Dysregulation of both mitochondrial biogenesis and mitophagy is critical to sustain oncogenic signaling pathways. However, the mechanism of mitophagy in promoting hepatocellular carcinoma (HCC) progression remains poorly understood. In this study, we investigated the clinical significance and biological involvement of mitochondrial inner membrane protein STOML2 in HCC. METHODS STOML2 was identified by gene expression profiles of HCC tissues and was measured in tissue microarray and cell lines. Gain/loss-of-function experiment was applied to study the biological function of STOML2 in HCC. Flow cytometry, Western blotting, laser confocal microscopy, transmission electron microscopy, and co-immunoprecipitation were used to detect and analyze mitophagy. ChIP and luciferase reporter assay were conducted to evaluate the relationship between STOML2 and HIF-1α. The sensitivity to lenvatinib was assessed in HCC both in vitro and in vivo. RESULTS Increased expression of STOML2 was found in HCC compared with paired peritumoral tissues. It was more significant in HCC with metastasis and correlated with worse overall survival and higher probability of recurrence after hepatectomy. Upregulation of STOML2 accelerated HCC cells colony formation, migration and invasion. Mechanically, TCGA dataset-based analysis showed enrichment of autophagy-related pathways in STOML2 highly-expressed HCC. Next, STOML2 was demonstrated to interact and stabilize PINK1 under cellular stress, amplify PINK1-Parkin-mediated mitophagy and then promote HCC growth and metastasis. Most interestingly, HIF-1α was upregulated and transcriptionally increased STOML2 expression in HCC cells under the treatment of lenvatinib. Furthermore, higher sensitivity to lenvatinib was found in HCC cells when STOML2 was downregulated. Combination therapy with lenvatinib and mitophagy inhibitor hydroxychloroquine obtained best efficacy. CONCLUSIONS Our findings suggested that STOML2 could amplify mitophagy through interacting and stabilizing PINK1, which promote HCC metastasis and modulate the response of HCC to lenvatinib. Combinations of pharmacologic inhibitors that concurrently block both angiogenesis and mitophagy may serve as an effective treatment for HCC.
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Affiliation(s)
- Yahui Zheng
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
- Center of Liver Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Chong Huang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
- Center of Liver Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Lu Lu
- Center of Liver Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Kangkang Yu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
- Center of Liver Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Jing Zhao
- Center of Liver Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Mingquan Chen
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
- Center of Liver Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Lu Liu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
- Center of Liver Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Qingfeng Sun
- Department of Infectious Diseases, Ruian People's Hospital, Ruian, 325200, China
| | - Zhifei Lin
- Center of Liver Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Jianming Zheng
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
- Center of Liver Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Jinhong Chen
- Center of Liver Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China.
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
| | - Jubo Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China.
- Center of Liver Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China.
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21
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Chen LY, Wang L, Ren YX, Pang Z, Liu Y, Sun XD, Tu J, Zhi Z, Qin Y, Sun LN, Li JM. The circular RNA circ-ERBIN promotes growth and metastasis of colorectal cancer by miR-125a-5p and miR-138-5p/4EBP-1 mediated cap-independent HIF-1α translation. Mol Cancer 2020; 19:164. [PMID: 33225938 PMCID: PMC7682012 DOI: 10.1186/s12943-020-01272-9] [Citation(s) in RCA: 149] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 10/21/2020] [Indexed: 12/15/2022] Open
Abstract
Background Circular RNA (circRNAs) and hypoxia have been found to play the key roles in the pathogenesis and progression of cancer including colorectal cancer (CRC). However, the expressions and functions of the specific circRNAs in regulating hypoxia-involved CRC metastasis, and the circRNAs that are relevant to regulate HIF-1α levels in CRC remain elusive. Methods qRT-PCR was used to detect the expression of circRNAs and mRNA in CRC cells and tissues. Fluorescence in situ hybridization (FISH) was used to analyze the location of circ-ERBIN. Function-based experiments were performed using circ-ERBIN overexpression and knockdown cell lines in vitro and in vivo, including CCK8, colony formation, EdU assay, transwell, tumor growth and metastasis models. Mechanistically, luciferase reporter assay, western blots and immunohistochemical stainings were performed. Results Circ-Erbin was highly expressed in the CRC cells and Circ-Erbin overexpression facilitated the proliferation, migration and metastasis of CRC in vitro and in vivo. Notably, circ-Erbin overexpression significantly promoted angiogenesis by increasing the expression of hypoxia induced factor (HIF-1α) in CRC. Mechanistically, circ-Erbin accelerated a cap-independent protein translation of HIF-1α in CRC cells as the sponges of miR-125a-5p and miR-138-5p, which synergistically targeted eukaryotic translation initiation factor 4E binding protein 1(4EBP-1). Conclusions Our findings uncover a key mechanism for circ-Erbin mediated HIF-1α activation by miR-125a-5p-5p/miR-138-5p/4EBP-1 axis and circ-ERBIN is a potential target for CRC treatment. Supplementary Information Supplementary information accompanies this paper at 10.1186/s12943-020-01272-9.
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Affiliation(s)
- Liang-Yan Chen
- Department of Pathology and Pathophysiology, Soochow University Medical School, Suzhou, 215123, People's Republic of China.,Department of Pathology, the Second Affiliated Hospital of Soochow University, Suzhou, 215004, People's Republic of China
| | - Lian Wang
- Department of Pathology and Pathophysiology, Soochow University Medical School, Suzhou, 215123, People's Republic of China
| | - Yue-Xiang Ren
- Department of Pathology and Pathophysiology, Soochow University Medical School, Suzhou, 215123, People's Republic of China
| | - Zheng Pang
- Department of Pathology and Pathophysiology, Soochow University Medical School, Suzhou, 215123, People's Republic of China
| | - Yao Liu
- Department of Pathology and Pathophysiology, Soochow University Medical School, Suzhou, 215123, People's Republic of China
| | - Xiao-Dong Sun
- Department of Pathology and Pathophysiology, Soochow University Medical School, Suzhou, 215123, People's Republic of China
| | - Jian Tu
- Department of Pathology, the Second Affiliated Hospital of Soochow University, Suzhou, 215004, People's Republic of China
| | - Zheng Zhi
- Department of Pathology and Pathophysiology, Soochow University Medical School, Suzhou, 215123, People's Republic of China
| | - Yan Qin
- Department of Pathology and Pathophysiology, Soochow University Medical School, Suzhou, 215123, People's Republic of China.,Department of Pathology, the Affiliated Hospital of Jiangnan University, Wuxi 4th People's Hospital, Wuxi, 214062, People's Republic of China
| | - Li-Na Sun
- Department of Pathology and Pathophysiology, Soochow University Medical School, Suzhou, 215123, People's Republic of China.
| | - Jian-Ming Li
- Department of Pathology and Pathophysiology, Soochow University Medical School, Suzhou, 215123, People's Republic of China. .,Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
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22
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Liao LE, Hu DD, Zheng Y. A Four-Methylated lncRNAs-Based Prognostic Signature for Hepatocellular Carcinoma. Genes (Basel) 2020; 11:genes11080908. [PMID: 32784402 PMCID: PMC7463540 DOI: 10.3390/genes11080908] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 07/21/2020] [Accepted: 08/06/2020] [Indexed: 02/01/2023] Open
Abstract
Currently, an increasing number of studies suggest that long non-coding RNAs (lncRNAs) and methylation-regulated lncRNAs play a critical role in the pathogenesis of various cancers including hepatocellular carcinoma (HCC). Therefore, methylated differentially expressed lncRNAs (MDELs) may be critical biomarkers of HCC. In this study, 63 MDELs were identified by screening The Cancer Genome Atlas (TCGA) HCC lncRNAs expression data set and lncRNAs methylation data set. Based on univariate and multivariate survival analysis, four MDELs (AC025016.1, LINC01164, LINC01183 and LINC01269) were selected to construct the survival prognosis prediction model. Through the PI formula, the study indicates that our new prediction model performed well and is superior to the traditional staging method. At the same time, compared with the previous prediction models reported in the literature, the results of time-dependent receiver operating characteristic (ROC) curve analysis show that our 4-MDELs model predicted overall survival (OS) stability and provided better prognosis. In addition, we also applied the prognostic model to Cancer Cell Line Encyclopedia (CCLE) cell lines and classified different hepatoma cell lines through the model to evaluate the sensitivity of different hepatoma cell lines to different drugs. In conclusion, we have established a new risk scoring system to predict the prognosis, which may have a very important guiding significance for the individualized treatment of HCC patients.
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Affiliation(s)
- Le-En Liao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China; (L.-E.L.); (D.-D.H.)
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China
| | - Dan-Dan Hu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China; (L.-E.L.); (D.-D.H.)
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China
| | - Yun Zheng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China; (L.-E.L.); (D.-D.H.)
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, China
- Correspondence: ; Tel.: +86-20-8734-3676
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Zhang L, Jin Y, Yang H, Li Y, Wang C, Shi Y, Wang Y. SMYD3 promotes epithelial ovarian cancer metastasis by downregulating p53 protein stability and promoting p53 ubiquitination. Carcinogenesis 2020; 40:1492-1503. [PMID: 31002112 DOI: 10.1093/carcin/bgz078] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 03/28/2019] [Accepted: 04/17/2019] [Indexed: 12/13/2022] Open
Abstract
Epithelial ovarian cancer (EOC) has a very poor prognosis because of tumor invasiveness. Here, we reported that SET and MYND domain containing protein 3 (SMYD3), a lysine methyltransferase, was frequently upregulated in EOC and associated with poor prognosis. A series of in vitro assays demonstrated that SMYD3 significantly upgraded the migration ability of EOC cells. The results of in vivo EOC metastasis models further confirmed that overexpression of SMYD3 promoted EOC progression. Mechanistic investigations indicated that SMYD3 cloud decrease p53 protein stability and induce epithelial-mesenchymal transition in EOC cells. SMYD3 interacts with p53 directly via the post-SET domain and destabilizes p53 by inducing p53 translocation from the nucleus to the cytoplasm and promoting p53 ubiquitination modification independent of MDM2. Furthermore, the mass spectrometry results showed that SMYD3 interacts with UBE2R2, an ubiquitin-conjugating enzyme (E2) of the ubiquitin-proteasome pathway. The combination of UBE2R2-SMYD3-p53 significantly promotes the ubiquitination and degradation of p53. These results pointed that SMYD3 might be a new E3 ligase of p53. Further analysis confirmed that lysines 381, 382 and 386 of p53 are the key sites for the ubiquitination modification of SMYD3 to p53. In summary, our results define the important role of SMYD3 in the metastasis process of EOC and present a new therapeutic target against EOC.
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Affiliation(s)
- Liwei Zhang
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China
| | - Yue Jin
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China
| | - Hao Yang
- Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Yu Li
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China
| | - Chao Wang
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China
| | - Yongheng Shi
- Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yu Wang
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China
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Restriction of exogenous DNA expression by SAMHD1. Sci Bull (Beijing) 2020; 65:573-586. [PMID: 36659189 DOI: 10.1016/j.scib.2019.12.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 11/09/2019] [Accepted: 11/19/2019] [Indexed: 01/21/2023]
Abstract
SAMHD1 (Sterile Alpha Motif and Histidine-aspartate Domain containing protein 1) has been documented as a host factor that restricts HIV-1 and some DNA viruses. In this work, we attempted to explore possible effects of SAMHD1 on exogenous DNA and show that SAMHD1 exerts a general inhibition on the expression of exogenous DNA in vitro and in mice. This inhibition is achieved through repressing transcription of exogenous DNA. Intriguingly, unlike SAMHD1's restriction of HIV-1, such restriction does not require the dNTPase or RNase activities, or T592 phosphorylation of SAMHD1. Mechanistically, SAMHD1 enhances the expression of interferon regulatory factor-1 (IRF1), while IRF1 upregulation was demonstrated to inhibit exogenous DNA expression in a similar fashion as SAMHD1. IFNλ1, whose induction has been associated with IRF1 activation, is dispensable for SAMHD1/IRF1-mediated restriction of exogenous DNA, and neither type I nor II interferons appear to be involved. We also demonstrate that SAMHD1/IRF1-mediated restriction can effectively inhibit hepatitis B virus (HBV) antigen expression and progeny virus production in mouse models. In conclusion, these data support restriction of exogenous DNA as a novel function of SAMHD1.
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Yang X, Wang Z, Kai J, Wang F, Jia Y, Wang S, Tan S, Shen X, Chen A, Shao J, Zhang F, Zhang Z, Zheng S. Curcumol attenuates liver sinusoidal endothelial cell angiogenesis via regulating Glis-PROX1-HIF-1α in liver fibrosis. Cell Prolif 2020; 53:e12762. [PMID: 32119185 PMCID: PMC7106966 DOI: 10.1111/cpr.12762] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 12/13/2019] [Accepted: 12/21/2019] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Hepatic sinusoidal angiogenesis owing to dysfunctional liver sinusoidal endothelial cells (LSECs) accompanied by an abnormal angioarchitecture is a symbol related to liver fibrogenesis, which indicates a potential target for therapeutic interventions. However, there are few researches connecting angiogenesis with liver fibrosis, and the deeper mechanism remains to be explored. MATERIALS AND METHODS Cell angiogenesis and angiogenic protein were examined in primary LSECs of rats, and multifarious cellular and molecular assays revealed the efficiency of curcumol intervention in fibrotic mice. RESULTS We found that curcumol inhibited angiogenic properties through regulating their upstream mediator hypoxia-inducible factor-1α (HIF-1α). The transcription activation of HIF-1α was regulated by hedgehog signalling on the one hand, and the protein stabilization of HIF-1α was under the control of Prospero-related homeobox 1 (PROX1) on the other. A deubiquitinase called USP19 could be recruited by PROX1 and involved in ubiquitin-dependent degradation of HIF-1α. Furthermore, our researches revealed that hedgehog signalling participated in the activation of PROX1 transcription probably in vitro. Besides, curcumol was found to ameliorate liver fibrosis and sinusoid angiogenesis via hedgehog pathway in carbon tetrachloride (CCl4 ) induced liver fibrotic mice. The protein expression of key regulatory factors, PROX1 and HIF-1α, was consistent with the Smo, the marker protein of Hh signalling pathway. CONCLUSIONS In this article, we evidenced that curcumol controlling LSEC-mediated angiogenesis could be a promising therapeutic approach for liver fibrosis.
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Affiliation(s)
- Xiang Yang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Zhimin Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Jun Kai
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Feixia Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Yan Jia
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Shijun Wang
- Shandong University of Traditional Chinese MedicineJinanChina
| | - Shanzhong Tan
- Nanjing Hospital Affiliated to Nanjing University of Chinese MedicineNanjingChina
| | - Xikun Shen
- Suzhou Hospital of Traditional Chinese MedicineSuzhouChina
| | - Anping Chen
- Department of PathologySchool of MedicineSaint Louis UniversitySt. LouisMOUSA
| | - Jiangjuan Shao
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
- Jiangsu Key Laboratory of Therapeutic Material of Chinese MedicineSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
- Jiangsu Key Laboratory of Therapeutic Material of Chinese MedicineSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Zili Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
- Jiangsu Key Laboratory of Therapeutic Material of Chinese MedicineSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
| | - Shizhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
- Jiangsu Key Laboratory of Therapeutic Material of Chinese MedicineSchool of PharmacyNanjing University of Chinese MedicineNanjingChina
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Lu Y, Yang L, Qin A, Qiao Z, Huang B, Jiang X, Wu J. miR-1470 regulates cell proliferation and apoptosis by targeting ALX4 in hepatocellular carcinoma. Biochem Biophys Res Commun 2020; 522:716-723. [PMID: 31791584 DOI: 10.1016/j.bbrc.2019.10.139] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 10/19/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. MicroRNAs (miRNAs) have been proven to play essential roles in different cancers, including HCC. The current study was mainly focused on the role of miR-1470 in HCC progression. METHODS Quantitative real-time PCR (qRT-PCR) was performed to detect the expression levels of miR-1470 and Aristaless-like homeobox-4 (ALX4). The CCK-8 and EdU assays were used to examine cell proliferation. Flow cytometric analysis was used to elucidate the cell cycle and cell apoptosis. A xenograft tumor assay was carried out to verify the effect of miR-1470 on tumor formation in vivo. RESULTS According to the qRT-PCR assay, miR-1470 was proven to be overexpressed in HCC. As shown by the CCK-8 assay, EdU assay and flow cytometric analysis, miR-1470 overexpression promoted cell proliferation and inhibited cell apoptosis. ALX4 was proven via a dual luciferase reporter assay to be a downstream target gene of miR-1470. ALX4 was downregulated in HCC. The results of a rescue assay revealed that miR-1470 had an oncogenic role in HCC by regulating ALX4. CONCLUSION miR-1470 exhibits an oncogenic role in HCC by targeting ALX4. The data from our study may provide novel insight for the identification of new biomarkers and treatment strategies for HCC.
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Affiliation(s)
- Yijie Lu
- Department of general surgery, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, 26 Daoqian Street, Gusu District, Suzhou, 215002, China
| | - Liu Yang
- Department of gastroenterology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, 26 Daoqian Street, Gusu District, Suzhou, 215002, China
| | - Ancheng Qin
- Department of general surgery, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, 26 Daoqian Street, Gusu District, Suzhou, 215002, China
| | - Zhiming Qiao
- Department of general surgery, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, 26 Daoqian Street, Gusu District, Suzhou, 215002, China
| | - Bo Huang
- Department of general surgery, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, 26 Daoqian Street, Gusu District, Suzhou, 215002, China
| | - Xinwei Jiang
- Department of general surgery, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, 26 Daoqian Street, Gusu District, Suzhou, 215002, China.
| | - Jianwu Wu
- Department of general surgery, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, 26 Daoqian Street, Gusu District, Suzhou, 215002, China.
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Ma XL, Hu B, Tang WG, Xie SH, Ren N, Guo L, Lu RQ. CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma. J Hematol Oncol 2020; 13:11. [PMID: 32024555 PMCID: PMC7003355 DOI: 10.1186/s13045-020-0845-z] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 01/16/2020] [Indexed: 12/11/2022] Open
Abstract
Background Aberrant AKT activation contributes to cancer stem cell (CSC) traits in hepatocellular carcinoma (HCC). We previously reported that CD73 activated AKT signaling via the Rap1/P110β cascade. Here, we further explored the roles of CD73 in regulating CSC characteristics of HCC. Methods CD73 expression modulations were conducted by lentiviral transfections. CD73+ fractions were purified by magnetic-based sorting, and fluorescent-activated cell sorting was used to assess differentiation potentials. A sphere-forming assay was performed to evaluate CSC traits in vitro, subcutaneous NOD/SCID mice models were generated to assess in vivo CSC features, and colony formation assays assessed drug resistance capacities. Stemness-associated gene expression was also determined, and underlying mechanisms were investigated by evaluating immunoprecipitation and ubiquitylation. Results We found CD73 expression was positively associated with sphere-forming capacity and elevated in HCC spheroids. CD73 knockdown hindered sphere formation, Lenvatinib resistance, and stemness-associated gene expression, while CD73 overexpression achieved the opposite effects. Moreover, CD73 knockdown significantly inhibited the in vivo tumor propagation capacity. Notably, we found that CD73+ cells exhibited substantially stronger CSC traits than their CD73– counterparts. Mechanistically, CD73 exerted its pro-stemness activity through dual AKT-dependent mechanisms: activating SOX9 transcription via c-Myc, and preventing SOX9 degradation by inhibiting glycogen synthase kinase 3β. Clinically, the combined analysis of CD73 and SOX9 achieved a more accurate prediction of prognosis. Conclusions Collectively, CD73 plays a critical role in sustaining CSCs traits by upregulating SOX9 expression and enhancing its protein stability. Targeting CD73 might be a promising strategy to eradicate CSCs and reverse Lenvatinib resistance in HCC.
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Affiliation(s)
- Xiao-Lu Ma
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China
| | - Bo Hu
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Wei-Guo Tang
- Department of Hepatobiliary and Pancreatic Surgery, Minhang Hospital, Fudan University, Shanghai, 201100, China
| | - Su-Hong Xie
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China
| | - Ning Ren
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. .,Department of Hepatobiliary and Pancreatic Surgery, Minhang Hospital, Fudan University, Shanghai, 201100, China.
| | - Lin Guo
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China.
| | - Ren-Quan Lu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China.
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Liu Y, Tao S, Liao L, Li Y, Li H, Li Z, Lin L, Wan X, Yang X, Chen L. TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway. Nat Commun 2020; 11:348. [PMID: 31953436 PMCID: PMC6969153 DOI: 10.1038/s41467-019-14190-2] [Citation(s) in RCA: 173] [Impact Index Per Article: 34.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 12/18/2019] [Indexed: 12/20/2022] Open
Abstract
Tumor cells often exhibit augmented capacity to maintain endoplasmic reticulum (ER) homeostasis under adverse conditions, yet the underlying mechanisms are not well defined. Here, through the evaluation of all human TRIM proteins, we find that TRIM25 is significantly induced upon ER stress. Upregulation of TRIM25 ameliorates oxidative stress, promotes ER-associated degradation (ERAD), and reduces IRE1 signaling in the UPR pathway. In contrast, depletion of TRIM25 leads to ER stress and attenuates tumor cell growth in vitro and in vivo. Mechanistically, TRIM25 directly targets Keap1 by ubiquitination and degradation. This leads to Nrf2 activation, which bolsters anti-oxidant defense and cell survival. TRIM25 expression is positively associated with Nrf2 expression and negatively with Keap1 expression in hepatocellular carcinoma (HCC) xenografts and specimens. Moreover, high TRIM25 expression correlates with poor patient survival in HCC. These findings reveal TRIM25 as a regulator of ER homeostasis and a potential target for tumor therapy. The unfolded protein response allows tumour cells to adapt to ER stress, and aberrant activation of Nrf2 confers cancer progression. Here, the authors show that TRIM25 is induced during ER stress and promotes tumour cell survival by targeting Keap1 for degradation, leading to Nrf2 activation.
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Affiliation(s)
- Yanfeng Liu
- Shenzhen Laboratory of Tumor Cell Biology, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, P. R. China.,Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Shishi Tao
- Shenzhen Laboratory of Tumor Cell Biology, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, P. R. China
| | - Lijuan Liao
- Shenzhen Laboratory of Tumor Cell Biology, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, P. R. China
| | - Yang Li
- Shenzhen Laboratory of Tumor Cell Biology, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, P. R. China
| | - Hongchang Li
- Shenzhen Laboratory of Tumor Cell Biology, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, P. R. China
| | - Zhihuan Li
- Dongguan Enlife Stem Cell Biotechnology Institute, Zheshang Building, #430 Dongguan Ave., Dongguan, Guangdong, 523000, China
| | - Lilong Lin
- Dongguan Enlife Stem Cell Biotechnology Institute, Zheshang Building, #430 Dongguan Ave., Dongguan, Guangdong, 523000, China
| | - Xiaochun Wan
- Shenzhen Laboratory of Tumor Cell Biology, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, P. R. China
| | - Xiaolu Yang
- Department of Cancer Biology and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
| | - Liang Chen
- Shenzhen Laboratory of Tumor Cell Biology, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, P. R. China.
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Zhou DK, Qian XH, Cheng J, Chen LH, Wang WL. Clinical significance of down-regulated HINT2 in hepatocellular carcinoma. Medicine (Baltimore) 2019; 98:e17815. [PMID: 31770197 PMCID: PMC6890357 DOI: 10.1097/md.0000000000017815] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 09/19/2019] [Accepted: 10/08/2019] [Indexed: 12/13/2022] Open
Abstract
To study the clinical significance of HINT2 expression in patients with HCC.We investigated HINT2 mRNA expression in tumors and adjacent non-tumor hepatic tissues from 106 HCC patients using quantitative real-time PCR. Appropriate statistical methods were then applied to assess the relationships between the HINT2 mRNA level and clinical parameters.HINT2 was significantly down-regulated in HCC (P < .0001). No significant correlation was found between HINT2 expression and clinicopathological factors in HCC patients. A Kaplan-Meier survival curve showed that HINT2 expression is related to recurrence-free survival (P < .05). Multivariate analyses revealed that tumor size and HINT2 expression are risk factors for HCC recurrence.HINT2 is down-regulated in HCC, and low HINT2 expression predicts earlier tumor recurrence. HINT2 expression may serve as a prognostic indicator of recurrence in HCC.
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Affiliation(s)
- Dong-Kai Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province
| | - Xiao-Hui Qian
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province
| | - Jun Cheng
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province
| | - Ling-Hui Chen
- Diagnosis and Treatment Center of Thyroid Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Wei-Lin Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province
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Meng F. A novel role of HIF-1α/PROX-1/LYVE-1 axis on tissue regeneration after renal ischaemia/reperfusion in mice. Arch Physiol Biochem 2019; 125:321-331. [PMID: 29633855 DOI: 10.1080/13813455.2018.1459728] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Context: Renal ischaemia reperfusion (I/R) is a common clinical condition with a high morbidity and mortality rate. To date, I/R-induced renal injury remains an ineffective treatment. Objective: We hypothesis that angiogenesis and lymphangiogenesis markers, prospero homeobox-1 (PROX-1) and lymphatic endothelial hyaluronan receptor-1 (LYVE-1), are critical during I/R. Material and methods: Kunming mice were subjected to I/R and observed for the following eight consecutive days. Pathology analysis and protein distribution were detected by H&E staining, immunohistochemistry and immunofluorescence confocal analysis. Results: After I/R treatment, renal pathology was changed. HIF-1α was induced in the early stage and colocalisation with PROX-1 mainly in the renal tubular region, whereas PROX-1 and LYVE-1 were colocalised in the glomerulus of the endothelial region. Conclusions: In this study, we revealed HIF-1α/PROX-1/LVYE-1 axis dynamic changes in different regions after I/R and demonstrated for the first time it activates during I/R repair.
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Affiliation(s)
- Fanwei Meng
- a Department of Anatomy and Physiology, Shandong College of Traditional Chinese Medicine , Yantai , China
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31
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Sun X, Huang T, Zhang C, Zhang S, Wang Y, Zhang Q, Liu Z. Long non-coding RNA LINC00968 reduces cell proliferation and migration and angiogenesis in breast cancer through up-regulation of PROX1 by reducing hsa-miR-423-5p. Cell Cycle 2019; 18:1908-1924. [PMID: 31213129 DOI: 10.1080/15384101.2019.1632641] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background: Breast cancer (BC) is a common invasive malignancy in women with unclear etiology. A recent study suggested that long non-coding RNA (lncRNA), LINC00968 had a tumor-promoting effect in cancer. However, the role of LINC00968 in BC remains unclear. Therefore, we conducted the present study to determine the effect of LINC00968 in BC and its underlying mechanism. Methods: The expression of LINC00968 and hsa-miR-423-5p in BC tissues and cells was determined using reverse transcription quantitative polymerase chain reaction and western blot analysis. Dual luciferase reporter, RNA pull-down and RNA immunoprecipitation assays were used to determine the relationship among LINC00968, PROX1 and hsa-miR-423-5p. Gain- and loss-function approaches were utilized to examine the effects of LINC00968, PROX1 and hsa-miR-423-5p on cell proliferation, migration, tube formation in vitro; and tumor growth and angiogenesis in vivo. Results: LINC00968 expression reduced while hsa-miR-423-5p increased in BC tissues relative to adjacent normal tissues. Overexpression of LINC00968 was observed to inhibit BC cell proliferation, migration and tube formation abilities in vitro as well as tumor growth in vivo through inhibition of hsa-miR-423-5p. And hsa-miR-423-5p mediated BC cellular functions and tumor growth through down-regulating PROX1. LINC00968 was identified as a competing endogenous RNA to upregulate PROX1 by downregulating hsa-miR-423-5p. More importantly, it was found that LINC00968 increased PROX1 expression in vivo in a concentration-dependent manner. Conclusion: Taken together, this study suggests that LINC00968 inhibits the progression of BC through impeding hsa-miR-423-5p-mediated PROX1 inhibition. LINC00968 may be a potential therapeutic target for BC therapy that warrants further studies.
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Affiliation(s)
- Xianfu Sun
- a Department of Breast Oncology, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , P.R. China
| | - Tao Huang
- a Department of Breast Oncology, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , P.R. China
| | - Chengjuan Zhang
- b Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , P.R. China
| | - Shengze Zhang
- a Department of Breast Oncology, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , P.R. China
| | - Yingjie Wang
- a Department of Breast Oncology, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , P.R. China
| | - Qiang Zhang
- a Department of Breast Oncology, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , P.R. China
| | - Zhenzhen Liu
- a Department of Breast Oncology, The Affiliated Cancer Hospital of Zhengzhou University , Zhengzhou , P.R. China
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Rudzińska M, Grzanka M, Stachurska A, Mikula M, Paczkowska K, Stępień T, Paziewska A, Ostrowski J, Czarnocka B. Molecular Signature of Prospero Homeobox 1 (PROX1) in Follicular Thyroid Carcinoma Cells. Int J Mol Sci 2019; 20:ijms20092212. [PMID: 31060342 PMCID: PMC6539481 DOI: 10.3390/ijms20092212] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 04/24/2019] [Accepted: 04/28/2019] [Indexed: 01/15/2023] Open
Abstract
The prospero homeobox 1 (PROX1) transcription factor is a product of one of the lymphangiogenesis master genes. It has also been suggested to play a role in carcinogenesis, although its precise role in tumour development and metastasis remains unclear. The aim of this study was to gain more knowledge on the PROX1 function in thyroid tumorigenesis. Follicular thyroid cancer-derived cells—CGTH-W-1—were transfected with PROX1-siRNA (small interfering RNA) and their proliferation, cell cycle, apoptosis and motility were then analysed. The transcriptional signature of PROX1 depletion was determined using RNA-Sequencing (RNA-Seq) and the expression of relevant genes was further validated using reverse transcriptase quantitative PCR (RT-qPCR), Western blot and immunocytochemistry. PROX1 depletion resulted in a decreased cell motility, with both migratory and invasive potential being significantly reduced. The cell morphology was also affected, while the other studied cancer-related cell characteristics were not significantly altered. RNA-seq analysis revealed significant changes in the expression of transcripts encoding genes involved in both motility and cytoskeleton organization. Our transcriptional analysis of PROX1-depleted follicular thyroid carcinoma cells followed by functional and phenotypical analyses provide, for the first time, evidence that PROX1 plays an important role in the metastasis of thyroid cancer cells by regulating genes involved in focal adhesion and cytoskeleton organization in tumour cells.
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Affiliation(s)
- Magdalena Rudzińska
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland.
| | - Małgorzata Grzanka
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland.
| | - Anna Stachurska
- Department of Immunohematology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland.
| | - Michał Mikula
- Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, 02-781 Warsaw, Poland.
| | - Katarzyna Paczkowska
- Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, 02-781 Warsaw, Poland.
| | - Tomasz Stępień
- Clinic of Endocrinological and General Surgery, Medical University of Lodz, 93-513 Lodz, Poland.
| | - Agnieszka Paziewska
- Department of Gastroenterology, Hepatology and Clinical Oncology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland.
| | - Jerzy Ostrowski
- Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, 02-781 Warsaw, Poland.
- Department of Gastroenterology, Hepatology and Clinical Oncology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland.
| | - Barbara Czarnocka
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland.
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Homeobox Genes and Hepatocellular Carcinoma. Cancers (Basel) 2019; 11:cancers11050621. [PMID: 31058850 PMCID: PMC6562709 DOI: 10.3390/cancers11050621] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 04/27/2019] [Accepted: 04/27/2019] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common type of cancer, and is the third leading cause of cancer-related deaths each year. It involves a multi-step progression and is strongly associated with chronic inflammation induced by the intake of environmental toxins and/or viral infections (i.e., hepatitis B and C viruses). Although several genetic dysregulations are considered to be involved in disease progression, the detailed regulatory mechanisms are not well defined. Homeobox genes that encode transcription factors with homeodomains control cell growth, differentiation, and morphogenesis in embryonic development. Recently, more aberrant expressions of Homeobox genes were found in a wide variety of human cancer, including HCC. In this review, we summarize the currently available evidence related to the role of Homeobox genes in the development of HCC. The objective is to determine the roles of this conserved transcription factor family and its potential use as a therapeutic target in future investigations.
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Zhao J, Gray SG, Greene CM, Lawless MW. Unmasking the pathological and therapeutic potential of histone deacetylases for liver cancer. Expert Rev Gastroenterol Hepatol 2019; 13:247-256. [PMID: 30791763 DOI: 10.1080/17474124.2019.1568870] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, currently ranking as one of the highest neoplastic-related mortalities in the world. Due to the difficulty in early diagnosis and lack of effective treatment options, the 5-year survival rate of HCC remains extremely low. Histone deacetylation is one of the most important epigenetic mechanisms, regulating cellular events such as differentiation, proliferation and cell cycle. Histone deacetylases (HDACs), the chief mediators of this epigenetic mechanism, are often aberrantly expressed in various tumours including HCC. Areas covered: This review focuses on the most up-to-date findings of HDACs and their associated molecular mechanisms in HCC onset and progression. In addition, a potential network between HDACs and non-coding RNAs including microRNAs and long noncoding RNAs underlying hepatocarcinogenesis is considered. Expert opinion: Unmasking the role of HDACs and their association with HCC pathogenesis could have implications for future personalized therapeutic and diagnostic targeting.
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Affiliation(s)
- Jun Zhao
- a Experimental Medicine, UCD School of Medicine and Medical Science , Mater Misericordiae University Hospital , Dublin , Ireland
| | - Steven G Gray
- b Department of Clinical Medicine , Trinity Centre for Health Sciences, Trinity Translational Medicine Institute, St. James's Hospital & Trinity College , Dublin , Ireland
| | - Catherine M Greene
- c Clinical Microbiology , Royal College of Surgeons in Ireland, Beaumont Hospital , Dublin , Ireland
| | - Matthew W Lawless
- a Experimental Medicine, UCD School of Medicine and Medical Science , Mater Misericordiae University Hospital , Dublin , Ireland
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Luo Y, Huang K, Zheng J, Zhang J, Zhang L. TGF-β1 promotes cell migration in hepatocellular carcinoma by suppressing reelin expression. Gene 2018; 688:19-25. [PMID: 30447345 DOI: 10.1016/j.gene.2018.11.033] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 11/01/2018] [Accepted: 11/13/2018] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is a leading cause of worldwide cancer mortality. Intrahepatic dissemination and extrahepatic metastasis are key factors in malignant growth of HCC. Reducing HCC-associated metastasis is critically dependent on uncovering molecular signaling pathways that promote HCC metastasis. In this study, we explored the effect of TGF-β1 and RELN on cell migration, and the relationship between TGF-β1 and RELN in HCC cells. The data presented that TGF-β1 and RELN showed an opposite expression pattern, and either increased expression of TGF-β1 or decreased expression of RELN increased HCC cell migration ability. We also found TGF-β1 enhanced cell migration ability was through repressing RELN expression, as overexpression of RELN impaired TGF-β1 enhanced cell migration. Our work revealed the relationship between TGF-β1 and RELN and uncovered the important role of RELN in suppressing cell migration in HCC cells.
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Affiliation(s)
- Yijiao Luo
- Department of Traditional Chinese and Western Medicine, Xianyang Caihong Hospital, Xianyang City, Shanxi Province 712021, PR China
| | - Kebin Huang
- Department of Clinical Laboratory, Chinese People's Liberation Army Third Hospital, Baoji City, Shanxi Province 721004, PR China
| | - Jianyuan Zheng
- Department of Clinical Laboratory, The First Affiliated Hospital of Xi 'an Medical College, Xian City, Shanxi Province 710021, PR China
| | - Jiming Zhang
- Department of Traditional Chinese and Western Medicine, Xianyang Caihong Hospital, Xianyang City, Shanxi Province 712021, PR China.
| | - Lixia Zhang
- Department of Clinical Laboratory, Shaanxi People's Hospital, Xian City, Shanxi Province 710068, PR China.
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36
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He B, Dai L, Zhang X, Chen D, Wu J, Feng X, Zhang Y, Xie H, Zhou L, Wu J, Zheng S. The HDAC Inhibitor Quisinostat (JNJ-26481585) Supresses Hepatocellular Carcinoma alone and Synergistically in Combination with Sorafenib by G0/G1 phase arrest and Apoptosis induction. Int J Biol Sci 2018; 14:1845-1858. [PMID: 30443188 PMCID: PMC6231215 DOI: 10.7150/ijbs.27661] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 08/30/2018] [Indexed: 02/07/2023] Open
Abstract
The high activity of Histone deacetylases (HDACs) in hepatocellular carcinoma (HCC) usually positively correlates with poor prognosis of patients. Accordingly histone deacetylases inhibitors (HDACis) are considered to be potential agents treating patients with HCC. In our study, we evaluated effect of quisinostat alone and in combination with sorafenib in HCC cells via inducing G0/G1 phase arrest through PI3K/AKT/p21 pathway and apoptosis by JNK/c-Jun/caspase3 pathway in vitro and in vivo. The proliferation assay and flow cytometry were used to measure the viability, cell cycle and apoptosis. And Western blot assay was carried out to determine expression alternations of related proteins. Moreover HCCLM3 xenograft was further performed to detect antitumor effect of quisinostat in vivo. Here, we found that quisinostat impeded cell proliferation, and remarkably induced G0/G1 phase arrest and apoptosis in HCC cells in a dose-dependent manner. G0/G1 phase arrest was observed by alterations in PI3K/AKT/p21 proteins. Meanwhile the JNK, c-jun and caspase-3 were activated by quisinostat in a dose-dependent manner. Correspondingly quisinostat facilitated G0/G1 cycle arrest and apoptosis in HCC cells through PI3K/AKT/p21 pathways and JNK/c- jun/caspase3 pathways. Moreover, the potent tumor-suppressive effects facilitated by quisinostat, was significantly potentiated by combination with sorafenib in vitro and vivo. The combination treatment of quisinostat and sorafenib markedly suppressed cell proliferation and induced apoptosis in a synergistic manner. Moreover the therapy of quisinostat combined with sorafenib could apparently decrease tumor volume of a HCCLM3 xenograft model. Our study indicated that quisinostat, as a novel chemotherapy for HCC, exhibited excellent antitumor activity in vitro and vivo, which was even enhanced by the addition of sorafenib, implying combination of quisinostat with sorafenib a promising and alternative therapy for patients with advanced hepatocellular carcinoma.
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Affiliation(s)
- Bin He
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University
- NHFPC Key Laboratory of Combined Multi-organ Transplantation
- Key Laboratory of the diagnosis and treatment of organ Transplantation, CAMS
- Key Laboratory of Organ Transplantation, Zhejiang Province
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Longfei Dai
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University
- NHFPC Key Laboratory of Combined Multi-organ Transplantation
- Key Laboratory of the diagnosis and treatment of organ Transplantation, CAMS
- Key Laboratory of Organ Transplantation, Zhejiang Province
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Xiaoqian Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Diyu Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University
- NHFPC Key Laboratory of Combined Multi-organ Transplantation
- Key Laboratory of the diagnosis and treatment of organ Transplantation, CAMS
- Key Laboratory of Organ Transplantation, Zhejiang Province
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Jingbang Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University
- NHFPC Key Laboratory of Combined Multi-organ Transplantation
- Key Laboratory of the diagnosis and treatment of organ Transplantation, CAMS
- Key Laboratory of Organ Transplantation, Zhejiang Province
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Xiaode Feng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University
- NHFPC Key Laboratory of Combined Multi-organ Transplantation
- Key Laboratory of the diagnosis and treatment of organ Transplantation, CAMS
- Key Laboratory of Organ Transplantation, Zhejiang Province
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Yanpeng Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University
- NHFPC Key Laboratory of Combined Multi-organ Transplantation
- Key Laboratory of the diagnosis and treatment of organ Transplantation, CAMS
- Key Laboratory of Organ Transplantation, Zhejiang Province
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Haiyang Xie
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University
- NHFPC Key Laboratory of Combined Multi-organ Transplantation
- Key Laboratory of the diagnosis and treatment of organ Transplantation, CAMS
- Key Laboratory of Organ Transplantation, Zhejiang Province
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University
- NHFPC Key Laboratory of Combined Multi-organ Transplantation
- Key Laboratory of the diagnosis and treatment of organ Transplantation, CAMS
- Key Laboratory of Organ Transplantation, Zhejiang Province
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Jian Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University
- NHFPC Key Laboratory of Combined Multi-organ Transplantation
- Key Laboratory of the diagnosis and treatment of organ Transplantation, CAMS
- Key Laboratory of Organ Transplantation, Zhejiang Province
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University
- NHFPC Key Laboratory of Combined Multi-organ Transplantation
- Key Laboratory of the diagnosis and treatment of organ Transplantation, CAMS
- Key Laboratory of Organ Transplantation, Zhejiang Province
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
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Kim YJ, Yoo JE, Jeon Y, Chong JU, Choi GH, Song DG, Jung SH, Oh BK, Park YN. Suppression of PROX1-mediated TERT expression in hepatitis B viral hepatocellular carcinoma. Int J Cancer 2018; 143:3155-3168. [DOI: 10.1002/ijc.31731] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2017] [Revised: 05/22/2018] [Accepted: 06/14/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Young-Joo Kim
- Natural Products Research Center; Korea Institute of Science and Technology; Gangneung South Korea
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science; Yonsei University College of Medicine; Seoul South Korea
| | - Jeong Eun Yoo
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science; Yonsei University College of Medicine; Seoul South Korea
| | - Youngsic Jeon
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science; Yonsei University College of Medicine; Seoul South Korea
| | - Jae Uk Chong
- Department of Surgery; Yonsei University College of Medicine; Seoul South Korea
| | - Gi Hong Choi
- Department of Surgery; Yonsei University College of Medicine; Seoul South Korea
| | - Dae-Geun Song
- Systems Biotechnology Research Center; Korea Institute of Science and Technology; Gangneung South Korea
| | - Sang Hoon Jung
- Natural Products Research Center; Korea Institute of Science and Technology; Gangneung South Korea
| | - Bong-Kyeong Oh
- Institute of Medical Science, Hanyang University College of Medicine; Seoul South Korea
| | - Young Nyun Park
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science; Yonsei University College of Medicine; Seoul South Korea
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Fei M, Guan J, Xue T, Qin L, Tang C, Cui G, Wang Y, Gong H, Feng W. Hypoxia promotes the migration and invasion of human hepatocarcinoma cells through the HIF-1α-IL-8-Akt axis. Cell Mol Biol Lett 2018; 23:46. [PMID: 30258464 PMCID: PMC6149064 DOI: 10.1186/s11658-018-0100-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Accepted: 07/13/2018] [Indexed: 12/15/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide. The 5-year survival rate remains low despite considerable research into treatments of HCC, including surgery, radiotherapy and chemotherapy. Many mechanisms within HCC still require investigation, including the influence of hypoxia, which has a crucial role in many cancers and is associated with metastasis. Hypoxia inducible factor-1α (HIF-1α) is known to regulate the expression of many chemokines, including interleukin-8 (IL-8), which is associated with tumor metastasis. Although many studies have reported that HIF-1α is associated with HCC migration and invasion, the underlying mechanisms remain unknown. Methods The expression level of HIF-1α was determined in HCC cells. The correlation of IL-8 and HIF-1α expressions was assessed via knockdown of HIF-1α. HCC cells were also used to assess the influence of HIF-1α on HCC cell migration and invasion. LY294002, an inhibitor of the Akt pathway, was used to confirm the associated signaling pathways. Results We observed a significant attenuation of cell migration and invasion after silencing of HIF-1α. Exogenously expressing IL-8 restored migration and invasion. Akt was found to be involved in this process. Conclusion Hypoxia promotes HCC cell migration and invasion through the HIF-1α–IL-8–Akt axis.
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Affiliation(s)
- Maoyun Fei
- Department of General Surgery, The First People's Hospital of Huzhou, No.158 Guangchanghou Road, Zhejiang Province 313000 Huzhou, People's Republic of China
| | - Jianming Guan
- Department of Ultrasound, The First People's Hospital of Huzhou, No.158 Guangchanghou Road, Zhejiang Province 313000 Huzhou, People's Republic of China
| | - Tao Xue
- Central Laboratory, The First People's Hospital of Huzhou, No.158 Guangchanghou Road, Zhejiang Province 313000 Huzhou, People's Republic of China
| | - Lianjin Qin
- Department of General Surgery, The First People's Hospital of Huzhou, No.158 Guangchanghou Road, Zhejiang Province 313000 Huzhou, People's Republic of China
| | - Chengwu Tang
- Department of Hepatobiliary Pancreatic Surgery, The First People's Hospital of Huzhou, No.158 Guangchanghou Road, Zhejiang Province 313000 Huzhou, People's Republic of China
| | - Ge Cui
- Department of General Surgery, The First People's Hospital of Huzhou, No.158 Guangchanghou Road, Zhejiang Province 313000 Huzhou, People's Republic of China
| | - Yao Wang
- Department of General Surgery, The First People's Hospital of Huzhou, No.158 Guangchanghou Road, Zhejiang Province 313000 Huzhou, People's Republic of China
| | - Hui Gong
- Central Laboratory, The First People's Hospital of Huzhou, No.158 Guangchanghou Road, Zhejiang Province 313000 Huzhou, People's Republic of China
| | - Wenming Feng
- Department of Hepatobiliary Pancreatic Surgery, The First People's Hospital of Huzhou, No.158 Guangchanghou Road, Zhejiang Province 313000 Huzhou, People's Republic of China
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HIF-1α promotes the migration and invasion of hepatocellular carcinoma cells via the IL-8-NF-κB axis. Cell Mol Biol Lett 2018; 23:26. [PMID: 29881400 PMCID: PMC5984319 DOI: 10.1186/s11658-018-0077-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 03/05/2018] [Indexed: 02/06/2023] Open
Abstract
Background Hypoxia plays a critical role in many cancers. Hypoxia inducible factor-1α (HIF-1α) is an important mediator of the hypoxia response. It regulates the expression of various chemokines involved in tumor growth, angiogenesis and metastasis but the associated pathway needs further investigation. Methods The expression level of HIF-1α was determined in hepatocellular carcinoma (HCC) cells. The correlation of interleukin-8 (IL-8) and HIF-1α was assessed by knocking down HIF-1α. These cells were also used to assess its influence on HCC cell migration and invasion was checked. Pyrrolidinedithiocarbamate (PDTC), an inhibitor of NF-κB, was used to confirm the associated signaling pathway. Results HIF-1α was significantly expressed in HCC cells and found to promote HCC cell migration and invasion in an IL-8-dependent manner. NF-κB was confirmed to be involved in the process. Conclusions HIF-1α promotes HCC cell migration and invasion by modulating IL-8 via the NF-κB pathway.
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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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Shimagaki T, Yoshizumi T, Harimoto N, Yoshio S, Naito Y, Yamamoto Y, Ochiya T, Yoshida Y, Kanto T, Maehara Y. MicroRNA-125b expression and intrahepatic metastasis are predictors for early recurrence after hepatocellular carcinoma resection. Hepatol Res 2018; 48:313-321. [PMID: 28984009 DOI: 10.1111/hepr.12990] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 09/24/2017] [Accepted: 09/30/2017] [Indexed: 12/11/2022]
Abstract
AIM Early hepatocellular carcinoma (HCC) recurrence after curative resection is a known poor prognostic factor. We aimed to identify microRNAs associated with recurrence after curative HCC resection. METHODS To identify risk factors for early recurrence and metastasis, 694 patients who underwent primary curative HCC resection were analyzed. We evaluated microRNA expression in cancerous and non-cancerous tissues by microarray and quantitative PCR analyses using 16 HCC samples. We defined patients who had a recurrence within 1 year of resection as the early recurrence (ER) group, patients who had a recurrence within 1-5 years as the late recurrence (LR) group, and patients who did not recur during the 5-year observation period as the no recurrence (NR) group. We examined the relationship between microRNA expression and clinical features. RESULTS Multivariate analysis revealed that α-fetoprotein >31 ng/mL, tumor size >4 cm, and intrahepatic metastasis (IM) were significant factors. Afterwards, microarray analyses revealed that microRNA (miR)-125b-5p and miR-148a-3p were significantly downregulated in recurrent cases. The ratio of miR-125b-5p expression in cancerous versus non-cancerous tissue (miR-125b ratio), but not miR-148a-3p, was significantly lower in the ER group. Early recurrence was associated with reduced overall survival compared with the LR and NR group. The miR-125b ratio was significantly lower in the ER group than in the LR and NR groups. Multivariate analysis showed that a low miR-125b ratio and IM were independently associated with ER and disease-free survival. CONCLUSIONS Assessing tissue miR-125b-5p expression and IM is useful for stratifying patients at risk of early HCC recurrence after curative resection.
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Affiliation(s)
- Tomonari Shimagaki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Norifumi Harimoto
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Sachiyo Yoshio
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Yutaka Naito
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
| | - Yusuke Yamamoto
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
| | - Yoshihiro Yoshida
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tatsuya Kanto
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Wang L, Sun H, Wang X, Hou N, Zhao L, Tong D, He K, Yang Y, Song T, Yang J, Huang C. EGR1 mediates miR-203a suppress the hepatocellular carcinoma cells progression by targeting HOXD3 through EGFR signaling pathway. Oncotarget 2018; 7:45302-45316. [PMID: 27244890 PMCID: PMC5216724 DOI: 10.18632/oncotarget.9605] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 04/26/2016] [Indexed: 12/21/2022] Open
Abstract
EGR1 plays a critical role in cancer progression. However, its precise role in hepatocellular carcinoma has not been elucidated. In this study, we found that the overexpression of EGR1 suppresses hepatocellular carcinoma cell proliferation and increases cell apoptosis by binding to the miR-203a promoter sequence. In addition, we investigated the function of miR-203a on progression of HCC cells. We verified that the effect of overexpression of miR-203a is consistent with that of EGR1 in regulation of cell progression. Through bioinformatic analysis and luciferase assays, we confirmed that miR-203a targets HOXD3. Silencing HOXD3 could block transition of the G2/M phase, increase cell apoptosis, decrease the expression of cell cycle and apoptosis-related proteins, EGFR, p-AKT, p-ERK, CCNB1, CDK1 and Bcl2 by targeting EGFR through EGFR/AKT and ERK cell signaling pathways. Likewise, restoration of HOXD3 counteracted the effects of miR-203a expression.In conclusion, our findings are the first to demonstrate that EGR1 is a key player in the transcriptional control of miR-203a, and that miR-203a acts as an anti-oncogene to suppress HCC tumorigenesis by targeting HOXD3 through EGFR-related cell signaling pathways.
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Affiliation(s)
- Lumin Wang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P.R. China
| | - Hongfei Sun
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P.R. China
| | - Xiaofei Wang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P.R. China
| | - Ni Hou
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P.R. China
| | - Lingyu Zhao
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P.R. China
| | - Dongdong Tong
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P.R. China
| | - Kang He
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P.R. China
| | - Yang Yang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P.R. China
| | - Tusheng Song
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P.R. China
| | - Jun Yang
- Department of Pathology, Second Affiliated Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, P.R. China
| | - Chen Huang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P.R. China.,Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P.R. China.,Cardiovascular Research Center, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P.R. China
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Chang RM, Pei L, Fang F, Xu JF, Yang H, Zuo CH, Zhou JH, Luo GQ, Yang LY. YMO1 suppresses invasion and metastasis by inhibiting RhoC signaling and predicts favorable prognosis in hepatocellular carcinoma. Oncotarget 2018; 7:55585-55600. [PMID: 27487132 PMCID: PMC5342438 DOI: 10.18632/oncotarget.10866] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2015] [Accepted: 06/29/2016] [Indexed: 12/22/2022] Open
Abstract
Previous studies have shown that 4.1 proteins, which are deregulated in many cancers, contribute to cell adhesion and motility. Yurt/Mosaic eyes-like 1 (YMO1) is a member of 4.1 protein family but it is unclear whether YMO1 plays a role in tumor invasion. This study aimed to investigate the effects of YMO1 on hepatocellular carcinoma (HCC) and attempted to elucidate the underlying molecular mechanisms. YMO1 expression in HCC tissues and its correlation with clinicopathological features and postoperative prognosis was analyzed. The results showed that YMO1 was down-regulated in the highly metastatic HCC cell line and in human tumor tissues. Underexpression of YMO1 indicated poor prognosis of HCC patients. Restoration of YMO1 expression caused a significant decrease in cell migration and invasiveness in vitro. In vivo study showed that YMO1 reduced liver tumor invasion and metastasis in xenograft mice. YMO1 directly inhibited RhoC activation. YMO1 expression in HCC was regulated by PAX5. Analysis of YMO1 expression levels in human HCC patients revealed a significant correlation of YMO1 expression with PAX5 and RhoC. Our findings revealed that YMO1 predicts favorable prognosis and the data suggest that YMO1 suppresses tumor invasion and metastasis by inhibiting RhoC activity.
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Affiliation(s)
- Rui-Min Chang
- Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Lei Pei
- Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Feng Fang
- Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Jiang-Feng Xu
- Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Hao Yang
- Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Chao-Hui Zuo
- Department of Abdominal Surgical Oncology, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Jian-Hua Zhou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Geng-Qiu Luo
- Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Lian-Yue Yang
- Liver Cancer Laboratory, Xiangya Hospital, Central South University, Changsha 410008, China.,Department of Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
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Bufalin suppresses hepatocellular carcinoma invasion and metastasis by targeting HIF-1α via the PI3K/AKT/mTOR pathway. Oncotarget 2018; 7:20193-208. [PMID: 26958938 PMCID: PMC4991447 DOI: 10.18632/oncotarget.7935] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Accepted: 01/06/2016] [Indexed: 01/21/2023] Open
Abstract
It has been reported that there are multiple mechanisms by which bufalin could exert its antimetastatic effect. HIF-1α has been reported to be involved in tumor migration and invasion by regulating EMT. However, it is not known whether bufalin could exert the antimetastatic effect by modulating HIF-1α expression in hepatocellular carcinoma. In the present study, we aimed to evaluate the antimetastatic potential of bufalin in vivo and in vitro. Our results demonstrated that the liver/lung metastases were significantly reduced in bufalin-treated mice, as tested in the orthotopic transplanted and tail vein injection tumor models. Furthermore, the epithelial-to-mesenchymal transition (EMT) was inhibited in bufalin-treated tumors, as reflected the upregulation of E-cadherin, and downregulation of N-cadherin, vimentin, Snail. Similar results were observed in SMMC7721 cells treated with bufalin. Moreover, the transforming growth factor-β1 (TGF-β1)-induced EMT was also abrogated by bufalin. Mechanistically, our study demonstrated that hypoxia-inducible factor-1α (HIF-1α) played an important role in the antimetastatic effect of bufalin in hepatocellular carcinoma. Importantly, HIF-1α expression may be regulated through the inhibition of the PI3K/AKT/mTOR pathway. Taken together, our results suggest that bufalin suppresses hepatic tumor invasion and metastasis and that this process may be related to the PI3K/AKT/mTOR/ HIF-1α axis.
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Han SY, Han HB, Tian XY, Sun H, Xue D, Zhao C, Jiang ST, He XR, Zheng WX, Wang J, Pang LN, Li XH, Li PP. MicroRNA-33a-3p suppresses cell migration and invasion by directly targeting PBX3 in human hepatocellular carcinoma. Oncotarget 2018; 7:42461-42473. [PMID: 27285759 PMCID: PMC5173148 DOI: 10.18632/oncotarget.9886] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 05/23/2016] [Indexed: 01/16/2023] Open
Abstract
MicroRNAs (miRNAs) have been shown to function as either oncogenes or tumor suppressors by negatively regulating target genes involved in tumor initiation and progression. In this study, we demonstrated that down-regulation of miR-33a-3p in human primary hepatocellular cancer (HCC) specimens was significantly associated with metastases and poor survival. Over-expression of miR-33a-3p in HepG2 cells remarkably suppressed not only cell growth, migration and invasion, but also tumor growth and metastases in the chick embryo chorioallantoic membrane (CAM) assay, and down-regulated Pre-B-Cell Leukemia Homeobox 3 (PBX3) expression. Conversely, inhibition of miR-33a-3p in Bel-7402 cells resulted in increased of cell growth, spreading and invasion. Furthermore, rescue experiments by over-expression PBX3 completely eliminated the inhibitory effects of miR-33a-3p on tumor growth and metastasis, both in vitro and in vivo. The luciferase assay showed that 3′-untranslated regions (3′-UTRs) of PBX3 were inhibited significantly by miR-33a-3p, while mutations in the miR-33a-3p pairing residues rescued the luciferase expression. Taken together, our findings suggest that miR-33a-3p suppressed the malignant phenotype while also inhibiting PBX3 expression in hepatocellular cancer, implying that miR-33a-3p may be a promising biomarkers and therapy target for HCC intervention.
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Affiliation(s)
- Shu-Yan Han
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China.,Department of Integrative Medicine and Geriatric Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, PR China
| | - Hai-Bo Han
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China.,Department of Biobank, Peking University Cancer Hospital & Institute, Beijing 100142, PR China
| | - Xiu-Yun Tian
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China.,Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, PR China
| | - Hong Sun
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China.,Department of Integrative Medicine and Geriatric Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, PR China
| | - Dong Xue
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China.,Department of Integrative Medicine and Geriatric Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, PR China
| | - Can Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China.,Department of Integrative Medicine and Geriatric Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, PR China
| | - Shan-Tong Jiang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China.,Department of Integrative Medicine and Geriatric Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, PR China
| | - Xi-Ran He
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China.,Department of Integrative Medicine and Geriatric Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, PR China
| | - Wen-Xian Zheng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China.,Department of Integrative Medicine and Geriatric Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, PR China
| | - Jing Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China.,Department of Integrative Medicine and Geriatric Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, PR China
| | - Li-Na Pang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China.,Department of Integrative Medicine and Geriatric Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, PR China
| | - Xiao-Hong Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China.,Department of Integrative Medicine and Geriatric Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, PR China
| | - Ping-Ping Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, PR China.,Department of Integrative Medicine and Geriatric Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, PR China
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Gao T, Ma C, Li Y, Ju J, Kang X, Cai Y, Sun M. High Expression of Prospero-Related Homeobox-1 (PROX1) Is Associated With Poor Prognosis in Patients With Salivary Adenoid Cystic Carcinoma. J Oral Maxillofac Surg 2018; 76:1440-1446. [PMID: 29406257 DOI: 10.1016/j.joms.2017.12.032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 12/28/2017] [Accepted: 12/30/2017] [Indexed: 12/12/2022]
Abstract
PURPOSE Prospero-related homeobox-1 (PROX1) plays an important role in the invasion and metastasis of many human cancers. However, the expression pattern of PROX1 in salivary adenoid cystic carcinoma (SACC) remains unclear. The aim of this study was to investigate PROX1 expression and its prognostic value in SACC. MATERIALS AND METHODS PROX1 expression was determined by immunohistochemistry (IHC) in SACC tissue specimens. Correlations between PROX1 expression and clinicopathologic features were investigated. The Kaplan-Meier method was used to analyze the correlation between PROX1 expression and survival. Independent prognostic factors associated with overall survival (OS) were analyzed using Cox regression analysis. RESULTS The IHC data showed that the PROX1 positivity rate in SACC tissue specimens was significantly higher than that in normal salivary gland tissues (71.1 vs 13.3%; P < .05). PROX1 expression was detected mainly in the nucleolus. In addition, PROX1 expression was correlated with perineural invasion, local regional recurrence, and distant metastasis of patients with SACC (P < .05), and no significant association was found between PROX1 expression and other clinicopathologic parameters. Data indicated that patients with positive PROX1 expression had poor OS compared with those with negative PROX1 expression (P = .0005). Multivariate analysis showed that PROX1 expression, local regional recurrence, and distant metastasis were independent prognostic factors for OS. CONCLUSIONS These findings showed that PROX1 expression was statistically higher in SACC specimens. Positive expression of PROX1 might serve as a potential predictor of prognosis in SACC.
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Affiliation(s)
- Tao Gao
- Attending Physician, State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases; Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University; Department of Oral and Maxillofacial Surgery, The First Hospital of Yulin, Stomatological Hospital of Yulin, Shaanxi, China
| | - Chao Ma
- Resident, State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases; Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Yun Li
- Resident, State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases; Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Jun Ju
- Resident, State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Xi'an; Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an; Department of Otolaryngology Head and Neck Surgery, Navy General Hospital, Beijing, China
| | - Xiangfeng Kang
- Resident, Department of Pediatrics, The First Hospital of Yulin, Shaanxi, China
| | - Yuanlin Cai
- Resident, Department of Emergency Medicine, The First Hospital of Yulin, Shaanxi, China
| | - Moyi Sun
- Professor, State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases; Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, China.
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The role of prospero homeobox 1 (PROX1) expression in follicular thyroid carcinoma cells. Oncotarget 2017; 8:114136-114155. [PMID: 29371975 PMCID: PMC5768392 DOI: 10.18632/oncotarget.23167] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 11/29/2017] [Indexed: 12/17/2022] Open
Abstract
The prospero homeobox 1 (Prox1) transcription factor is a key player during embryogenesis and lymphangiogenesis. Altered Prox1 expression has been found in a variety of human cancers, including papillary thyroid carcinoma (PTC). Interestingly, Prox1 may exert tumor suppressive or tumor promoting effect, depending on the tissue context. In this study, we have analyzed Prox1 expression in normal and malignant human thyroid carcinoma cell lines. Moreover, we determined the effect of Prox1 silencing and overexpression on the cellular processes associated with the metastatic potential of tumor cells: proliferation, migration, invasion, apoptosis and anchorage-independent growth, in the follicular thyroid carcinoma (FTC) FTC-133 cell line. We found that Prox1 expression was significantly higher in FTC-derived cells than in PTC-derived cells and normal thyroid, and it was associated with the PI3K/Akt signaling pathway. In the FTC-133 cells, it was associated with cell invasive potential, motility and wound closure capacities, but not with proliferation or apoptosis. Modifying Prox1 expression also induced substantial changes in the cytoskeleton structure and cell morphology. In conclusion, we have shown that Prox1 plays an important role in the development of FTC and that its suppression prevents, whereas its overexpression promotes, the malignant behavior of thyroid follicular cancer cells.
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Liu Y, Zhang Y, Wang S, Dong QZ, Shen Z, Wang W, Tao S, Gu C, Liu J, Xie Y, Qin LX. Prospero-related homeobox 1 drives angiogenesis of hepatocellular carcinoma through selectively activating interleukin-8 expression. Hepatology 2017; 66:1894-1909. [PMID: 28646551 DOI: 10.1002/hep.29337] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 05/23/2017] [Accepted: 06/21/2017] [Indexed: 12/12/2022]
Abstract
UNLABELLED Angiogenesis has been proven to play an important role in the progression of hepatocellular carcinoma (HCC). However, the molecular mechanism underlying HCC angiogenesis is not well understood. In this study, Prospero-related homeobox 1 (PROX1) was identified as a novel proangiogenic factor in HCC cell lines and tissues. A strong positive correlation was found between the levels of PROX1 and microvessel density in HCC tissues. Knockdown of PROX1 expression in HCC cells significantly inhibited the in vitro capillary tube formation by human vascular endothelial cells and in vivo angiogenesis of HCC, while overexpression of PROX1 in HCC cells induced the opposite effects. PROX1 and nuclear factor κB p65 expression levels were positively correlated in both HCC tissues and cell lines. PROX1 enhances the nuclear accumulation of p65 and stabilizes p65 by recruiting ubiquitin-specific protease 7 to prevent p65 ubiquitination. Consequently, PROX1 activated nuclear factor κB signaling and selectively promoted expression of the proangiogenic interleukin-8 (IL-8) by epigenetically stimulating the IL-8 promoter. Finally, progression of high PROX1 expression HCC in tumor xenograft mice could be effectively contained by an anti-IL-8 monoclonal antibody. CONCLUSIONS We have identified PROX1 as a crucial promoter of HCC angiogenesis; our study provides an insight into PROX1's function in HCC progression and the potential therapeutic application of anti-IL-8 antibody in high PROX1 expression HCC patients. (Hepatology 2017;66:1894-1909).
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Affiliation(s)
- Yanfeng Liu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
- Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yonglong Zhang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shenghao Wang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Qiong-Zhu Dong
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
- Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhongliang Shen
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Wei Wang
- Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shuai Tao
- Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Chenjian Gu
- Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jing Liu
- Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Youhua Xie
- Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
- Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
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49
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ABCB5 promotes melanoma metastasis through enhancing NF-κB p65 protein stability. Biochem Biophys Res Commun 2017; 492:18-26. [PMID: 28821433 DOI: 10.1016/j.bbrc.2017.08.052] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 08/14/2017] [Indexed: 12/12/2022]
Abstract
Melanoma is the most aggressive type of skin cancer. Melanoma has an extremely poor prognosis because of its high potential for vascular invasion, metastasis and recurrence. The mechanism of melanoma metastasis is not well understood. ATP-binding cassette sub-family B member 5 (ABCB5) plays a key role in melanoma growth. However, it is uncertain what function ABCB5 may exert in melanoma metastasis. In this report, we for the first time demonstrate ABCB5 as a crucial factor that promotes melanoma metastasis. ABCB5 positive (ABCB5+) malignant melanoma initiating cells (MMICs) display a higher metastatic potential compared with ABCB5 negative (ABCB5-) melanoma subpopulation. Knockdown of ABCB5 expression reduces melanoma cell migration and invasion in vitro and melanoma pulmonary metastasis in tumor xenograft mice. ABCB5 and NF-κB p65 expression levels are positively correlated in both melanoma tissues and cell lines. Consequently, ABCB5 activates the NF-κB pathway by inhibiting p65 ubiquitination to enhance p65 protein stability. Our finding highlights ABCB5 as a novel pro-metastasis factor and provides a potential therapeutic target for melanoma.
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50
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Xiong L, Zhen S, Yu Q, Gong Z. HCV-E2 inhibits hepatocellular carcinoma metastasis by stimulating mast cells to secrete exosomal shuttle microRNAs. Oncol Lett 2017; 14:2141-2146. [PMID: 28781655 PMCID: PMC5530191 DOI: 10.3892/ol.2017.6433] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 06/02/2017] [Indexed: 12/29/2022] Open
Abstract
Exosomal miRNAs are emerging as mediators of the interaction between mast cells (MCs) and tumor cells. The exosomal miRNAs can be internalized by liver cancer cells to inhibit cell metastasis. We explored the interaction between MCs and hepatocellular carcinoma (HCC) cells. We used hepatitis C virus E2 envelope glycoprotein (HCV-E2) to stimulate MCs and harvest MCs-derived exosomes to detect the miRNAs and changes of exosomal miRNAs before and after stimulation. Through miRNA microarray analysis, we identified 19 differentially expressed miRNAs in exosomes derived from MCs with or without HCV-E2 treatment. HCV-E2 not only increased the level of miRNA-490 in MCs and their secreted exosomes but also increased the levels of miRNA-490 in recipient HepG2 cells, which ultimately inhibited the ERK1/2 pathway. The transfection of antagomiR-490 significantly decreased the levels of miR-490 in MCs, MCs-derived exosomes, and recipient HepG2 cells and increased migration of HepG2, indicating that miR-490 is involved in the regulation of HepG2 cell migration. The present study suggests that MCs can inhibit HCC cell metastasis by inhibiting the ERK1/2 pathway by transferring the exosomal shuttle microRNAs into HCC cells, which provides new insights for the biological therapy of HCC induced by hepatitis C.
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Affiliation(s)
- Li Xiong
- Department of Infectious Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Shuqing Zhen
- Department of Rheumatology, Hubei Xianning Ma Tang Rheumatism Hospital, Xianning, Hubei 437000, P.R. China
| | - Qionghua Yu
- Department of Infectious Disease, Clinical Medical College, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China
| | - Zuojiong Gong
- Department of Infectious Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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