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Luo Z, Wang Y, Zeng S, Yu L, Zhao Y, Wang H, Fan Y, Zhang Y, Wang L, Li Y, Niu Z, Zhang X, Zhang Y. Harnessing lysosomal genetics: development of a risk stratification panel and unveiling of DPP7 as a biomarker for colon adenocarcinoma. J Genet Genomics 2025:S1673-8527(25)00118-3. [PMID: 40254156 DOI: 10.1016/j.jgg.2025.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 04/08/2025] [Accepted: 04/12/2025] [Indexed: 04/22/2025]
Abstract
Lysosomal dysfunction has been implicated in the progression of colon adenocarcinoma (COAD), yet the prognostic significance and therapeutic potential of lysosome-related genes (LRGs) remain underexplored. In this study, we construct a 6-LRG-based prognostic risk stratification model (DPP7, ADAM8, CD1B, LRP2, ATP6V1C2, and PLAAT3) by integrating LASSO and Cox regression analyses. Stratifying patients based on median risk scores, we demonstrate that high-risk patients exhibit significantly worse clinical outcomes across the TCGA cohort and five independent GEO datasets. Furthermore, this panel outperforms 136 previously published models in terms of predictive accuracy for 1-, 3-, and 5-year survival rates. Validation multiplex immunofluorescence using an in-house tissue microarray cohort confirms the 6-LRG signature serves as an independent prognostic factor. Additionally, high-risk patients exhibit distinct immunosuppressive tumor microenvironment and aggressive malignancy characteristics. Functional depletion of DPP7 significantly inhibits tumor cell proliferation, migration, and metastasis in both in vitro and in vivo settings. Moreover, DPP7 silencing attenuates epithelial-mesenchymal transition, as evidenced by the upregulation of E-cadherin and downregulation of N-cadherin, Vimentin, and Snail. In conclusion, this study establishes an LRG-based model for COAD prognostic prediction and nominates DPP7 as a promising therapeutic target for COAD treatment.
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Affiliation(s)
- Zhengdong Luo
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, Shandong 250012, China
| | - Yanlei Wang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
| | - Shunjie Zeng
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, Shandong 250012, China
| | - Longchen Yu
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, Shandong 250012, China
| | - Yuxiao Zhao
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, Shandong 250012, China
| | - Hong Wang
- Department of Anesthesiology, Yidu Central Hospital, Weifang Medical University, Qingzhou, Shandong 262500, China
| | - Yingjing Fan
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, Shandong 250012, China
| | - Yanli Zhang
- Department of Clinical Laboratory, Shandong Provincial Third Hospital, Jinan, Shandong 250000, China
| | - Lili Wang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, Shandong 250012, China
| | - Yaping Li
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, Shandong 250012, China
| | - Zhongfang Niu
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, Shandong 250012, China
| | - Xin Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, Shandong 250012, China.
| | - Yi Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, Shandong 250012, China.
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Ivanova T, Sbirkov Y, Kazakova M, Sarafian V. Lysosomes and LAMPs as Autophagy Drivers of Drug Resistance in Colorectal Cancer. Cells 2025; 14:574. [PMID: 40277899 PMCID: PMC12025563 DOI: 10.3390/cells14080574] [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: 02/16/2025] [Revised: 04/04/2025] [Accepted: 04/08/2025] [Indexed: 04/26/2025] Open
Abstract
Colorectal cancer (CRC) is among the most malignant pathologies worldwide. A major factor contributing to the poor prognosis of neoplastic diseases is the development of drug resistance. It significantly reduces the utility of most therapeutic protocols and necessitates the search for novel biomarkers and treatment strategies to combat cancer. An evolutionarily conserved catabolic mechanism, autophagy maintains nutrient recycling and metabolic adaptation and is also closely related to carcinogenesis, playing a dual role. Autophagy inhibition can limit the growth of tumors and improve the response to cancer therapeutics. Lysosomes, key players in autophagy, are also considered promising targets for anticancer treatment. There are still insufficient data on the role of poorly studied glycoproteins related to autophagy, such as the lysosome-associated membrane glycoproteins (LAMPs). They can act as multifunctional molecules involved in a multitude of processes like autophagy and cancer development. In the current review, we summarize the recent data on the double-faceted role of autophagy in cancer with a focus on drug resistance in CRC and on the roles of lysosomes and LAMPs in these interconnected processes. Several lysosomotropic drugs are discussed as options to overcome cancer cell chemoresistance. The complex networks that underline defined autophagic pathways in the context of CRC carcinogenesis and the role of autophagy, especially of LAMPs as drivers of drug resistance, are outlined.
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Affiliation(s)
- Tsvetomira Ivanova
- Department of Medical Biology, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria; (Y.S.); (M.K.)
- Research Division of Molecular and Regenerative Medicine, Research Institute at Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
| | - Yordan Sbirkov
- Department of Medical Biology, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria; (Y.S.); (M.K.)
- Research Division of Molecular and Regenerative Medicine, Research Institute at Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
| | - Maria Kazakova
- Department of Medical Biology, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria; (Y.S.); (M.K.)
- Research Division of Molecular and Regenerative Medicine, Research Institute at Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
| | - Victoria Sarafian
- Department of Medical Biology, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria; (Y.S.); (M.K.)
- Research Division of Molecular and Regenerative Medicine, Research Institute at Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
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Li X, Liu Y, Liu S, Chen N. USF2-Mediated Transcription of BZW2 Contributes to CRC Malignant Progression by Affecting LAMP3. J Gene Med 2025; 27:e70016. [PMID: 40112348 DOI: 10.1002/jgm.70016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 02/10/2025] [Accepted: 02/24/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most frequent causes of cancer death in China, and its occurrence, development, and prognosis are closely related to the living state of patients. Basic leucine zipper and W2 domains 2 (BZW2), also known as eIF5-mimin protein 1 (5MP1), is a translational regulatory protein and highly expressed in CRC and promotes malignant progression of CRC, but the specific mechanism has not been clarified. METHODS The databases were used to mine related genes. The expression levels of genes were detected by quantitative real-time PCR (qRT-PCR) and western blot. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide (MTT) assay, 5-ethynyl-2'-deoxyuridine (EdU) staining, flow cytometry, transwell assay, and sphere formation assay were employed to examine the effects of BZW2 on the phenotypes in CRC cells in vitro. The mechanism of BZW2 in CRC progression was determined by chromatin immunoprecipitation (CHIP) and dual luciferase reporter assay. In vivo, xenograft animal model was performed to verify the results. RESULTS BZW2 was elevated in CRC tissues and cells and was associated with poor prognosis of patients. Functionally, BZW2 enhanced CRC cell proliferation, invasion, and sphere formation but restrained apoptosis. CHIP and dual luciferase reporter assay confirmed that upstream transcription factor 2 (USF2) regulated BZW2 transcription. Also, BZW2 could attenuate the effects of USF2 defection in CRC progression. Meanwhile, lysosomal associated membrane protein 3 (LAMP3) acted as the target of BZW2 and restored the action of BZW2 knockdown. Similarly, BZW2 was involved in tumorigenesis in vivo by the same mechanism in vitro. CONCLUSION These findings revealed a molecular basis for BZW2's promotion of CRC malignant progression and highlighted the role of BZW2 in promoting cancer stemness.
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Affiliation(s)
- Xintao Li
- Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- The Second Department of Internal Medicine, Shaanxi Provincial Cancer Hospital, Xi'an, China
| | - Yizhi Liu
- The Second Department of Internal Medicine, Shaanxi Provincial Cancer Hospital, Xi'an, China
| | - Shuang Liu
- The Second Department of Internal Medicine, Shaanxi Provincial Cancer Hospital, Xi'an, China
| | - Nanzheng Chen
- Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Feng X, Chen Y, Luo L, Fang Z, Ma S, Li Z, Huang J, Pan Y, Lv H, Gong S, Zheng X, Fan F, Chen P, Zhu J, Chu Q. Liubao insect tea polyphenols ameliorate DSS-induced experimental colitis by protecting intestinal barrier and regulating intestinal microbiota. Food Chem 2024; 467:142156. [PMID: 39632169 DOI: 10.1016/j.foodchem.2024.142156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 11/05/2024] [Accepted: 11/17/2024] [Indexed: 12/07/2024]
Abstract
Liubao insect tea (LIT) is a traditional tea produced from the excreta of Hydrillodes repugnalis that are fed with Liubao tea. In this study, LIT polyphenols (LITP) were extracted and identified, mainly consisting of brevifolin carboxylic acid, brevifolin, ellagic acid. The study aimed to explore the therapeutic potential of LITP in experimental colitis induced by dextran sulfate sodium in mice. LITP treatment effectively mitigated colitis symptoms, including body weight loss, diarrhoea and haematochezia, etc. Furthermore, LITP treatment significantly increased colon length, attenuated inflammatory cell infiltration and mucosal damage, safeguarded the integrity of the epithelial cell barrier, and reduced proinflammatory cytokines levels. Noteworthy alterations in the abundance of gut microbiota community were also observed, with increases in beneficial bacteria Akkermansia, Clostridia_UCG-014, and decreases in harmful bacteria Turicibacter and Erysipelatoclostridium. In conclusion, LITP exerted alleviative effects on colitis via fortifying intestinal barrier and modulating the intestinal microbiota.
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Affiliation(s)
- Xinyu Feng
- Tea Research Institute, Zhejiang University, Hangzhou, China; Department of Food Science, Zhejiang University, Hangzhou, China
| | - Yanwen Chen
- Tea Research Institute, Zhejiang University, Hangzhou, China; College of Life Sciences, Zhejiang University, Hangzhou, China
| | - Lina Luo
- Department of Food Science, Zhejiang University, Hangzhou, China
| | - Zhoutao Fang
- Zhejiang Minghuang Natural Products Development Co., Ltd., Hangzhou, China
| | - Shicheng Ma
- Wuzhou Liubao Tea Research Association, Wuzhou, China
| | | | - Jing Huang
- Tea Research Institute, Zhejiang University, Hangzhou, China; Institute of Landscape Architecture, Zhejiang University, Hangzhou, China
| | - Yani Pan
- Tea Research Institute, Zhejiang University, Hangzhou, China
| | - Helin Lv
- Tea Research Institute, Zhejiang University, Hangzhou, China
| | - Shuying Gong
- Tea Research Institute, Zhejiang University, Hangzhou, China
| | - Xiaodong Zheng
- Department of Food Science, Zhejiang University, Hangzhou, China
| | - Fangyuan Fan
- Tea Research Institute, Zhejiang University, Hangzhou, China
| | - Ping Chen
- Tea Research Institute, Zhejiang University, Hangzhou, China
| | - Jiajin Zhu
- Department of Food Science, Zhejiang University, Hangzhou, China.
| | - Qiang Chu
- Tea Research Institute, Zhejiang University, Hangzhou, China.
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Jeyapriya MS, Kumar SM, Nirmal MR. Lysosome-Associated Membrane Protein-3 (LAMP3) Expression in Oral Squamous Cell Carcinoma and Its Relationship With Clinicopathological Parameters: A Cross-Sectional Study. Cureus 2024; 16:e69790. [PMID: 39429383 PMCID: PMC11491047 DOI: 10.7759/cureus.69790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/20/2024] [Indexed: 10/22/2024] Open
Abstract
Background Oral squamous cell carcinoma (OSCC) accounts for the majority of oral cancers globally. It is characterized by metastasis, poor prognosis, high recurrence rate, and poor five-year survival rate due to late detection or diagnosis at an advanced stage. Novel biomarkers that can predict the prognosis of patients with OSCC are needed to improve survival. Lysosome-associated membrane protein-3 (LAMP3) glycoprotein, a member of the LAMP protein family, is a molecular marker for mature dendritic cells. LAMP3 expression has been correlated with unfavorable prognosis in patients with various cancers. Few studies have examined the relationship between LAMP3 and clinicopathological parameters in OSCC. This study aims to analyze the immunohistochemical expression of LAMP3 in OSCC and its relationship with clinicopathological characteristics. Methodology In this study, 75 formalin-fixed, paraffin-embedded samples of cases diagnosed with primary OSCC were obtained and immunostained with LAMP3 antibody. Its expression was compared with clinicopathological parameters such as age, sex, tobacco and alcohol consumption habits, differentiation, TNM staging, tumor location, lymph node metastasis, lymphovascular invasion, perineural invasion, and pattern of invasion. Results Higher LAMP3 expression was highly significantly associated with the TNM stage (p = 0.001). High expression of LAMP3 was significantly associated with T stage (p = 0.002) and lymph node metastasis (p = 0.002). All poorly differentiated OSCC cases (n = 2, 100%) showed a high expression of LAMP3. Conclusions High LAMP3 expression and its significant association with TNM stage, T stage, and lymph node metastasis suggest a potential role for LAMP3 in OSCC carcinogenesis. High LAMP3 expression in poorly differentiated OSCC might indicate that it plays a pivotal role in oncogenic cell transformation. Our results indicate that LAMP3 may be a predictive marker for poor prognosis in OSCC.
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Affiliation(s)
- Marytresa S Jeyapriya
- Oral Pathology and Microbiology, Karpaga Vinayaga Institute of Dental Sciences, Chengalpet, IND
| | - Sathish M Kumar
- Oral Pathology and Microbiology, Karpaga Vinayaga Institute of Dental Sciences, Chengalpet, IND
| | - Madhavan R Nirmal
- Oral and Maxillofacial Pathology, Rajah Muthiah Dental College and Hospital, Chidambaram, IND
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Schoenfeld K, Harwardt J, Kolmar H. Better safe than sorry: dual targeting antibodies for cancer immunotherapy. Biol Chem 2024; 405:443-459. [PMID: 38297991 DOI: 10.1515/hsz-2023-0329] [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: 10/17/2023] [Accepted: 01/11/2024] [Indexed: 02/02/2024]
Abstract
Antibody-based therapies are revolutionizing cancer treatment and experience a steady increase from preclinical and clinical pipelines to market share. While the clinical success of monoclonal antibodies is frequently limited by low response rates, treatment resistance and various other factors, multispecific antibodies open up new prospects by addressing tumor complexity as well as immune response actuation potently improving safety and efficacy. Novel antibody approaches involve simultaneous binding of two antigens on one cell implying increased specificity and reduced tumor escape for dual tumor-associated antigen targeting and enhanced and durable cytotoxic effects for dual immune cell-related antigen targeting. This article reviews antibody and cell-based therapeutics for oncology with intrinsic dual targeting of either tumor cells or immune cells. As revealed in various preclinical studies and clinical trials, dual targeting molecules are promising candidates constituting the next generation of antibody drugs for fighting cancer.
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Affiliation(s)
- Katrin Schoenfeld
- Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Peter-Grünberg-Strasse 4, D-64287 Darmstadt, Germany
| | - Julia Harwardt
- Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Peter-Grünberg-Strasse 4, D-64287 Darmstadt, Germany
| | - Harald Kolmar
- Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Peter-Grünberg-Strasse 4, D-64287 Darmstadt, Germany
- Centre for Synthetic Biology, Technical University of Darmstadt, Darmstadt, Germany
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Cui Z, Cong M, Yin S, Li Y, Ye Y, Liu X, Tang J. Role of protein degradation systems in colorectal cancer. Cell Death Discov 2024; 10:141. [PMID: 38485957 PMCID: PMC10940631 DOI: 10.1038/s41420-023-01781-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 12/11/2023] [Accepted: 12/14/2023] [Indexed: 03/18/2024] Open
Abstract
Protein degradation is essential for maintaining protein homeostasis. The ubiquitin‒proteasome system (UPS) and autophagy-lysosome system are the two primary pathways responsible for protein degradation and directly related to cell survival. In malignant tumors, the UPS plays a critical role in managing the excessive protein load caused by cancer cells hyperproliferation. In this review, we provide a comprehensive overview of the dual roles played by the UPS and autolysosome system in colorectal cancer (CRC), elucidating their impact on the initiation and progression of this disease while also highlighting their compensatory relationship. Simultaneously targeting both protein degradation pathways offers new promise for enhancing treatment efficacy against CRC. Additionally, apoptosis is closely linked to ubiquitination and autophagy, and caspases degrade proteins. A thorough comprehension of the interplay between various protein degradation pathways is highly important for clarifying the mechanism underlying the onset and progression of CRC.
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Affiliation(s)
- Zihan Cui
- Department of Pathology, Harbin Medical University, Harbin, 150081, China
| | - Mingqi Cong
- Department of Pathology, Harbin Medical University, Harbin, 150081, China
| | - Shengjie Yin
- Department of Oncology, Chifeng City Hospital, Chifeng, 024000, China
| | - Yuqi Li
- Department of Pathology, Harbin Medical University, Harbin, 150081, China
| | - Yuguang Ye
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, 150081, China.
| | - Xi Liu
- Cardiovascular Center, Inner Mongolia People's Hospital, Hohhot, Inner Mongolia, 010017, China.
| | - Jing Tang
- Department of Pathology, Harbin Medical University, Harbin, 150081, China.
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Bagheri Shirvan S, Shahabinejad M, Mohajertehran F, Nazari N. Evaluation of Mir-1290 as a Possible Diagnostic Factor in the Serum of Oral Squamous Cell Carcinoma Patients with Qualitative Real-Time Polymerase Chain Reaction. IRANIAN JOURNAL OF PATHOLOGY 2024; 19:244-249. [PMID: 39118790 PMCID: PMC11304459 DOI: 10.30699/ijp.2024.2010130.3161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 12/22/2023] [Indexed: 08/10/2024]
Abstract
Background & Objective This study aimed to determine the incidence of microRNA (miRNA; miR-1290) in the serum of oral squamous cell carcinoma (OSCC) patients compared to a control group using the qualitative real-time polymerase chain reaction (PCR) method. Methods Blood serum samples were obtained from patients diagnosed with OSCC and confirmed through biopsy. The samples were collected from patients referred to the Mashhad Dental Faculty and Ghaem Hospital. The OSCC group consisted of 17 patients, while the healthy group included 15 individuals. RNA was extracted from the patient samples, and samples with an A260/280 ratio between 1.8 and 2.0 (indicating acceptable RNA quality) were immediately converted into complementary DNA (cDNA) using albumin and cDNA reference genes. The SYBR green real-time reverse transcriptase PCR method was used to measure the presence of miR-1290 in the blood samples. Results A total of 32 patients were examined in this study, including 17 women (53.1%) and 15 men (46.9%). The mean age was 46.7 years in the healthy group and 54.6 years in the SCC group, indicating a significant difference (P<0.05). The expression level of the miR-1290 gene was higher in patients with SCC compared to the healthy group (P=0.000). While the expression level of miR-1290 was higher in grade 3 and advanced stage than in grades 2 and 1 and early stage, the differences were not statistically significant (P=0.173 and P=0.564 for grade and stage, respectively). Conclusion The expression level of miR-1290 may increase in SCC patients compared to healthy individuals, making it a potential circulating biomarker. Further investigations for diagnostic utility would be warranted.
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Affiliation(s)
- Siavash Bagheri Shirvan
- Student Research Committee, Faculty of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehdi Shahabinejad
- Oral and Maxillofacial Pathology Department, Oral and Maxillofacial Diseases Research Center, Faculty of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farnaz Mohajertehran
- Oral and Maxillofacial Pathology Department, Oral and Maxillofacial Diseases Research Center, Faculty of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
- Oral and Maxillofacial Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nazanin Nazari
- Student Research Committee, Faculty of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
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Fu B, Zhou M, Geng X, Jiang Y, Zeng H, Zhou X, Yu Z, Pan J, Zhu Y, Zheng H, Huang S, Gong Y, Huang D, Zhong Y. LAMP3 is a potent uterine corpus endometrial carcinoma prognostic biomarker associated with immune behavior. Aging (Albany NY) 2024; 16:714-745. [PMID: 38217544 PMCID: PMC10817406 DOI: 10.18632/aging.205414] [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: 08/20/2023] [Accepted: 11/21/2023] [Indexed: 01/15/2024]
Abstract
BACKGROUND Uterine corpus endometrial carcinoma (UCEC) is one of the most common gynecological malignancies and its incidence and mortality continue apace. Lysosome-associated membrane protein 3 (LAMP3) is the third member of the LAMP family and its overexpression has been described to be involved in the progression of breast, ovarian and cervical cancers, but there has been an absence of research focusing on its role in UCEC. METHODS WGCNA, TIMER, LinkedOmics, GSEA, Cytoscape, Kaplan-Meier plotter, GDC, GeneMANIA, cBioPortal, PDB, RNAinter, miRNet were applied in this research. RESULTS Our study uncovers that LAMP3 possesses higher expression levels in UCEC compared to normal tissues, and this differential expression profile is tightly aligned with clinical and pathological features, and patients demonstrating high LAMP3 expression tend to have a shorter survival expectancy. The high expression of LAMP3 is modulated by the designated ceRNA network. LAMP3 is engaged in UCEC progression by functioning in a variety of biological roles of relevance to immunity. Furthermore, we predicted several prospering drugs based on drug sensitivity. Finally, we also constructed possible docking patterns of LAMP3 with ABCA3, RAB9A, and SGTB. CONCLUSIONS LAMP3 is a formidable biomarker for UCEC and could be a prospective candidate for the diagnosis, treatment and prognostic assessment of UCEC.
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Affiliation(s)
- Bidong Fu
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Nanchang University, Nanchang, China
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Minqin Zhou
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Xitong Geng
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Yike Jiang
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Hong Zeng
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Xuanrui Zhou
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Zichuan Yu
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Jingying Pan
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Yanting Zhu
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Hao Zheng
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Shuhan Huang
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Yiyang Gong
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Da Huang
- Department of Thyroid Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yanying Zhong
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Nanchang University, Nanchang, China
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Lu H, Zhou J, Li X, Han X, Ma S, Feng C. MiR-526b-3p enhances sensitivity of head and neck squamous cell carcinoma cells to radiotherapy via suppressing exosomal LAMP3-mediated autophagy. Autoimmunity 2023; 56:2259125. [PMID: 37740656 DOI: 10.1080/08916934.2023.2259125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 09/10/2023] [Indexed: 09/24/2023]
Abstract
Lysosomal associated membrane protein 3 (LAMP3) has been reported to be a tumour promoter in multiple cancer types by modulating tumour cell autophagy. However, the potential mechanism of LAMP3 in radio-resistance of head and neck squamous cell carcinoma (HNSCC) remains unknown. Therefore, our current study aims to detect the impacts of LAMP3 on the resistance of HNSCC cells to radiotherapy and meanwhile explore its functional mechanism. Through RT-Qpcr examination, LAMP3 expression was identified to be expressed at a significantly high level in irradiation-resistant HNSCC cell lines compared with irradiation-sensitive HNSCC cell lines. Functional assays including CCK-8, colony formation and Transwell assays demonstrated that LAMP3 enhanced the radio-resistance through inducing autophagy to promote HNSCC cell growth. Furthermore, irradiation-resistant HNSCC cells could transfer exosomal LAMP3 to elevate LAMP3 expression in irradiation-sensitive HNSCC cells. Mechanistically, microRNA (miRNA) miR-526b-3p could inhibit LAMP3 expression so as to strengthen sensitivity of HNSCC cells to radiotherapy. In a word, exosomal LAMP3 expression promoted radioresistance of HNSCC cells via inducing autophagy, while this effect could be suppressed by miR-526b-3p in a targeted manner.
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Affiliation(s)
- Huixiang Lu
- Heavy Ion Radiotherapy Department, Wuwei Cancer Hospital & Institute, Wuwei Academy of Medical Sciences, Wuwei, Gansu, China
| | - Junnian Zhou
- Head, Neck and Maxillofacial Surgery Department, Wuwei Cancer Hospital, Wuwei, Gansu, China
| | - Xiaojun Li
- Heavy Ion Radiotherapy Department, Wuwei Cancer Hospital & Institute, Wuwei Academy of Medical Sciences, Wuwei, Gansu, China
| | - Xiaoqin Han
- Head, Neck and Maxillofacial Surgery Department, Wuwei Cancer Hospital, Wuwei, Gansu, China
| | - Shuping Ma
- Heavy Ion Radiotherapy Department, Wuwei Cancer Hospital & Institute, Wuwei Academy of Medical Sciences, Wuwei, Gansu, China
| | - Chunlan Feng
- Heavy Ion Radiotherapy Department, Wuwei Cancer Hospital & Institute, Wuwei Academy of Medical Sciences, Wuwei, Gansu, China
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Pasquereau-Kotula E, du Merle L, Sismeiro O, Pietrosemoli N, Varet H, Legendre R, Trieu-Cuot P, Dramsi S. Transcriptome profiling of human col\onic cells exposed to the gut pathobiont Streptococcus gallolyticus subsp. gallolyticus. PLoS One 2023; 18:e0294868. [PMID: 38033043 PMCID: PMC10688619 DOI: 10.1371/journal.pone.0294868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 11/09/2023] [Indexed: 12/02/2023] Open
Abstract
Streptococcus gallolyticus sp. gallolyticus (SGG) is a gut pathobiont involved in the development of colorectal cancer (CRC). To decipher SGG contribution in tumor initiation and/or acceleration respectively, a global transcriptome was performed in human normal colonic cells (FHC) and in human tumoral colonic cells (HT29). To identify SGG-specific alterations, we chose the phylogenetically closest relative, Streptococcus gallolyticus subsp. macedonicus (SGM) as control bacterium. We show that SGM, a bacterium generally considered as safe, did not induce any transcriptional changes on the two human colonic cells. The transcriptional reprogramming induced by SGG in normal FHC and tumoral HT29 cells was significantly different, although most of the genes up- and down-regulated were associated with cancer disease. Top up-regulated genes related to cancer were: (i) IL-20, CLK1, SORBS2, ERG1, PIM1, SNORD3A for normal FHC cells and (ii) TSLP, BHLHA15, LAMP3, ZNF27B, KRT17, ATF3 for cancerous HT29 cells. The total number of altered genes were much higher in cancerous than in normal colonic cells (2,090 vs 128 genes being affected, respectively). Gene set enrichment analysis reveals that SGG-induced strong ER- (endoplasmic reticulum) stress and UPR- (unfolded protein response) activation in colonic epithelial cells. Our results suggest that SGG induces a pro-tumoral shift in human colonic cells particularly in transformed cells potentially accelerating tumor development in the colon.
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Affiliation(s)
- Ewa Pasquereau-Kotula
- Institut Pasteur, Université Paris Cité, Biology of Gram-positive Pathogens Unit, Paris, France
| | - Laurence du Merle
- Institut Pasteur, Université Paris Cité, Biology of Gram-positive Pathogens Unit, Paris, France
| | - Odile Sismeiro
- Institut Pasteur, Université Paris Cité, Biology of Gram-positive Pathogens Unit, Paris, France
- Institut Pasteur, Université Paris Cité, Bioinformatics and Biostatistics Hub, Paris, France
| | - Natalia Pietrosemoli
- Institut Pasteur, Université Paris Cité, Bioinformatics and Biostatistics Hub, Paris, France
| | - Hugo Varet
- Institut Pasteur, Université Paris Cité, Bioinformatics and Biostatistics Hub, Paris, France
| | - Rachel Legendre
- Institut Pasteur, Université Paris Cité, Bioinformatics and Biostatistics Hub, Paris, France
| | - Patrick Trieu-Cuot
- Institut Pasteur, Université Paris Cité, Biology of Gram-positive Pathogens Unit, Paris, France
| | - Shaynoor Dramsi
- Institut Pasteur, Université Paris Cité, Biology of Gram-positive Pathogens Unit, Paris, France
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Kang J, Kim M, Yoon DY, Kim WS, Choi SJ, Kwon YN, Kim WS, Park SH, Sung JJ, Park M, Lee JS, Park JE, Kim SM. AXL +SIGLEC6 + dendritic cells in cerebrospinal fluid and brain tissues of patients with autoimmune inflammatory demyelinating disease of CNS. Clin Immunol 2023; 253:109686. [PMID: 37414380 DOI: 10.1016/j.clim.2023.109686] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 05/26/2023] [Accepted: 06/12/2023] [Indexed: 07/08/2023]
Abstract
Inflammatory demyelinating disease of the CNS (IDD) is a heterogeneous group of autoimmune diseases, and multiple sclerosis is the most common type. Dendritic cells (DCs), major antigen-presenting cells, have been proposed to play a central role in the pathogenesis of IDD. The AXL+SIGLEC6+ DC (ASDC) has been only recently identified in humans and has a high capability of T cell activation. Nevertheless, its contribution to CNS autoimmunity remains still obscure. Here, we aimed to identify the ASDC in diverse sample types from IDD patients and experimental autoimmune encephalomyelitis (EAE). A detailed analysis of DC subpopulations using single-cell transcriptomics for the paired cerebrospinal fluid (CSF) and blood samples of IDD patients (total n = 9) revealed that three subtypes of DCs (ASDCs, ACY3+ DCs, and LAMP3+ DCs) were overrepresented in CSF compared with their paired blood. Among these DCs, ASDCs were also more abundant in CSF of IDD patients than in controls, manifesting poly-adhesional and stimulatory characteristics. In the brain biopsied tissues of IDD patients, obtained at the acute attack of disease, ASDC were also frequently found in close contact with T cells. Lastly, the frequency of ASDC was found to be temporally more abundant in acute attack of disease both in CSF samples of IDD patients and in tissues of EAE, an animal model for CNS autoimmunity. Our analysis suggests that the ASDC might be involved in the pathogenesis of CNS autoimmunity.
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Affiliation(s)
- Junho Kang
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Moonhang Kim
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Da-Young Yoon
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Woo-Seok Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Seok-Jin Choi
- Department of Neurology, Seoul National University Hospital, Seoul National University of Medicine, Seoul, Republic of Korea
| | - Young-Nam Kwon
- Department of Neurology, Seoul National University Hospital, Seoul National University of Medicine, Seoul, Republic of Korea
| | - Won-Seok Kim
- Department of Neurology, Seoul National University Hospital, Seoul National University of Medicine, Seoul, Republic of Korea
| | - Sung-Hye Park
- Department of Pathology, Seoul National University Hospital, Seoul National University of Medicine, Seoul, Republic of Korea
| | - Jung-Joon Sung
- Department of Neurology, Seoul National University Hospital, Seoul National University of Medicine, Seoul, Republic of Korea
| | - Myungsun Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Jung Seok Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Jong-Eun Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
| | - Sung-Min Kim
- Department of Neurology, Seoul National University Hospital, Seoul National University of Medicine, Seoul, Republic of Korea.
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Zhu J, Long T, Gao L, Zhong Y, Wang P, Wang X, Li Z, Hu Z. RPL21 interacts with LAMP3 to promote colorectal cancer invasion and metastasis by regulating focal adhesion formation. Cell Mol Biol Lett 2023; 28:31. [PMID: 37062845 PMCID: PMC10108486 DOI: 10.1186/s11658-023-00443-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 03/28/2023] [Indexed: 04/18/2023] Open
Abstract
BACKGROUND Metastasis is the leading cause of death among patients with colorectal cancer (CRC). Therefore, it is important to explore the molecular mechanisms of metastasis to develop effective therapeutic targets for CRC. In the present study, ribosomal protein L21 (RPL21) was considered as being involved in promoting CRC metastasis, yet the underlying mechanism requires further investigation. METHODS Immunohistochemistry, western blotting, and quantitative reverse transcription polymerase chain reaction were performed to measure the expression of RPL21 and lysosome-associated membrane protein 3 (LAMP3) in CRC tissues and cells. Wound healing, transwell migration, and invasion assays were performed to study the migration and invasion of cultured CRC cells. An orthotopic CRC mouse model was developed to investigate the metastatic ability of CRC. Transcriptome sequencing was conducted to identify the genes related to RPL21. The dual-luciferase reporter gene assay was performed to determine the transcriptional activity of transcription factor EB (TFEB). The GST/His pull-down assay was performed to investigate the specific binding sites of RPL21 and LAMP3. The cell adhesion assay was performed to determine the adhesion ability of CRC cells. Immunofluorescence staining was performed to observe focal adhesions (FAs). RESULTS RPL21 was highly expressed in CRC, contributing to tumor invasiveness and poor patient prognosis. Functionally, RPL21 promoted the migration and invasion of CRC cells in vitro and tumor metastasis in vivo. Moreover, LAMP3 was identified as being highly related to RPL21 and was essential in promoting the migration and invasion of CRC cells. Mechanistically, RPL21 activated the transcriptional function of TFEB to upregulate LAMP3 expression. RPL21 directly bound to the aa 341-416 domain of LAMP3 via its aa 1-40 and aa 111-160 segments. The combination of RPL21 and LAMP3 enhanced the stability of the RPL21 protein by suppressing the degradation of the ubiquitin-proteasome system. Furthermore, RPL21 and LAMP3 promoted the formation of immature FAs by activating the FAK/paxillin/ERK signaling pathway. CONCLUSIONS RPL21 promoted invasion and metastasis by regulating FA formation in a LAMP3-dependent manner during CRC progression. The interaction between RPL21 and LAMP3 may function as a potential therapeutic target against CRC.
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Affiliation(s)
- Jiaxian Zhu
- Department of Pathology, Shenzhen Hospital, Southern Medical University, 1333 Xinhu Road, Shenzhen, 518101, Guangdong, People's Republic of China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Ting Long
- Department of Pathology, Shenzhen Hospital, Southern Medical University, 1333 Xinhu Road, Shenzhen, 518101, Guangdong, People's Republic of China
| | - Lingfang Gao
- Department of Pathology, Shenzhen Hospital, Southern Medical University, 1333 Xinhu Road, Shenzhen, 518101, Guangdong, People's Republic of China
| | - Yan Zhong
- Department of Pathology, Shenzhen Hospital, Southern Medical University, 1333 Xinhu Road, Shenzhen, 518101, Guangdong, People's Republic of China
| | - Ping Wang
- Department of Pathology, Shenzhen Hospital, Southern Medical University, 1333 Xinhu Road, Shenzhen, 518101, Guangdong, People's Republic of China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Xiaoyan Wang
- Department of Pathology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China
- Key Laboratory of Molecular Tumour Pathology of Guangdong Province, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Zuguo Li
- Department of Pathology, Shenzhen Hospital, Southern Medical University, 1333 Xinhu Road, Shenzhen, 518101, Guangdong, People's Republic of China.
- Key Laboratory of Molecular Tumour Pathology of Guangdong Province, Guangzhou, 510515, Guangdong, People's Republic of China.
| | - Zhiyan Hu
- Department of Pathology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, People's Republic of China.
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China.
- Key Laboratory of Molecular Tumour Pathology of Guangdong Province, Guangzhou, 510515, Guangdong, People's Republic of China.
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Mohajertehran F, Mohtasham N, Ahmadi M, Shahabinejad M, Mohammadi M. RT-qPCR Analysis of LAMP3 (CD208) Gene Expression in Oral Lichen Planus and Oral Squamous Cell Carcinoma. Rep Biochem Mol Biol 2023; 12:36-41. [PMID: 37724152 PMCID: PMC10505466 DOI: 10.52547/rbmb.12.1.36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 02/04/2023] [Indexed: 09/20/2023]
Abstract
Background Many new studies have been conducted on cellular proteins to use them as prognostic markers or in target therapy through determining the increase or decrease in their expression in the lichen planus and OSCC. LAMP3 protein is one of these proteins which has been recently considered. Thus, considering the unknown etiology of lichen planus, significance of their early diagnosis and treatment and lack of a suitable and final treatment for this disease and oral cancers, and preventing the progression of lichen planus, which can turn into OSCC, we decided to investigate the level of expression of this gene and its effect on the progression, study the connection between these two conditions and the probable factors contributing to their etiopathogenesis. Methods In this study, ninety-four paraffin blocks tissue samples of patients were obtained together with their demographic documents. LAMP3 expression was measured RT-qPCR method. Results The results show that there is not any significant difference between age and sex population of our study. in squamous cell carcinoma the amount of expression of LAMP3 was higher than lichen planus and healthy margin. Average LAMP3 Gene expression in grade III was higher than group grade I & II in which considering significant level of 5%, it is statistically significant. Conclusions According to the findings of this study, it can be concluded that the expression of the LAMP3 gene in SCC lesions is higher than in healthy tissue. Hence, LAMP3 gene expression can be used as a diagnostic biomarker.
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Affiliation(s)
- Farnaz Mohajertehran
- Oral and Maxillofacial Pathology Department, Oral and Maxillofacial Diseases Research Center, Faculty of Dentistry, Mashhad University of Medical Sciences.
- Oral and Maxillofacial Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Nooshin Mohtasham
- Oral and Maxillofacial Pathology Department, Oral and Maxillofacial Diseases Research Center, Faculty of Dentistry, Mashhad University of Medical Sciences.
| | - Mojtaba Ahmadi
- Oral and Maxillofacial Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mehdi Shahabinejad
- Oral and Maxillofacial Pathology Department, Oral and Maxillofacial Diseases Research Center, Faculty of Dentistry, Mashhad University of Medical Sciences.
| | - Maryam Mohammadi
- Oral and Maxillofacial Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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15
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Association of β-Catenin, APC, SMAD3/4, Tp53, and Cyclin D1 Genes in Colorectal Cancer: A Systematic Review and Meta-Analysis. Genet Res (Camb) 2022; 2022:5338956. [PMID: 36072013 PMCID: PMC9402361 DOI: 10.1155/2022/5338956] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 06/27/2022] [Indexed: 11/25/2022] Open
Abstract
Objectives Accumulating evidence indicates that the expression and/or variants of several genes play an essential role in the progress of colorectal cancer (CRC). The current study is a meta-analysis undertaken to estimate the prognosis and survival associated with CTNNB1/β-catenin, APC, Wnt, SMAD3/4, TP53, and Cyclin D1 genes among CRC patients. Methods The authors searched PubMed, EMBASE, and Science Direct for relevant reports published between 2000 and 2020 and analyzed them to determine any relationship between the (immunohistochemically/sequencing-detected) gene expression and variants of the selected genes and the survival of CRC patients. Results The analysis included 34,074 patients from 64 studies. To evaluate association, hazard ratios (HRs) were estimated for overall survival (OS) or disease-free survival (DFS), with a 95% confidence interval (CIs). Pooled results showed that β-catenin overexpression, APC mutation, SMAD-3 or 4 loss of expression, TP53 mutations, and Cyclin D1 expression were associated with shorter OS. β-Catenin overexpression (HR: 0.137 (95% CI: 0.131–0.406)), loss of expression of SMAD3 or 4 (HR: 0.449 (95% CI: 0.146–0.753)), the mutations of TP53 (HR: 0.179 (95% CI: 0.126–0.485)), and Cyclin D1 expression (HR: 0.485 (95% CI: 0.772–0.198)) also presented risk for shorter DFS. Conclusions The present meta-analysis indicates that overexpression or underexpression and variants of CTNNB1/β-catenin, APC, SMAD3/4, TP53, and Cyclin D1 genes potentially acted as unfavorable biomarkers for the prognosis of CRC. The Wnt gene was not associated with prognosis.
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16
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Identification and Validation of a Novel Prognostic Gene Model for Colorectal Cancer. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:9774219. [PMID: 35924107 PMCID: PMC9343208 DOI: 10.1155/2022/9774219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 06/18/2022] [Accepted: 06/22/2022] [Indexed: 11/23/2022]
Abstract
Aims Colon cancer (CRC), with high morbidity and mortality, is a common and highly malignant cancer, which always has a bad prognosis. So it is urgent to employ a reasonable manner to assess the prognosis of patients. We developed and validated a gene model for predicting CRC risk. Methods The Gene Expression Omnibus (GEO) database was used to extract the gene expression profiles of CRC patients (N = 181) from GEO to identify genes that were differentially expressed between CRC patients and controls and then stable signature genes by firstly using both robust likelihood-based modeling with 1000 iterations and random survival forest variable hunting algorithms. Cluster analysis using the longest distance method was drawn out, and Kaplan–Meier (KM) survival analysis was used to compare the clusters. Meanwhile, the risk score was evaluated in three independent datasets including the GEO and Illumina HiSeq sequencing platforms. The corresponding risk index was calculated, and samples were clustered into high- and low-risk groups according to the median. And survival ROC analysis was used to evaluate the prognostic model. Finally, the Gene Set Enrichment Analysis (GSEA) was performed for further functional enrichment analyses. Results A 10-gene model was obtained, including 7 negative impact factors (SLC39A14, AACS, ERP29, LAMP3, TMEM106C, TMED2, and SLC25A3) and 3 positive ones (CNPY2, GRB10, and PBK), which related with several important oncogenic pathways (KRAS signaling, TNF-α signaling pathway, and WNT signaling pathway) and several cancer-related cellular processes (epithelial mesenchymal transition and cellular apoptosis). By using colon cancer datasets from The Cancer Genome Atlas (TCGA), the model was validated in KM survival analysis (P ≤ 0.001) and significant analysis with recurrence time (P = 0.0018). Conclusions This study firstly developed a stable and effective 10-gene model by using novel combined methods, and CRC patients might be able to use it as a prognostic marker for predicting their survival and monitoring their long-term treatment.
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17
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Manzoor S, Muhammad JS, Maghazachi AA, Hamid Q. Autophagy: A Versatile Player in the Progression of Colorectal Cancer and Drug Resistance. Front Oncol 2022; 12:924290. [PMID: 35912261 PMCID: PMC9329589 DOI: 10.3389/fonc.2022.924290] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/06/2022] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer (CRC) is among the topmost malignancies for both genders. Despite the high incidence rate and advances in diagnostic tools, treatment in many cases is still ineffective. Most cancerous lesions in CRC begin as benign, followed by the development of invasive forms and metastases. The development of CRC has been linked to defects in autophagy, which plays both a pro-and anti-tumor role and is mainly context-dependent. Autophagy suppression could enhance apoptosis via p53 activation, or autophagy also promotes tumor progression by maintaining tumor growth and increasing resistance to chemotherapy. Autophagy promotes the invasion and metastasis of CRC cells via increased epithelial-mesenchymal transition (EMT). Moreover, dysbiosis of gut microbiota upregulated autophagy and metastasis markers. Autophagy responses may also modulate the tumor microenvironment (TME) via regulating the differentiation process of several innate immune cells. Treatments that promote tumor cell death by stimulating or inhibiting autophagy could be beneficial if used as an adjunct treatment, but the precise role of various autophagy-modulating drugs in CRC patients is needed to be explored. In this article, we present an overview of the autophagy process and its role in the pathogenesis and therapeutic resistance of CRC. Also, we focused on the current understanding of the role of the EMT and TME, including its relation to gut microbiota and immune cells, in autophagic manipulation of CRC. We believe that there is a potential link between autophagy, TME, EMT, and drug resistance, suggesting that further studies are needed to explore this aspect.
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Affiliation(s)
- Shaista Manzoor
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Jibran Sualeh Muhammad
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Azzam A. Maghazachi
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Qutayba Hamid
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montreal, QC, Canada
- *Correspondence: Qutayba Hamid,
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18
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Wang D, Wan B, Zhang X, Sun P, Lu S, Liu C, Zhu L. Nuclear respiratory factor 1 promotes the growth of liver hepatocellular carcinoma cells via E2F1 transcriptional activation. BMC Gastroenterol 2022; 22:198. [PMID: 35448958 PMCID: PMC9027447 DOI: 10.1186/s12876-022-02260-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 04/04/2022] [Indexed: 11/13/2022] Open
Abstract
Background Recent studies have shown that functional mitochondria are essential for cancer cells. Nuclear respiratory factor 1 (NRF1) is a transcription factor that activates mitochondrial biogenesis and the expression of the respiratory chain, but little is known about its role and underlying mechanism in liver hepatocellular carcinoma (LIHC). Methods NRF1 expression was analyzed via public databases and 24 paired LIHC samples. Clinical-pathological information and follow-up data were collected from 165 patients with LIHC or online datasets. Furthermore, cellular proliferation and the cell cycle were analyzed by MTT, Clone-forming assay and flow cytometric analyses. NRF1 target genes were analyzed by Chromatin immunoprecipitation sequencing (ChIP-Seq). PCR and WB analysis was performed to detect the expression of related genes. ChIP and luciferase activity assays were used to identify NRF1 binding sites. Results Our results showed that NRF1 expression was upregulated in LIHC compared to normal tissues. NRF1 expression was associated with tumour size and poor prognosis in patients. Knockdown of NRF1 repressed cell proliferation and overexpression of NRF1 accelerated the G1/S phase transition. Additionally, data from ChIP-seq pointed out that some NRF1 target genes are involved in the cell cycle. Our findings indicated that NRF1 directly binds to the E2F1 promoter as a transcription factor and regulates its gene expression. Conclusion Therefore, this study revealed that NRF1 promotes cancer cell growth via the indirect transcriptional activation of E2F1 and is a potential biomarker in LIHC. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-022-02260-7.
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Affiliation(s)
- Dan Wang
- Institute of Special Environmental Medicine, Nantong University, 9 Se Yuan Road, Nantong, 226019, Jiangsu, China
| | - Baolan Wan
- Institute of Special Environmental Medicine, Nantong University, 9 Se Yuan Road, Nantong, 226019, Jiangsu, China
| | - Xiaojing Zhang
- Department of Clinical Biobank, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Pingping Sun
- Department of Clinical Biobank, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Shu Lu
- Department of Intensive Care Unit, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Chenxu Liu
- Department of Biochemistry and Molecular Biology, Medical School, Nantong University, Nantong, 226001, Jiangsu, China
| | - Li Zhu
- Institute of Special Environmental Medicine, Nantong University, 9 Se Yuan Road, Nantong, 226019, Jiangsu, China.
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19
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Generation of Human Lung Organoid Cultures from Healthy and Tumor Tissue to Study Infectious Diseases. J Virol 2022; 96:e0009822. [DOI: 10.1128/jvi.00098-22] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Three-dimensional (3D) human lung organoids reflect the native cell composition of the lung as well as its physiological properties. Human 3D lung organoids offer ideal conditions, such as timely availability in large quantities and high physiological relevance for reassessment and prediction of disease outbreaks of respiratory pathogens and pathogens that use the lung as a primary entry portal.
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20
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Yao S, Ertay A, Zhou Y, Yao L, Hill C, Chen J, Guan Y, Sun H, Ewing RM, Liu Y, Lv X, Wang Y. GRK6 Depletion Induces HIF Activity in Lung Adenocarcinoma. Front Oncol 2021; 11:654812. [PMID: 34136390 PMCID: PMC8201516 DOI: 10.3389/fonc.2021.654812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 04/26/2021] [Indexed: 12/24/2022] Open
Abstract
G protein-coupled receptor kinase 6 (GRK6) is expressed in various tissues and is involved in the development of several diseases including lung cancer. We previously reported that GRK6 is down-regulated in lung adenocarcinoma patients, which induces cell invasion and metastasis. However, further understanding of the role of GRK6 in lung adenocarcinoma is required. Here we explored the functional consequence of GRK6 inhibition in lung epithelial cells. Analysis of TCGA data was coupled with RNA sequencing (RNA-seq) in alveolar epithelial type II (ATII) cells following depletion of GRK6 with RNA interference (RNAi). Findings were validated in ATII cells followed by tissue microarray analysis. Pathway analysis suggested that one of the Hallmark pathways enriched upon GRK6 inhibition is 'Hallmark_Hypoxia' (FDR = 0.014). We demonstrated that GRK6 depletion induces HIF1α (hypoxia-inducible factor 1 alpha) levels and activity in ATII cells. The findings were further confirmed in lung adenocarcinoma samples, in which GRK6 expression levels negatively and positively correlate with HIF1α expression (P = 0.015) and VHL expression (P < 0.0001), respectively. Mechanistically, we showed the impact of GRK6 on HIF activity could be achieved via regulation of VHL levels. Taken together, targeting the HIF pathway may provide new strategies for therapy in GRK6-depleted lung adenocarcinoma patients.
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Affiliation(s)
- Sumei Yao
- Department of Respiratory Medicine, The Second Affiliated Hospital of Nantong University, Nantong, China
| | - Ayse Ertay
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom
| | - Yilu Zhou
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom.,Institute for Life Sciences, University of Southampton, Southampton, United Kingdom
| | - Liudi Yao
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom
| | - Charlotte Hill
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom
| | - Jinliang Chen
- Department of Respiratory Medicine, The Second Affiliated Hospital of Nantong University, Nantong, China
| | - Yangbo Guan
- Department of Urology, Affiliated Hospital of Nantong University, Nantong, China
| | - Hui Sun
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Rob M Ewing
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom.,Institute for Life Sciences, University of Southampton, Southampton, United Kingdom
| | - Yifei Liu
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, China.,Medical School of Nantong University, Nantong, China
| | - Xuedong Lv
- Department of Respiratory Medicine, The Second Affiliated Hospital of Nantong University, Nantong, China
| | - Yihua Wang
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom.,Institute for Life Sciences, University of Southampton, Southampton, United Kingdom
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21
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Wang D, Lu S, Zhang X, Huang L, Zhao H. Co-expression of KIAA1199 and hypoxia-inducible factor 1α is a biomarker for an unfavorable prognosis in hepatocellular carcinoma. Medicine (Baltimore) 2020; 99:e23369. [PMID: 33327261 PMCID: PMC7738140 DOI: 10.1097/md.0000000000023369] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Advanced studies demonstrated that hypoxic stress induced KIAA1199 expression leading to enhanced cell migration. KIAA1199 is a protein related with cancer metastasis. Hypoxia inducible factor 1α (HIF-1α) is a transcriptional factor that maintains oxygen homeostasis. Both KIAA1199 and HIF-1α were upregulated in many human cancers. In the present study, co-expression of KIAA1199 and HIF-1α was evaluated for the clinicopathological characteristics and survival in hepatocellular carcinoma (HCC). Clinical-pathological information and follow-up data were collected from 152 HCC patients. KIAA1199 and HIF-1α expression were scored based on the percentage and intensity of immunohistochemical staining in pathological slide. Correlations between clinical features and the expression of KIAA1199 and HIF-1α were evaluated by Chi-square test, Kaplan-Meier curves and multivariate Cox regression analysis. The frequency of KIAA1199 high expression was higher in HCC than adjacent tissue. KIAA1199(H)/HIF-1α(H) tumors were more frequently of TNM (P = .011), tumor size (P = .021), vascular invasion (P = .002) and HBV (P = .001). In survival analysis, KIAA1199(H)/HIF-1α(H) patients had the worst prognosis. Using the combination of the two parameters increased the prognostic value (P < .01 vs P = .03). KIAA1199 in combination with HIF-1α expression tends to indicate a more accurate prognosis.
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Affiliation(s)
- Dan Wang
- Institute of Special Environmental Medicine, Nantong University
- Department of Clinical Biobank
| | - Shu Lu
- Department of Intensive Care Unit
| | | | - Linlin Huang
- Institute of Special Environmental Medicine, Nantong University
| | - Hui Zhao
- Department of Interventional Radiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
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22
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Wu H, Li J, Chen J, Yin Y, Da P, Chen Q, Zhang Z, Wang J, Wang G, Qiu X. Efficacy of radiation exposure in laryngeal squamous cell carcinoma is mediated by the LAMP3/LAMC2/tenascin-C pathway. Exp Biol Med (Maywood) 2019; 244:1070-1080. [PMID: 31390898 PMCID: PMC6775573 DOI: 10.1177/1535370219867643] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 07/12/2019] [Indexed: 12/19/2022] Open
Abstract
The present study explored the role of LAMP3 and related molecular mechanisms in the efficacy of radiation exposure in laryngeal squamous cell carcinoma (LSCC). A lentivirus vector containing the LAMP3 gene was transfected into HEp-2 cells to construct siRNA-LAMP3 and complementation (siLAMP3+LAMP3) groups. Treatment with 4 Gy or 8 Gy radiation was administered to evaluate the role of LAMP3 in radiation therapy. Apoptosis was detected by Annexin V/propidium iodide double staining. Cell migration and invasion were measured in vitro using Transwell and Matrigel assays. Downstream genes regulated by LAMP3 were analyzed using RNA sequencing. Furthermore, a patient-derived xenograft (PDX) model of LSCC was established to verify the efficacy of radiation exposure and the associated signaling pathways downstream of LAMP3. The efficacy of radiation showed that cell proliferation was significantly inhibited by siRNA-LAMP3 knockdown. Increased apoptosis was also observed. Notably, the inhibitory effect was attenuated and apoptosis rates were decreased after LAMP3 complementation. In vitro cellular assays showed that migration and invasion were significantly suppressed by siRNA-LAMP3 knockdown and increased after LAMP3 complementation. Analysis of the efficacy of radiation exposure in the PDX model showed that LAMP3-specific knockdown inhibited tumor growth and that tumor growth was further reduced by the combined radiotherapy treatment. According to transcriptome analysis, the extracellular matrix-receptor interaction pathway is regulated by LAMP3, and further analysis revealed significant differences in key-associated molecules, including laminin subunit gamma-2 (LAMC2) and tenascin-C (TNC). Validation of the in vivo PDX model using qPCR and Western blot analyses supported the abovementioned results. The present findings suggest that reduced LAMP3 expression enhances the efficacy of radiation exposure in LSCC by regulating the LAMP3/LAMC2/TNC signaling pathway.
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Affiliation(s)
- Hao Wu
- Department of Otorhinolaryngology – Head and Neck Surgery,
Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, P.R.
China
| | - Juanjuan Li
- Department of Otorhinolaryngology – Head and Neck Surgery,
Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, P.R.
China
| | - Jianqiu Chen
- Department of Otolaryngology – Head and Neck Surgery, General
Hospital of Jinan Military Region, Jinan, Shandong 250031, P.R. China
| | - Yong Yin
- Department of Otorhinolaryngology – Head and Neck Surgery,
Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, P.R.
China
| | - Peng Da
- Department of Otorhinolaryngology – Head and Neck Surgery,
Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, P.R.
China
| | - Qingwen Chen
- Department of Otorhinolaryngology – Head and Neck Surgery,
Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, P.R.
China
| | - Zhenxin Zhang
- Department of Otorhinolaryngology – Head and Neck Surgery,
Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, P.R.
China
| | - Jinxing Wang
- Department of Physiology and Hypoxic Biomedicine, Institute of
Special Environmental Medicine, Nantong University, Nantong, Jiangsu 226001,
P.R. China
| | - Guohua Wang
- Department of Physiology and Hypoxic Biomedicine, Institute of
Special Environmental Medicine, Nantong University, Nantong, Jiangsu 226001,
P.R. China
| | - Xiaoxia Qiu
- Department of Otorhinolaryngology – Head and Neck Surgery,
Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, P.R.
China
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23
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Yang C, Shen S, Zheng X, Ye K, Sun Y, Lu Y, Ge H. Long noncoding RNA HAGLR acts as a microRNA-143-5p sponge to regulate epithelial-mesenchymal transition and metastatic potential in esophageal cancer by regulating LAMP3. FASEB J 2019; 33:10490-10504. [PMID: 31311326 DOI: 10.1096/fj.201802543rr] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Homeobox D gene cluster antisense growth-associated long noncoding RNA (HAGLR) functions as a crucial regulator in the progression and development of human cancers. We analyzed effects of HAGLR, microRNA (miR)-143-5p and lysosome-associated membrane glycoprotein (LAMP)3 on esophageal cancer (EC) and the related mechanisms. Microarray analysis was used to screen out EC-related genes and the regulation network among HAGLR, miR-143-5p, and LAMP3. The regulatory mechanisms of HAGLR and miR-143-5p in EC were analyzed following the treatment of miR-143-5p mimic, miR-143-5p inhibitor, HAGLR vector, or small interfering RNA against HAGLR in EC cells. The expression of N-cadherin, vimentin, Twist1, Snail1, and E-cadherin as well as the abilities of cell proliferation, invasion, and migration were measured. The effects of the HAGLR/miR-143-5p/LAMP3 axis were determined in vivo by assessing tumor formation in nude mice. The expression of HAGLR and LAMP3 was increased, whereas that of miR-143-5p was diminished in EC tissues and cells. HAGLR could competitively bind to miR-143-5p, and miR-143-5p targeted LAMP3. Down-regulated HAGLR or up-regulated miR-143-5p increased E-cadherin expression and significantly diminished expression of LAMP3, N-cadherin, vimentin, Twist1, and Snail1. Moreover, down-regulated HAGLR inhibited cell proliferation, invasion, migration, epithelial-mesenchymal transition (EMT), and tumor growth. Moreover, down-regulation of HAGLR inhibited LAMP3 expression by sponging miR-143-5p, thereby suppressing the progression of EC. Taken together, our results suggest HAGLR acts as a competing endogenous RNA of miR-143-5p to increase the expression of LAMP3, thus promoting EMT, proliferation, invasion, and migration in EC cells.-Yang, C., Shen, S., Zheng, X., Ye, K., Sun, Y., Lu, Y., Ge, H. Long noncoding RNA HAGLR acts as a microRNA-143-5p sponge to regulate epithelial-mesenchymal transition and metastatic potential in esophageal cancer by regulating LAMP3.
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Affiliation(s)
- Chengliang Yang
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Sining Shen
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaoli Zheng
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Ke Ye
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanan Sun
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Yufei Lu
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Hong Ge
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
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24
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Xia Q, Zhou Y, Yong H, Wang X, Zhao W, Ding G, Zhu J, Li X, Feng Z, Wang B. Elevated epiregulin expression predicts poor prognosis in gastric cancer. Pathol Res Pract 2019; 215:873-879. [PMID: 30738695 DOI: 10.1016/j.prp.2019.01.030] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 01/05/2019] [Accepted: 01/25/2019] [Indexed: 02/06/2023]
Abstract
Epiregulin (EREG) is a novel family member of EGF-like ligands and have elevated expression in a variety of human cancers. EREG expression promotes tumor progression and metastasis and reduces patient survival. However, the expression of EREG and its prognostic value are not clear in gastric cancer (GC). We assessed EREG mRNA and protein expression in GC tissues from Chinese patients using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical staining of tissue microarray, and analyzed the correlation between the level of EREG expression and patient clinical characteristics and prognosis. We found that EREG expression was significantly higher in GC tissues than in matched adjacent noncancerous tissues. High EREG protein expression in GC was significantly associated with TNM stage including tumor size, lymph node metastases and distant metastases as well as poor overall survival. These finding demonstrate that EREG is an independent prognostic biomarker for GC.
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Affiliation(s)
- Qiuyan Xia
- Department of Oncology, The Affiliated Aoyang Hospital of Jiangsu University, Zhangjiagang 215617, China
| | - Yan Zhou
- Department of Oncology, The Affiliated Aoyang Hospital of Jiangsu University, Zhangjiagang 215617, China; Jiangsu University Aoyang Institute of Oncology, Zhangjiagang 215617, China
| | - Hongmei Yong
- Department of Oncology, Huai'an Hospital Affiliated of Xuzhou Medical College and Huai'an Second People's Hospital, Huai'an 223200, China
| | - Xudong Wang
- Clinical Biobank, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Wei Zhao
- Department of Pathology, Nanjing Medical University, Nanjing 210029, China
| | - Guipeng Ding
- Department of Pathology, Nanjing Medical University, Nanjing 210029, China
| | - Jin Zhu
- Huadong Medical Institute of Biotechniques, Nanjing 210029, China
| | - Xiaohua Li
- The Center for Pathology & Laboratory Medicine, The Affiliated Aoyang Hospital of Jiangsu University, Zhangjiagang 215617, China; School of Medicine, Jiangsu University, Zhenjiang 212013, China; The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Zhenqing Feng
- Department of Oncology, The Affiliated Aoyang Hospital of Jiangsu University, Zhangjiagang 215617, China; Key Laboratory of Antibody Technique of Ministry of Health, Nanjing Medical University, Nanjing 210029, China; Collaborative Innovation Center for Cancer Personalized Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing 210029, China.
| | - Bing Wang
- Department of Oncology, The Affiliated Aoyang Hospital of Jiangsu University, Zhangjiagang 215617, China; Department of Oncology, Shanghai Ruijin Hospital Luwan Branch, Shanghai Jiaotong University, Shanghai 200020, China.
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25
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Wang D, Zhang X, Lu Y, Wang X, Zhu L. Hypoxia inducible factor 1α in hepatocellular carcinoma with cirrhosis: Association with prognosis. Pathol Res Pract 2018; 214:1987-1992. [DOI: 10.1016/j.prp.2018.09.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 08/23/2018] [Accepted: 09/11/2018] [Indexed: 01/16/2023]
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26
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Liu S, Mao Q, Xue W, Zhang X, Qi Y, Wang Y, Chen P, Zhou Q. High expression of ALPPL2 is associated with poor prognosis in gastric cancer. Hum Pathol 2018; 86:49-56. [PMID: 30496798 DOI: 10.1016/j.humpath.2018.11.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Revised: 11/15/2018] [Accepted: 11/16/2018] [Indexed: 12/11/2022]
Abstract
Alkaline phosphatase placental-like 2 (ALPPL2) is a member of the ALPP alkaline phosphatase family and is reported to be associated with the growth of some tumors. Gastric cancer is one of the most common cancers worldwide. We previously identified a distinct expression pattern of ALPPL2 between gastric cancer and adjacent normal tissues. In this study, we examined the expression of ALPPL2 in gastric adenocarcinoma and its ability to predict prognosis. We used bioinformatics analysis and immunohistochemistry to examine the expression pattern of ALPPL2 and analyzed the associations between ALPPL2 level and perioperative characteristics and the prognosis of gastric adenocarcinoma patients by Kaplan-Meier plotter analysis. Our results indicated that the expression of ALPPL2 was significantly increased in gastric adenocarcinoma (P < .01) and was an independent factor (P < .05) that could provide reliable prognostic information on gastric adenocarcinoma patients. High expression of ALPPL2 was associated with advanced TNM stage (P < .05) and high HER-2 expression (P < .01). Our study suggests that ALPPL2 has the potential to reveal prognostic information on gastric cancer.
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Affiliation(s)
- Shuang Liu
- Department of Clinical Bio-bank, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China; Department of Pathology, Medical School of Nantong University, Nantong, Jiangsu 226001, China
| | - Qinsheng Mao
- Department of General Surgery, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China
| | - Wanjiang Xue
- Department of General Surgery, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China
| | - Xiaojing Zhang
- Department of Clinical Bio-bank, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China
| | - Yue Qi
- Department of Clinical Bio-bank, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China
| | - Yingjing Wang
- Department of Clinical Bio-bank, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China
| | - Pei Chen
- Department of Clinical Bio-bank, Nantong University Affiliated Hospital, Nantong, Jiangsu 226001, China
| | - Qing Zhou
- Department of Education and Training Office, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.
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27
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Bednarczyk M, Zmarzły N, Grabarek B, Mazurek U, Muc-Wierzgoń M. Genes involved in the regulation of different types of autophagy and their participation in cancer pathogenesis. Oncotarget 2018; 9:34413-34428. [PMID: 30344951 PMCID: PMC6188136 DOI: 10.18632/oncotarget.26126] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 08/30/2018] [Indexed: 12/13/2022] Open
Abstract
Autophagy is a highly conserved mechanism of self-digestion that removes damaged organelles and proteins from cells. Depending on the way the protein is delivered to the lysosome, four basic types of autophagy can be distinguished: macroautophagy, selective autophagy, chaperone-mediated autophagy and microautophagy. Macroautophagy involves formation of autophagosomes and is controlled by specific autophagy-related genes. The steps in macroautophagy are initiation, phagophore elongation, autophagosome maturation, autophagosome fusion with the lysosome, and proteolytic degradation of the contents. Selective autophagy is macroautophagy of a specific cellular component. This work focuses on mitophagy (selective autophagy of abnormal and damaged mitochondria), in which the main participating protein is PINK1 (phosphatase and tensin homolog-induced putative kinase 1). In chaperone-mediated autophagy, the substrate is bound to a heat shock protein 70 chaperone before it is delivered to the lysosome. The least characterized type of autophagy is microautophagy, which is the degradation of very small molecules without participation of an autophagosome. Autophagy can promote or inhibit tumor development, depending on the severity of the disease, the type of cancer, and the age of the patient. This paper describes the molecular basis of the different types of autophagy and their importance in cancer pathogenesis.
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Affiliation(s)
- Martyna Bednarczyk
- Department of Internal Diseases, School of Public Health in Bytom, Medical University of Silesia in Katowice, 40–055 Katowice, Poland
| | - Nikola Zmarzły
- Department of Molecular Biology, School of Pharmacy with The Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, 40–055 Katowice, Poland
| | - Beniamin Grabarek
- Department of Molecular Biology, School of Pharmacy with The Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, 40–055 Katowice, Poland
| | - Urszula Mazurek
- Department of Molecular Biology, School of Pharmacy with The Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, 40–055 Katowice, Poland
| | - Małgorzata Muc-Wierzgoń
- Department of Internal Diseases, School of Public Health in Bytom, Medical University of Silesia in Katowice, 40–055 Katowice, Poland
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28
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Lam KC, Vyshenska D, Hu J, Rodrigues RR, Nilsen A, Zielke RA, Brown NS, Aarnes EK, Sikora AE, Shulzhenko N, Lyng H, Morgun A. Transkingdom network reveals bacterial players associated with cervical cancer gene expression program. PeerJ 2018; 6:e5590. [PMID: 30294508 PMCID: PMC6170155 DOI: 10.7717/peerj.5590] [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: 05/20/2018] [Accepted: 08/15/2018] [Indexed: 12/13/2022] Open
Abstract
Cervical cancer is the fourth most common cancer in women worldwide with human papillomavirus (HPV) being the main cause the disease. Chromosomal amplifications have been identified as a source of upregulation for cervical cancer driver genes but cannot fully explain increased expression of immune genes in invasive carcinoma. Insight into additional factors that may tip the balance from immune tolerance of HPV to the elimination of the virus may lead to better diagnosis markers. We investigated whether microbiota affect molecular pathways in cervical carcinogenesis by performing microbiome analysis via sequencing 16S rRNA in tumor biopsies from 121 patients. While we detected a large number of intra-tumor taxa (289 operational taxonomic units (OTUs)), we focused on the 38 most abundantly represented microbes. To search for microbes and host genes potentially involved in the interaction, we reconstructed a transkingdom network by integrating a previously discovered cervical cancer gene expression network with our bacterial co-abundance network and employed bipartite betweenness centrality. The top ranked microbes were represented by the families Bacillaceae, Halobacteriaceae, and Prevotellaceae. While we could not define the first two families to the species level, Prevotellaceae was assigned to Prevotella bivia. By co-culturing a cervical cancer cell line with P. bivia, we confirmed that three out of the ten top predicted genes in the transkingdom network (lysosomal associated membrane protein 3 (LAMP3), STAT1, TAP1), all regulators of immunological pathways, were upregulated by this microorganism. Therefore, we propose that intra-tumor microbiota may contribute to cervical carcinogenesis through the induction of immune response drivers, including the well-known cancer gene LAMP3.
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Affiliation(s)
- Khiem Chi Lam
- College of Pharmacy, Oregon State University, Corvallis, OR, USA.,Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Dariia Vyshenska
- College of Pharmacy, Oregon State University, Corvallis, OR, USA
| | - Jialu Hu
- College of Pharmacy, Oregon State University, Corvallis, OR, USA.,School of Computer Science, Northwestern Polytechnical University, Xi'an, China
| | | | - Anja Nilsen
- Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Ryszard A Zielke
- College of Pharmacy, Oregon State University, Corvallis, OR, USA
| | | | - Eva-Katrine Aarnes
- Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | | | - Natalia Shulzhenko
- Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR, USA
| | - Heidi Lyng
- Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Andrey Morgun
- College of Pharmacy, Oregon State University, Corvallis, OR, USA
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29
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Zhang X, Liu L, Deng X, Li D, Cai H, Ma Y, Jia C, Wu B, Fan Y, Lv Z. MicroRNA 483-3p targets Pard3 to potentiate TGF-β1-induced cell migration, invasion, and epithelial-mesenchymal transition in anaplastic thyroid cancer cells. Oncogene 2018; 38:699-715. [PMID: 30171257 PMCID: PMC6756112 DOI: 10.1038/s41388-018-0447-1] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 07/09/2018] [Accepted: 07/14/2018] [Indexed: 01/06/2023]
Abstract
Anaplastic thyroid cancer (ATC) is associated with poor prognosis and is often untreatable. MicroRNA 483-3p (miR-483) and partitioning-defective 3 (Pard3), a member of the Pard family, have functions and regulatory mechanisms in ATC. The abnormal regulation of miR-483 may play an important role in tumorigenesis, and Par3 is known to regulate cell polarity, cell migration, and cell division. Tumor proliferation promoted by the regulation of miRNA expression can be regulated in thyroid cancer by upregulating transforming growth factor-β1 (TGF-β1), which is thought to interact with Pard3. When compared with adjacent non-tumor tissues, we found that miR-483 was upregulated and Pard3 was downregulated in 80 thyroid tumor samples. Disease-free survival was decreased when expression of miR-483 was upregulated and Pard3 expression was downregulated. Cell growth, migration, and invasion were induced by overexpression of miR-483. However, knockdown of miR-483 resulted in a loss of cell invasion and viability, both in vitro and in vivo. The expression of Pard3 was increased by the inhibition of miR-483, but TGF-β1-induced cell migration and invasion were decreased by miR-483 inhibition. A dual-luciferase reporter assay determined that Pard3 expression was downregulated when targeted with miR-483. The epithelial–mesenchymal transition (EMT), as well as Tiam1-Rac signaling, was induced by TGF-β1, which was decreased by the overexpression of Pard3. Pard3 decreased the inhibition of EMT and Tiam-Rac1 signaling, which resulted from transfection of ATC cells with miR-483. Overall, the results showed that downregulation of Pard3 resulted in increased cell invasion and EMT in ATC, which was promoted by treatment with miR-483. These findings suggest novel therapeutic targets and treatment strategies for this disease.
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Affiliation(s)
- Xiaoping Zhang
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China.,Shanghai Center of Thyroid Diseases, Shanghai, 200072, China
| | - Lin Liu
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China.,Shanghai Center of Thyroid Diseases, Shanghai, 200072, China
| | - Xianzhao Deng
- Center of Thyroid, Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Dan Li
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China.,Shanghai Center of Thyroid Diseases, Shanghai, 200072, China
| | - Haidong Cai
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China.,Shanghai Center of Thyroid Diseases, Shanghai, 200072, China
| | - Yushui Ma
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China.,Shanghai Center of Thyroid Diseases, Shanghai, 200072, China
| | - Chengyou Jia
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China.,Shanghai Center of Thyroid Diseases, Shanghai, 200072, China
| | - Bo Wu
- Center of Thyroid, Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
| | - Youben Fan
- Center of Thyroid, Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
| | - Zhongwei Lv
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China. .,Shanghai Center of Thyroid Diseases, Shanghai, 200072, China.
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30
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Cui D, Sajan P, Shi J, Shen Y, Wang K, Deng X, Zhou L, Hu P, Gao L. MiR-148a increases glioma cell migration and invasion by downregulating GADD45A in human gliomas with IDH1 R132H mutations. Oncotarget 2018; 8:25345-25361. [PMID: 28445981 PMCID: PMC5421935 DOI: 10.18632/oncotarget.15867] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 02/13/2017] [Indexed: 01/09/2023] Open
Abstract
High-grade gliomas are severe tumors with poor prognosis. An R132H mutation in the isocitrate dehydrogenase (IDH1) gene prolongs the life of glioma patients. In this study, we investigated which genes are differentially regulated in IDH1 wild type (IDH1WT) or IDH1 R132H mutation (IDH1R132H) glioblastoma cells. Growth arrest and DNA-damage-inducible protein (GADD45A) was downregulated and microRNA 148a (miR-148a) was upregulated in in IDH1R132H human glioblastomas tissues. The relationship between GADD45A and miR-148a is unknown. In vitro experiments showed that GADD45A negatively regulates IDH1R132H glioma cell proliferation, migration, and invasion, and neurosphere formation in IDH1R132H glioblastoma stem cells (GSC). In addition, a human orthotopic xenograft mouse model showed that GADD45A reduced tumorigenesis in vivo. Our findings demonstrated that miR-148a promotes glioma cell invasion and tumorigenesis by downregulating GADD45A. Our findings provide novel insights into how GADD45A is downregulated by miR-148a in IDH1R132H glioma and may help to identify therapeutic targets for the effective treatment of high-grade glioma.
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Affiliation(s)
- Daming Cui
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Pandey Sajan
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Jinlong Shi
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, People's Republic of China
| | - Yiwen Shen
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200070, People's Republic of China
| | - Ke Wang
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Xianyu Deng
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Lin Zhou
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Pingping Hu
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Liang Gao
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
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Li J, Huang J, Huang F, Jin Q, Zhu H, Wang X, Chen M. Decreased expression of IDH1-R132H correlates with poor survival in gastrointestinal cancer. Oncotarget 2018; 7:73638-73650. [PMID: 27655638 PMCID: PMC5342004 DOI: 10.18632/oncotarget.12039] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 08/25/2016] [Indexed: 12/20/2022] Open
Abstract
Isocitrate dehydrogenase (IDH1) is an NADP-dependent enzyme that catalyzes the decarboxylation of isocitrate to alpha-ketoglutarate. The IDH1-R132H mutation predicts a better clinical outcome for glioma patients, and the expression of IDH1-R132H correlates with a favorable outcome in patients with brain tumors. Here, we investigated IDH1-R132H expression in both gastric (n=526) and colorectal (n=399) tissues by performing immunohistochemistry analyses on tissue microarrays. We also tested whether IDH1-R132H expression correlated with various clinical parameters. In both gastric and colorectal cancer, expression of IDH1-R132H was associated with tumor stage. Patients with low IDH1-R132H expression had a poor overall survival. Our data indicate that IDH1-R132H expression could be used as a predictive marker of prognosis for patients with gastrointestinal cancer.
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Affiliation(s)
- Jieying Li
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Jianfei Huang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Fang Huang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Qing Jin
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Huijun Zhu
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Xudong Wang
- Department of Laboratory Medicine & Department of Clinical Tissue Bank, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Meng Chen
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NC, USA
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Gao L, Zhang H, Zhang B, Zhu J, Chen C, Liu W. B3GNT3 overexpression is associated with unfavourable survival in non-small cell lung cancer. J Clin Pathol 2018; 71:642-647. [PMID: 29483137 DOI: 10.1136/jclinpath-2017-204860] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Revised: 12/21/2017] [Accepted: 01/29/2018] [Indexed: 12/25/2022]
Abstract
OBJECTIVE The aim of this study was to evaluate the expression of beta-1,3-N-acetylglucosaminyltransferase-3 (B3GNT3) in non-small cell lung cancer (NSCLC) patients and to investigate the relevance of B3GNT3 expression in tumour prognosis. METHODS In this study, B3GNT3 expression was examined in five pairs of resectable NSCLC tissue by Western blot and in 42 pairs of resectable NSCLC tissue by quantitative real-time PCR (qRT-PCR). Immunohistochemistry and statistical analysis were performed to assess the relationship between B3GNT3 expression scores and clinicopathological parameters, as well as clinical prognosis in a retrospective cohort of 176 NSCLC patients. RESULTS Both B3GNT3 mRNA and protein expression levels were significantly higher in NSCLC tissue than in adjacent normal tissue. In the 176 NSCLC cases, a high B3GNT3 expression level was positively correlated with lymph node metastasis (P<0.001) and advanced TNM stage (P=0.043). Kaplan-Meier analysis indicated that patients with high B3GNT3 expression had significantly lower disease-free survival (DFS) (P<0.001) and overall survival (OS) (P<0.001) than those with low B3GNT3 expression. Moreover, in the multivariate analyses, B3GNT3 expression was an independent prognostic factor for DFS (HR 0.329, 95% CI 0.213 to 0.508, P<0.001) and OS (HR 0.383, 95% CI 0.249 to 0.588, P<0.001). CONCLUSIONS Our study demonstrated that high expression of B3GNT3 was associated with unfavourable DFS and OS in NSCLC patients, suggesting that B3GNT3 might be a potential prognostic biomarker for NSCLC.
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Affiliation(s)
- Liuwei Gao
- Department of Lung Cancer, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Hua Zhang
- Department of Lung Cancer, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Bin Zhang
- Department of Lung Cancer, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Jinfang Zhu
- Department of Lung Cancer, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Chen Chen
- Department of Lung Cancer, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Weiran Liu
- Department of Anesthesiology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
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Wu DM, Shi J, Liu T, Deng SH, Han R, Xu Y. Integrated analysis reveals down-regulation of SPARCL1 is correlated with cervical cancer development and progression. Cancer Biomark 2018; 21:355-365. [DOI: 10.3233/cbm-170501] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Zhang X, Wang W, Li P, Wang X, Ni K. High TREM2 expression correlates with poor prognosis in gastric cancer. Hum Pathol 2018; 72:91-99. [DOI: 10.1016/j.humpath.2017.10.026] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2017] [Revised: 10/18/2017] [Accepted: 10/20/2017] [Indexed: 12/16/2022]
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Tang Z, Shen Q, Xie H, Zhou X, Li J, Feng J, Liu H, Wang W, Zhang S, Ni S. Elevated expression of FABP3 and FABP4 cooperatively correlates with poor prognosis in non-small cell lung cancer (NSCLC). Oncotarget 2018; 7:46253-46262. [PMID: 27323829 PMCID: PMC5216795 DOI: 10.18632/oncotarget.10086] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Accepted: 05/29/2016] [Indexed: 12/20/2022] Open
Abstract
Fatty acid binding proteins (FABPs) are intracellular lipid-binding proteins that are involved in a variety of biological cellular processes, including tumorigenesis. In this study, we explored the expression pattern of FABP3 and FABP4 in non-small cell lung cancer (NSCLC) as well as their roles in prognosis. We determined mRNA expression of FABP3 and FABP4 in matched pairs of cancerous and non-cancerous fresh frozen tissues from 30 NSCLC patients. Tissue microarray immunohistochemical analysis (TMA-IHC) was applied to determine the protein expression of FABP3 and FABP4 in 281 cancerous and 121 matched adjacent non-cancerous tissue samples. Our results showed that both mRNA and protein expression of FABP3 and FABP4 were significantly higher in cancerous tissues when compared to non-cancerous tissues. Furthermore, high expression of FABP3 or FABP4 in NSCLC was significantly associated with advanced tumor node metastasis (TNM) stage and had a negative impact on the overall survival of NSCLC patients. Concurrent high expression of FABP3 and FABP4 was significantly related to TNM stage. In conclusion, our research demonstrated that high FABP3 or FABP4 expression had strong prognostic value for overall survival in NSCLC. Detection of FABP3 and FABP4 cooperatively was helpful to predict the prognosis of NSCLC.
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Affiliation(s)
- Zhiyuan Tang
- Department of Respiratory Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China
| | - Qin Shen
- Department of Respiratory Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China
| | - Hao Xie
- Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China
| | - Xiaoyu Zhou
- Department of Respiratory Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China
| | - Jun Li
- Department of Respiratory Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China
| | - Jian Feng
- Department of Respiratory Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China
| | - Hua Liu
- Department of Respiratory Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China
| | - Wei Wang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China
| | - Shu Zhang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China
| | - Songshi Ni
- Department of Respiratory Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China
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Expression profile and prognostic value of NNMT in patients with pancreatic cancer. Oncotarget 2018; 7:19975-81. [PMID: 26942567 PMCID: PMC4991432 DOI: 10.18632/oncotarget.7891] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2015] [Accepted: 02/09/2016] [Indexed: 01/15/2023] Open
Abstract
The elevation of Nicotinamide N-methyltransferase (NNMT) has been reported in pancreatic cancer tissues and cell lines, but its clinical and prognostic implications remain controversial. This study aimed at investigating the expression of NNMT in pancreatic benign and malignant tissues and the prognostic value of NNMT in pancreatic cancer. The expression of NNMT in tissue specimens of 28 chronic pancreatitis patients and 178 pancreatic cancer patients were assayed with immunohistochemistry on tissue microarray. The NNMT expression levels of pancreatic patients were correlated with their clinicopathological characteristics. The influences of NNMT expression and patients' clinicopathological characteristics on overall survival (OS) were analyzed. The percentage of NNMT high expression (NNMTh) in pancreatic cancer (55.6%) was significantly higher than those in chronic pancreatitis (21.4%) and paracancerous tissues (14.8%) (p < 0.001). NNMTh tends to significantly correlate with unfavorable clinicopathological features such as age > 60 years old (p = 0.014), tumor diameter > 4 cm (p < 0.001), TNM stage III or IV (p < 0.001) and poor tumor differentiation (p = 0.004). The median OS of patients with NNMTh and NNMTl were 7.0 months (95% CI: 5.275–8.725) and 11.5 months (95% CI: 9.759–13.241) respectively (p = 0.005). On multivariate analysis, NNMTl (hazards ratio [HR]: 0.399; 95% CI: 0.284–0.560; p < 0.001), absence of neurological involvement (HR: 0.651; 95% CI: 0.421–0.947; p = 0.041), TNM stage I or II (HR: 0.506; 95% CI: 0.299–0.719; p = 0.015) and well tumor differentiation (HR: 0.592; 95% CI: 0.319–0.894; p = 0.044) were significant favorable prognostic factors of OS. In conclusion, NNMT is upregulated in pancreatic cancer, correlates with unfavorable clinicopathological features and may serve as an independent prognosticator of patients' survival.
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Tiam1 promotes thyroid carcinoma metastasis by modulating EMT via Wnt/β-catenin signaling. Exp Cell Res 2018; 362:532-540. [DOI: 10.1016/j.yexcr.2017.12.019] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 12/20/2017] [Accepted: 12/21/2017] [Indexed: 12/17/2022]
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Gui Y, Liu WB, Chen H, Ma JL, Li JS. Expression of LAMP3 and its correlation with clinicopathologic characteristics and prognosis in hepatocellular carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:367-374. [PMID: 31938120 PMCID: PMC6957939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Accepted: 11/10/2017] [Indexed: 06/10/2023]
Abstract
Lysosome-associated membrane protein (LAMP) 3 is one of members of lysosome-associated membrane protein family, which has been reported to play an important role in multiple malignant tumors. However, there is less research about the expression of LAMP3 in hepatocellular carcinoma (HCC). The purpose of this study was to investigate the expression of LAMP3 and explore its roles in HCC.The expression of LAMP3 in 99 cases of HCC tissues was performed by immunohistochemistry. In addition, the expression of LAMP3 in 20 pairs of HCC tissues and pericarcinomatous tissues was determined by quantitative real-time polymerase chain reaction and Western blotting. Immunohistochemical staining showed that LAMP3 was mainly expressed in the cytoplasm. And the expression of LAMP3 in HCC tissues (64/99, 64.6%) was significantly lower than that in pericarcinomatous tissues (23/99, 23.2%). In addition, the expression of LAMP3 mRNA and protein in HCC tissues was also significantly lower than that in pericarcinomatous tissues for 20 pairs of HCC samples. Low expression of LAMP3 was correlated with age, tumor-node-metastasis (TNM) staging, Edmondson grade, alpha-fetoprotein (AFP). Kaplan-Meier analysis showed that patients with low expression of LAMP3 had worse overall survival (OS) and disease-free survival (DFS). Multivariate analysis revealed that low expression of LAMP3 was an independent prognostic factor of OS and DFS for HCC patients.The results suggested that LAMP3 may play an important role in the development and progression of hepatocellular carcinoma, and serve as an independent prognostic predictor for HCC patients after surgical resection.
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Affiliation(s)
- Yang Gui
- Department of General Surgery, Affiliated Provincial Hospital of Anhui Medical UniversityHefei, Anhui, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary SurgeryHefei, Anhui, China
| | - Wen-Bin Liu
- Department of General Surgery, Affiliated Provincial Hospital of Anhui Medical UniversityHefei, Anhui, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary SurgeryHefei, Anhui, China
| | - Hao Chen
- Department of General Surgery, Affiliated Provincial Hospital of Anhui Medical UniversityHefei, Anhui, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary SurgeryHefei, Anhui, China
| | - Jin-Liang Ma
- Department of General Surgery, Affiliated Provincial Hospital of Anhui Medical UniversityHefei, Anhui, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary SurgeryHefei, Anhui, China
| | - Jian-Sheng Li
- Department of General Surgery, Affiliated Provincial Hospital of Anhui Medical UniversityHefei, Anhui, China
- Anhui Province Key Laboratory of Hepatopancreatobiliary SurgeryHefei, Anhui, China
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Wang GH, Zhao CM, Huang Y, Wang W, Zhang S, Wang X. BRCA1 and BRCA2 expression patterns and prognostic significance in digestive system cancers. Hum Pathol 2017; 71:135-144. [PMID: 29126833 DOI: 10.1016/j.humpath.2017.10.032] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 10/18/2017] [Accepted: 10/25/2017] [Indexed: 01/19/2023]
Abstract
The role of BRCA1 and BRCA2 genes is mainly to maintain genome integrity in response to DNA damage through different mechanisms. Deregulation of BRCA1 and BRCA2 is associated with the development of tumor and altered sensitivity to chemotherapeutic agents. In this study, we determined protein expression of BRCA1 and BRCA2 in 4 digestive system cancers (gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer) by immunohistochemistry on tissue microarrays. A total of 1546 samples of 4 types of cancer tissues, their matched adjacent nontumor tissues, and corresponding benign tissues were studied, respectively. Immunohistochemistry expression patterns of the 2 proteins and their correlation with patients' clinical parameters and overall survival were analyzed. The results showed that low expression of cytoplasmic BRCA1 and BRCA2 was commonly associated with advanced tumor-lymph node-metastasis stage, whereas high expression of nuclear BRCA1 was generally correlated with advanced tumor stages in these cancers. High expression of cytoplasmic BRCA1 and BRCA2 had significantly favorable overall survival in digestive system cancers; in contrast, BRCA1 nuclear expression usually predicted poor outcomes. We conclude that BRCA1 and BRCA2 could be used as clinicopathological biomarkers to evaluate the prognosis of digestive system cancers.
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Affiliation(s)
- Gui-Hua Wang
- Department of Laboratory Medicine, Department of Tissue Bank, Affiliated Hospital of Nantong University, School of Public Health, Nantong University, Nantong, Jiangsu, PR China, 226001
| | - Chun-Mei Zhao
- Department of Laboratory Medicine, Department of Tissue Bank, Affiliated Hospital of Nantong University, School of Public Health, Nantong University, Nantong, Jiangsu, PR China, 226001
| | - Ying Huang
- Department of Laboratory Medicine, Department of Tissue Bank, Affiliated Hospital of Nantong University, School of Public Health, Nantong University, Nantong, Jiangsu, PR China, 226001
| | - Wei Wang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, PR China, 226001
| | - Shu Zhang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, PR China, 226001
| | - Xudong Wang
- Department of Laboratory Medicine, Department of Tissue Bank, Affiliated Hospital of Nantong University, School of Public Health, Nantong University, Nantong, Jiangsu, PR China, 226001.
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Li Y, Du W, Han J, Ge J. LAMP3 promotes the invasion of osteosarcoma cells via SPP1 signaling. Mol Med Rep 2017; 16:5947-5953. [PMID: 28849219 PMCID: PMC5865773 DOI: 10.3892/mmr.2017.7349] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 06/09/2017] [Indexed: 01/27/2023] Open
Abstract
Osteosarcoma is the most common type of primary bone cancer in children and young adults. The prognosis of osteosarcoma is very poor when it is diagnosed with metastasis. Lysosomal‑associated membrane protein 3 (LAMP3) is a tumor‑specific protein induced by hypoxia, which stimulates invasion and metastasis of various cancer cells via hypoxia‑inducible factor (HIF). A previous study from our group has reported that expression of LAMP3 is significantly increased in lung metastatic osteosarcoma compared with primary osteosarcoma using microarray analysis, suggesting that LAMP3 may be involved in metastatic osteosarcoma. The present study therefore aimed to investigate the role of LAMP3 in osteosarcoma metastasis. Knockdown of LAMP3 decreased the invasion of two osteosarcoma cell lines in vitro. Furthermore, knockdown of LAMP3 increased the expression of secreted phosphoprotein 1 (SPP1), cadherin 1, and keratin 19, while it decreased the expression of matrix metallopeptidase 2, collagen type III α 1, twist family bHLH transcription factor 1 and cadherin 2. Concurrent knockdown of SPP1 and LAMP3 attenuated the changes in gene expression profile induced by LAMP3 knockdown alone. Gene ontology and KEGG analysis demonstrated that SPP1 was involved in cell adhesion, focal adhesion, and extracellular matrix‑receptor interaction. In conclusion, the present results suggest that LAMP3 may be involved in the invasion and metastasis of osteosarcoma via regulating signaling downstream of SPP1. Thus, LAMP3/SPP1 signaling may serve as a potential target in the future to prevent osteosarcoma metastasis.
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Affiliation(s)
- Yu Li
- Department of Bone Trauma, Yantaishan Hospital, Yantai, Shandong 264000, P.R. China
| | - Wei Du
- Department of Spine Branch, Yantaishan Hospital, Yantai, Shandong 264000, P.R. China
| | - Jian Han
- Department of Bone Oncology, Yantaishan Hospital, Yantai, Shandong 264000, P.R. China
| | - Junbo Ge
- Department of Bone Trauma, Yantaishan Hospital, Yantai, Shandong 264000, P.R. China
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Alessandrini F, Pezzè L, Ciribilli Y. LAMPs: Shedding light on cancer biology. Semin Oncol 2017; 44:239-253. [PMID: 29526252 DOI: 10.1053/j.seminoncol.2017.10.013] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 10/27/2017] [Accepted: 10/29/2017] [Indexed: 01/09/2023]
Abstract
Lysosomes are important cytoplasmic organelles whose critical functions in cells are increasingly being understood. In particular, despite the long-standing accepted concept about the role of lysosomes as cellular machineries solely assigned to degradation, it has been demonstrated that they play active roles in homeostasis and even in cancer biology. Indeed, it is now well documented that during the process of cellular transformation and cancer progression lysosomes are changing localization, composition, and volume and, through the release of their enzymes, lysosomes can also enhance cancer aggressiveness. LAMPs (lysosome associated membrane proteins) represent a family of glycosylated proteins present predominantly on the membrane of lysosomes whose expression can vary among different tissues, suggesting a separation of functions. In this review we focus on the functions and roles of the different LAMP family members, with a particular emphasis on cancer progression and metastatic spread. LAMP proteins are involved in many different aspects of cell biology and can influence cellular processes such as phagocytosis, autophagy, lipid transport, and aging. Interestingly, for all the five members identified so far (LAMP1, LAMP2, LAMP3, CD68/Macrosialin/LAMP4, and BAD-LAMP/LAMP5), a role in cancer has been suggested. While this is well documented for LAMP1 and LAMP2, the involvement of the other three proteins in cancer progression and aggressiveness has recently been proposed and remains to be elucidated. Here we present different examples about how LAMP proteins can influence and support tumor growth and metastatic spread, emphasizing the impact of each single member of the family.
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Affiliation(s)
- Federica Alessandrini
- Laboratory of Molecular Cancer Genetics, Centre for Integrative Biology (CIBIO), University of Trento, Povo (TN), Italy
| | - Laura Pezzè
- Laboratory of Molecular Cancer Genetics, Centre for Integrative Biology (CIBIO), University of Trento, Povo (TN), Italy
| | - Yari Ciribilli
- Laboratory of Molecular Cancer Genetics, Centre for Integrative Biology (CIBIO), University of Trento, Povo (TN), Italy.
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Abstract
OBJECTIVE Several studies have demonstrated that abnormal glutathione peroxidases 1 (Gpx1) expression can influence the biological behavior of malignant cells. However, the roles of Gpx1 in laryngeal squamous cell carcinoma (LSCC) remain unknown. The purpose of this study is to analyze the Gpx1 expression and prognostic significance in LSCC patients. METHODS Gpx1 mRNA levels in laryngeal tissues were determined by qRT-PCR. Meanwhile, We examined the expression levels of Gpx1 protein in 140 primary tumor tissues and 28 cases of normal tissues by immunohistochemistry (IHC) analysis on tissue microarrays (TMA). RESULTS Our results revealed that the frequency of high Gpx1 was significantly higher in cancer tissue compared to normal surgical margins; Gpx1 expression correlated with clinical features and overall survival (OS). Gpx1 overexpression was significantly associated with lymph node metastasis (P=0.023) and TNM stage (P=0.008); Kaplan-Meier survival curves revealed that patients with high Gpx1 expression had worse prognoses than patients with low Gpx1 expression; By multivariate analysis, we revealed that high Gpx1 expression level (HR 2.101, 95%CI 1.011-4.367; P=0.047) was an independent prognostic factor of survival in LSCC patients. CONCLUSION We speculate that Gpx1 can be applied to predict the prognosis in LSCC patients.
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Zhang W, Yan Y, Gu M, Wang X, Zhu H, Zhang S, Wang W. High expression levels of Wnt5a and Ror2 in laryngeal squamous cell carcinoma are associated with poor prognosis. Oncol Lett 2017; 14:2232-2238. [PMID: 28781662 PMCID: PMC5530173 DOI: 10.3892/ol.2017.6386] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Accepted: 03/30/2017] [Indexed: 12/16/2022] Open
Abstract
The present study investigated the prognostic significance of Wnt family member 5a (Wnt5a) and receptor tyrosine kinase-like orphan receptor 2 (Ror2) expression in laryngeal squamous cell carcinoma (LSCC). The protein expression levels of Wnt5a and Ror2 were analyzed in specimens from 137 patients with LSCC, using immunohistochemical staining of tissue microarrays and pairs of LSCC and adjacent tissue samples, and examined the associations between the two markers and various clinicopathological parameters. The Wnt5a and Ror2 expression levels were significantly higher in LSCC tissues than in normal tissue samples (Wnt5a, P=0.015; Ror2, P=0.039), and were significantly associated with high tumor stage (P<0.001), lymph node metastasis (Wnt5a, P=0.029; Ror2, P=0.018), and with each other (P=0.002). Patients with LSCC with high Wnt5a or Ror2 expression had poorer prognosis compared with those with low Wnt5a (P=0.022) or Ror2 (P=0.038) expression. Thus, Wnt5a and Ror2 may affect LSCC development, and are potential biomarkers in LSCC.
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Affiliation(s)
- Wei Zhang
- Department of Otorhinolaryngology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Yongbing Yan
- Department of Otorhinolaryngology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Miao Gu
- Department of Otorhinolaryngology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Xudong Wang
- Department of Surgical Comprehensive Laboratory, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Huijun Zhu
- Department of Clinical Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Shu Zhang
- Department of Clinical Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Wei Wang
- Department of Clinical Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
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Lu J, Ma H, Lian S, Huang D, Lian M, Zhang Y, Huang J, Feng X. Clinical Significance and Prognostic Value of the Expression of LAMP3 in Oral Squamous Cell Carcinoma. DISEASE MARKERS 2017; 2017:1218254. [PMID: 28607528 PMCID: PMC5451762 DOI: 10.1155/2017/1218254] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 04/05/2017] [Accepted: 04/30/2017] [Indexed: 01/27/2023]
Abstract
Recent studies demonstrated high expression of lysosome-associated membrane protein 3 (LAMP3) in a variety of malignancies including esophageal squamous cell carcinoma, gastrointestinal cancer, breast cancer, and cervical cancer and its involvement in several biological activities of tumor cells. However, the expression of LAMP3 and its value in oral squamous cell carcinoma (OSCC) remain unclear. In this study, we examined the expression of LAMP3 in OSCC tissue samples and investigated the relationship between LAMP3 and clinical characteristics of patients with OSCC. We examined mRNA and protein levels of LAMP3 in OSCC tissues and neighboring normal tissues using quantitative real-time polymerase chain reaction and immunohistochemistry analyses, respectively. Both the mRNA and protein levels of LAMP3 were significantly higher in OSCC tissues than in adjacent normal tissues. Chi-square analysis showed that the high LAMP3 expression was notably linked to the degree of tumor differentiation and advanced TNM stage. Univariate and multivariate analyses showed that the high LAMP3 expression was an independent prognostic marker in OSCC. Our results suggest that LAMP3 might act as a potential anticancer target and a prognostic marker in patients with OSCC.
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Affiliation(s)
- Jun Lu
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Hengcheng Ma
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Shuijin Lian
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Dan Huang
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Min Lian
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Ye Zhang
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Jianfei Huang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Xingmei Feng
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
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45
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Mao Y, Jia Y, Zhu H, Wang W, Jin Q, Huang F, Zhang S, Li X. High expression of PFTK1 in cancer cells predicts poor prognosis in colorectal cancer. Mol Med Rep 2017; 16:224-230. [PMID: 28498444 DOI: 10.3892/mmr.2017.6560] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Accepted: 02/15/2017] [Indexed: 11/05/2022] Open
Abstract
The serine/threonine-protein kinase PFTAIRE 1 (PFTK1) is a member of the cyclin‑dependent kinase family that is highly expressed in several malignant tumors, including hepatocellular carcinoma, esophageal, breast and gastric cancers, and glioma. It contributes to tumor progression and influences tumor prognosis. However, the expression and clinicopathological significance of PFTK1 in human colorectal cancer (CRC) remain to be elucidated. The present study aimed to examine the expression of PFTK1 and to evaluate the clinical significance of its expression in human CRC. Reverse transcription‑quantitative polymerase chain reaction was performed on 10 fresh CRC and 10 surrounding normal tissue samples to detect and compare the expression of PFTK1 mRNA in CRC and normal colorectal tissues. Immunohistochemistry was performed on 179 CRC tissue specimens and 47 control samples of normal colorectal lesions to characterize the expression of PFTK1 protein. Kaplan‑Meier overall survival (OS) rate and Cox regression analyses were performed to evaluate the prognosis of patients with CRC. The expression of PFTK1 mRNA in CRC tissues (1.433±0.168) was significantly higher compared with normal tissues (0.853±0.107; t=1.97 ('t' was the value obtained from quantification of the mRNA data, following a paired t‑test), P=0.008). High PFTK1 expression in cancerous cells was detected in 92 of the CRC specimens (51.40%), and high levels of PFTK1 were associated with tumor node metastasis (TNM) stage (P=0.042), tumor classification (P=0.022) and preoperative carcinoembryonic antigen (CEA) level (P<0.001). Kaplan‑Meier OS rate and Cox regression analysis revealed that high PFTK1 expression level (hazard ratio (HR)=1.999; P=0.019) was an independent prognostic factor of CRC patients. The degree of differentiation (HR, 0.368, P=0.003), TNM classification (HR, 2.118, P=0.001) and preoperative CEA level (HR, 2.302, P=0.003) were also predictors of the prognosis of patients with CRC. The present study suggested that PFTK1 may be a potential anticancer target and prognostic marker in patients with CRC.
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Affiliation(s)
- Youjun Mao
- Department of Vascular Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
| | - Yuqing Jia
- Department of General Surgery, Friendliness Hospital, Yangzhou, Jiangsu 225009, P.R. China
| | - Huijun Zhu
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Wei Wang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Qin Jin
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Fang Huang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Shu Zhang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Xiaoqiang Li
- Department of Vascular Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
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46
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Zhao W, Ding G, Wen J, Tang Q, Yong H, Zhu H, Zhang S, Qiu Z, Feng Z, Zhu J. Correlation between Trop2 and amphiregulin coexpression and overall survival in gastric cancer. Cancer Med 2017; 6:994-1001. [PMID: 28256068 PMCID: PMC5430091 DOI: 10.1002/cam4.1018] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 11/14/2016] [Accepted: 12/27/2016] [Indexed: 12/28/2022] Open
Abstract
Gastric cancer (GC) is a multistep and multistage disease and the majority of GC cells could overexpressed one or more oncogenes. Trop2 and amphiregulin (AREG) are both overexpressed in various epithelial cell cancers and have the role in the increases tumor cells division and metastasis. However, little is known about the function and correlation of two oncogenes coexpressed in GC. The expression level of these two genes in 791 cases of GC tissues were tested, the correlations between two genes expression and clinical pathological characteristics and overall survival in GC patients through immunohistochemistry (IHC) were analyzed. This study also explored the mRNA expression level of two genes in 26 cases of freshly GC tissues by qRT‐PCR. The results indicated that Trop2+/AREG+ coexpression was higher in GC tissues than in adjacent tissues. Trop2+/AREG+ protein coexpression were associated with Tumor Node Metastasis (TNM) stage (χ2 = 50.345, P < 0.001), tumor size (χ2 = 40.349, P < 0.001), lymph node metastases (χ2 = 26.481, P < 0.001), and distant metastases (χ2 = 8.387, P = 0.039). GC patients with Trop2+ and AREG+ protein coexpression had poor overall survival rates (HR = 3.682, 95% CI = 2.038–6.654, P < 0.001). The expression level of Trop2/AREG were positively correlated (r 0.254 and P < 0.001). The result of the mRNA expression was similar to that of the protein expression. Overall, Trop2 and AREG could be seen as prognostic cobiomarker in GC and combined detection of Trop2 and AREG could be viewed as helpful in predicting the prognosis of the GC patients.
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Affiliation(s)
- Wei Zhao
- Department of Pathology, Nanjing Medical University, Nanjing, 210029, China.,School of Public Health, Nantong University, Nantong, 226019, China
| | - Guipeng Ding
- Department of Pathology, Nanjing Medical University, Nanjing, 210029, China
| | - Jinbo Wen
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, 210029, China
| | - Qi Tang
- Key Laboratory of Antibody Technique of Ministry of Health, Nanjing Medical University, Nanjing, 210029, China
| | - Hongmei Yong
- Department of Oncology, Huai'an Hospital Affiliated of Xuzhou Medical College and Huai'an Second People's Hospital, Huai'an, 223001, China
| | - Huijun Zhu
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, 226019, China
| | - Shu Zhang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, 226019, China
| | - Zhenning Qiu
- Key Laboratory of Antibody Technique of Ministry of Health, Nanjing Medical University, Nanjing, 210029, China
| | - Zhenqing Feng
- Department of Pathology, Nanjing Medical University, Nanjing, 210029, China.,Key Laboratory of Antibody Technique of Ministry of Health, Nanjing Medical University, Nanjing, 210029, China.,Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 210029, China.,Key Laboratory of Cancer Biomarkers, Prevent and Treatment, Cancer Center, Nanjing Medical University, Nanjing, 210029, China
| | - Jin Zhu
- Key Laboratory of Antibody Technique of Ministry of Health, Nanjing Medical University, Nanjing, 210029, China.,Huadong Medical Institute of Biotechniques, Nanjing, 210029, China
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47
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Wang D, Cao X, Zhang Y, Liu Y, Yao C, Ge W, Xu Y. LAMP3 expression correlated with poor clinical outcome in human ovarian cancer. Tumour Biol 2017; 39:1010428317695014. [PMID: 28349821 DOI: 10.1177/1010428317695014] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Lysosome-associated membrane protein 3 belongs to the lysosome-associated membrane glycoprotein family, which is associated with lymph node, metastasis, poor overall survival, and resistance to chemotherapy and radiotherapy. Epithelial ovarian cancer is one of the most deadly global female gynecologic malignant tumors. Its clinical outcome is poor and most epithelial ovarian cancer patients tend to relapse because of drug resistance. However, lysosome-associated membrane protein 3 expression in epithelial ovarian cancer and its relationship between clinicopathologic factors remain poorly understood. To clarify the prognostic implications of lysosome-associated membrane protein 3 in epithelial ovarian cancer, we analyzed both messenger RNA and protein levels of lysosome-associated membrane protein 3 in ovarian carcinomas. Polymerase chain reaction results showed higher expression of lysosome-associated membrane protein 3 messenger RNA in epithelial ovarian cancer than in noncancerous tissues. Immunohistochemical results showed that high lysosome-associated membrane protein 3 cytoplasmic expression was significantly related to tumor grade ( p = 0.038), lymph node metastasis ( p = 0.049), metastasis ( p < 0.001), level of CA125 ( p = 0.030), and International Federation of Gynecology and Obstetrics (FIGO) ( p < 0.001). High lysosome-associated membrane protein 3 nuclear expression was significantly associated with tumor grade ( p = 0.046), tumor single or double (representative whether the tumor involving one or both ovaries) ( p = 0.016), metastasis ( p < 0.001), and FIGO stage ( p < 0.001). Survival analysis indicated that high lysosome-associated membrane protein 3 cytoplasmic expression (hazard ratio: 4.632, 95% confidence interval: 2.421-8.864; p < 0.001), patients' age (hazard ratio: 1.729, 95% confidence interval: 1.027-2.911; p = 0.039), and FIGO stage (hazard ratio: 2.049, 95% confidence interval: 1.113-3.774; p = 0.021) were significantly correlated with poor survival outcome of epithelial ovarian cancer patients.
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Affiliation(s)
- Di Wang
- 1 Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, China
| | - Xuemin Cao
- 2 Department of Biology, Nantong University, Nantong, China
| | - Yuquan Zhang
- 1 Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, China
| | - Yuanlin Liu
- 1 Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, China
| | - Chan Yao
- 3 Department of Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Wenliang Ge
- 4 Department of Pediatric Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Yunzhao Xu
- 1 Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, China
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Zhao W, Zhu H, Zhang S, Yong H, Wang W, Zhou Y, Wang B, Wen J, Qiu Z, Ding G, Feng Z, Zhu J. Trop2 is overexpressed in gastric cancer and predicts poor prognosis. Oncotarget 2017; 7:6136-45. [PMID: 26716416 PMCID: PMC4868745 DOI: 10.18632/oncotarget.6733] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 12/08/2015] [Indexed: 12/20/2022] Open
Abstract
The cell surface protein Trop2 is overexpressed in a variety of human cancers. Trop2 expression increases tumor development and metastasis and reduces patient survival. However, little is known about the role of Trop2 expression and its prognostic value in gastric cancer (GC), particularly in Chinese populations. We analyzed Trop2 expression in GC tissues collected from Chinese GC patients. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry on tissue microarrays were performed to assess levels of Trop2 mRNA and protein in GC, and correlations between Trop2 expression and clinical characteristics and prognosis were analyzed. Trop2 expression was higher in GC tissues than in neighboring non-tumor tissues. Increased Trop2 protein levels in GC were associated with increased differentiation, tumor node metastasis stage, tumor size, lymph node metastasis, distant metastasis, and H. pylori infection. GC patients with high Trop2 expression also had poor overall survival rates. These data suggest Trop2 is a useful prognostic biomarker for GC.
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Affiliation(s)
- Wei Zhao
- Department of Pathology, Nanjing Medical University, Nanjing 210029, China.,School of Public Health, Nantong University, Nantong 226019, China
| | - Huijun Zhu
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong 226019, China
| | - Shu Zhang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong 226019, China
| | - Hongmei Yong
- Department of Oncology, Huai'an Hospital Affiliated of Xuzhou Medical College and Huai'an Second People's Hospital, Huai'an 223001, China
| | - Wei Wang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong 226019, China
| | - Yan Zhou
- Department of Oncology, AoYoung Hospital, Zhangjiagang, Jiangsu 215617, China
| | - Bing Wang
- Department of Oncology, AoYoung Hospital, Zhangjiagang, Jiangsu 215617, China
| | - Jinbo Wen
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing 210029, China
| | - Zhenning Qiu
- Key Laboratory of Antibody Technique of Ministry of Health, Nanjing Medical University, Nanjing 210029, China
| | - Guipeng Ding
- Department of Pathology, Nanjing Medical University, Nanjing 210029, China
| | - Zhenqing Feng
- Department of Pathology, Nanjing Medical University, Nanjing 210029, China.,Key Laboratory of Antibody Technique of Ministry of Health, Nanjing Medical University, Nanjing 210029, China.,Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 210029, China.,Key Laboratory of Cancer Biomarkers, Prevent and Treatment, Cancer Center, Nanjing Medical University, Nanjing 210029, China
| | - Jin Zhu
- Key Laboratory of Antibody Technique of Ministry of Health, Nanjing Medical University, Nanjing 210029, China.,Huadong Medical Institute of Biotechniques, Nanjing 210029, China
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49
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Malaguarnera L, Marsullo A, Zorena K, Musumeci G, Di Rosa M. Vitamin D 3 regulates LAMP3 expression in monocyte derived dendritic cells. Cell Immunol 2017; 311:13-21. [PMID: 27697285 DOI: 10.1016/j.cellimm.2016.09.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Revised: 09/27/2016] [Accepted: 09/27/2016] [Indexed: 12/18/2022]
Abstract
The family of lysosome-associated membrane proteins (LAMPs) encompassing LAMP1, LAMP2 and DC-LAMP (LAMP3) are the major constituents of the glycoconjugates coat present on the inside of the lysosomal membrane. LAMP3 is highly expressed only in certain cell types and during the differentiation stages. Its expression is linked the maturation of dendritic cells, inflammation, poor prognosis of certain tumors, and the locus where it is encoded was identified as a risk factor for Parkinson's disease (PD). Here, we investigated the capacity of Vitamin D3 to modulate the expression of LAMP3 during the dendritic cells differentiation and maturation. Our results demonstrated that the Vitamin D3 reduce the LAMP3 mRNA/protein expression during the dendritic cells differentiation and maturation, via NFκB pathways. Furthermore, we demonstrated that the Vitamin D3 was able to modulate the expression of LAMP3 likewise to in vitro tolerogenic dendritic cells. In summary, these data showed that the decrease of LAMP3 expression by Vitamin D3could enhance the tolerogenic characteristic of dendritic cells.
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Affiliation(s)
- L Malaguarnera
- Department of Biomedical and Biotechnology Sciences, University of Catania, Italy
| | - A Marsullo
- Department of Biomedical and Biotechnology Sciences, University of Catania, Italy
| | - K Zorena
- Department of Clinical and Experimental Endocrinology, Institute of Maritime and Tropical Medicine, Medical University of Gdansk, Poland
| | - G Musumeci
- Departments of Clinical and Experimental Medicine, Internal Medicine Division, Human Anatomy and Histology Section, School of Medicine, University of Catania, Catania, Italy
| | - M Di Rosa
- Department of Biomedical and Biotechnology Sciences, University of Catania, Italy.
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50
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Yao S, Zhong L, Liu J, Feng J, Bian T, Zhang Q, Chen J, Lv X, Chen J, Liu Y. Prognostic value of decreased GRK6 expression in lung adenocarcinoma. J Cancer Res Clin Oncol 2016; 142:2541-2549. [PMID: 27601164 DOI: 10.1007/s00432-016-2244-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2016] [Accepted: 08/31/2016] [Indexed: 01/15/2023]
Abstract
BACKGROUND In recent years, G protein-coupled receptor kinases (GRKs) have been implicated in cancer metastasis through phosphorylation of the activated form of G protein-coupled receptors. However, little is known of GRK6 expression in lung adenocarcinoma (LADC) and its potential prognostic value in LADC. METHODS In this study, protein expression of GRK6 was determined in LADC tissues (n = 122) and normal lung tissues (n = 45) by immunohistochemistry (IHC) analysis on tissue microarray (TMA). In addition, mRNA level of GRK6 in matched pairs of cancerous and non-cancerous fresh frozen tissues from 20 LADC patients was investigated using real-time quantitative PCR (qPCR). Furthermore, protein expression level of GRK6 was evaluated in matched pairs of cancerous and non-cancerous fresh frozen tissues from another 18 LADC patients. Univariate and multivariate analyses based on Cox proportional hazards regression models were performed to investigate the correlation between GRK6 expression and overall survival of LADC patients. RESULTS According to the IHC analysis on TMA, GRK6 expression was significantly down-regulated in LADC patients, but high in normal lung tissue (P < 0.001). Besides, our qPCR and western blot results confirmed GRK6 down-regulation in both mRNA and protein levels in LADC tissues as compared to matched adjacent non-cancerous tissues (all P < 0.001). Additionally, For TMA slides, protein expression of GRK6 was significantly associated with staging (P = 0.030), pathology grade (P = 0.036). Consistent with the associated poor clinicopathologic features, patients with GRK6 low expression tumors had a worse overall survival compared to patients with GRK6 high expression tumors. Further multivariate analysis using the Cox proportional hazards model revealed that GRK6 expression level (P = 0.004) was an independent prognostic factor for overall survival. CONCLUSION These findings indicate for the first time that decreased expression of GRK6 may serve as an independent predictor of overall survival in LADC patients.
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Affiliation(s)
- Sumei Yao
- Department of Respiratory Medicine, The Second Affiliated Hospital of Nantong University, Nantong, 226001, People's Republic of China
| | - Lou Zhong
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, People's Republic of China
| | - Jian Liu
- Department of Chemotherapy, Affiliated Hospital of Nantong University, Nantong, 226001, People's Republic of China
| | - Jia Feng
- Department of Pathology, Affiliated Hospital of Nantong University, No. 20, Xisi Road, Nantong, 226001, Jiangsu Province, People's Republic of China
| | - Tingting Bian
- Department of Pathology, Affiliated Hospital of Nantong University, No. 20, Xisi Road, Nantong, 226001, Jiangsu Province, People's Republic of China
| | - Qing Zhang
- Department of Pathology, Affiliated Hospital of Nantong University, No. 20, Xisi Road, Nantong, 226001, Jiangsu Province, People's Republic of China
| | - Jinliang Chen
- Department of Respiratory Medicine, The Second Affiliated Hospital of Nantong University, Nantong, 226001, People's Republic of China
| | - Xuedong Lv
- Department of Respiratory Medicine, The Second Affiliated Hospital of Nantong University, Nantong, 226001, People's Republic of China
| | - Jianrong Chen
- Department of Respiratory Medicine, The Second Affiliated Hospital of Nantong University, Nantong, 226001, People's Republic of China
| | - Yifei Liu
- Department of Pathology, Affiliated Hospital of Nantong University, No. 20, Xisi Road, Nantong, 226001, Jiangsu Province, People's Republic of China.
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