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1
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Thomas P, Ramani P, Ramasubramanian A, Sekar D. Characterizing
miR-20a-3p
Expression in the Progression of Oral Squamous Cell Carcinoma. JOURNAL OF ADVANCED ORAL RESEARCH 2025; 16:34-42. [DOI: 10.1177/23202068241307076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
Aim:
This study aims to elucidate the role of
miR-20a-3p
in the inhibition of tumor suppressor genes, thereby enhancing the development and advancement of oral squamous cell carcinoma (OSCC) by fostering the proliferation and viability of tumor cells. Additionally, the study seeks to evaluate the potential of
miR-20a-3p
as a prognostic biomarker for more effective treatment strategies in OSCC patients.
Materials and Methods:
This observational, analytical study utilized a convenience sampling method, involving a total of 63 OSCC biopsy samples and corresponding nontumor oral tissues from the same patients. The expression levels of
miR-20a-3p
were quantified using quantitative real-time polymerase chain reaction. Clinical information, including tumor stage, and grade was obtained. Statistical analysis included unpaired Student’s
t
tests to compare
miR-20a-3p
expression levels between normal and OSCC samples, and one-way ANOVA to compare expression across different grades and stages of the tumor, using SPSS version 19.
Results:
Our findings demonstrate that
miR-20a-3p
expression was significantly downregulated in OSCC samples compared to healthy controls (
p
< .001). Additionally, we observed a correlation between
miR-20a-3p
downregulation and OSCC histological grade and staging.
miR-20a-3p
expression levels were significantly different across different grades of OSCC, particularly between well-differentiated squamous cell carcinoma (WDSCC) and poorly differentiated squamous cell carcinoma (PDSCC) (
p
< .006) and moderately differentiated squamous cell carcinoma and PDSCC (
p
< .008). There was a significant difference in
miR-20a-3p
expression between normal tissues and Stage II (
p
< .006) and Stage IV (
p
< .001) OSCC.
Conclusion:
The study confirms that
miR-20a-3p
acts as a tumor suppressor in OSCC and holds potential as a biomarker for prognosis and personalized treatment strategies. miR-20a-3p expression is significantly reduced in OSCC tissues compared to normal tissues, and its levels vary with tumor grade and stage. These findings underscore the importance of further research into miRNAs as therapeutic targets.
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Affiliation(s)
- Priya Thomas
- Annoor Dental College, Muvattupuzha, Kerala, India
- Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Science (SIMATS), Saveetha University, Chennai, Tamil Nadu, India
| | - Pratibha Ramani
- Department of Oral Pathology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
| | - Abilasha Ramasubramanian
- Department of Oral Pathology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
| | - Durairaj Sekar
- Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Science (SIMATS), Saveetha University, Chennai, Tamil Nadu, India
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2
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Alizadeh M, Ghasemi H, Bazhan D, Mohammadi Bolbanabad N, Rahdan F, Arianfar N, Vahedi F, Khatami SH, Taheri-Anganeh M, Aiiashi S, Armand N. MicroRNAs in disease States. Clin Chim Acta 2025; 569:120187. [PMID: 39938625 DOI: 10.1016/j.cca.2025.120187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 02/08/2025] [Accepted: 02/08/2025] [Indexed: 02/14/2025]
Abstract
This review highlights the role of miRNAs in various diseases affecting major organ systems. miRNAs are small, non-coding RNA molecules that regulate numerous genes. Dysregulation of miRNAs is linked to many pathological conditions due to their involvement in gene silencing and cellular pathways. We discuss miRNA expression patterns, their physiological and pathological roles, and how changes in miRNA levels contribute to disease. Notably, miRNAs like miR-499 and miR-21 are implicated in heart failure and atherosclerosis. miRNA dysregulation is also associated with colorectal and gastric cancers, influencing tumorigenesis and chemoresistance. In neurological diseases, miRNAs exhibit diverse profiles that affect neurodevelopment and degeneration. Additionally, miRNAs modulate cell function in reproductive organs, impacting fertility and cancer progression. miRNAs such as miR-192 and miR-204 serve as biomarkers for nephropathy and acute kidney injury. These miRNAs are involved in skeletal muscle diseases, contributing to conditions like osteoporosis and sarcopenia. miRNAs function as oncogenes or tumor suppressors in cancer, highlighting their potential in diagnostics and therapy. Further research is needed to develop miRNA-based diagnostics and treatments.
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Affiliation(s)
- Mehdi Alizadeh
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hassan Ghasemi
- Research Center for Environmental Contaminants (RCEC), Abadan University of Medical Sciences, Abadan, Iran
| | - Donya Bazhan
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Fereshteh Rahdan
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Narges Arianfar
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farzaneh Vahedi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Seyyed Hossein Khatami
- Student Research Committee, Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mortaza Taheri-Anganeh
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
| | - Saleh Aiiashi
- Abadan University of Medical Sciences, Abadan, Iran.
| | - Nezam Armand
- Dietary Supplements and Probiotic Research Center, Alborz University of Medical Sciences, Karaj, Iran.
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3
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Olarewaju O, Hu Y, Tsay HC, Yuan Q, Eimterbäumer S, Xie Y, Qin R, Ott M, Sharma AD, Balakrishnan A. MicroRNA miR-20a-5p targets CYCS to inhibit apoptosis in hepatocellular carcinoma. Cell Death Dis 2024; 15:456. [PMID: 38937450 PMCID: PMC11211328 DOI: 10.1038/s41419-024-06841-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 06/13/2024] [Accepted: 06/17/2024] [Indexed: 06/29/2024]
Abstract
Hepatocellular carcinoma is a primary liver cancer, characterised by diverse etiology, late diagnoses, and poor prognosis. Hepatocellular carcinoma is mostly resistant to current treatment options, therefore, identification of more effective druggable therapeutic targets is needed. We found microRNA miR-20a-5p is upregulated during mouse liver tumor progression and in human hepatocellular carcinoma patients. In this study, we elucidated the therapeutic potential of targeting oncogenic miR-20a-5p, in vivo, in a xenograft model and in two transgenic hepatocellular carcinoma mouse models via adeno-associated virus-mediated miR-20a-Tough-Decoy treatment. In vivo knockdown of miR-20a-5p attenuates tumor burden and prolongs survival in the two independent hepatocellular carcinoma mouse models. We identified and validated cytochrome c as a novel target of miR-20a-5p. Cytochrome c plays a key role in initiation of the apoptotic cascade and in the electron transport chain. We show for the first time, that miR-20a modulation affects both these key functions of cytochrome c during HCC development. Our study thus demonstrates the promising 'two birds with one stone' approach of therapeutic in vivo targeting of an oncogenic miRNA, whereby more than one key deregulated cellular process is affected, and unequivocally leads to more effective attenuation of HCC progression and significantly longer overall survival.
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Affiliation(s)
- Olaniyi Olarewaju
- Department of Gastroenterology, Hepatology, Infectious Diseases, and Endocrinology, Hannover Medical School, Hannover, Germany
- AAV Gene Therapy Research Group, Research Beyond Borders (RBB), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, 88400, Germany
| | - Yuhai Hu
- Department of Gastroenterology, Hepatology, Infectious Diseases, and Endocrinology, Hannover Medical School, Hannover, Germany
- Department of Hepatopancreatobiliary Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
| | - Hsin-Chieh Tsay
- Department of Gastroenterology, Hepatology, Infectious Diseases, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Qinggong Yuan
- Department of Gastroenterology, Hepatology, Infectious Diseases, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Simon Eimterbäumer
- Department of Gastroenterology, Hepatology, Infectious Diseases, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Yu Xie
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, China
| | - Renyi Qin
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, China
| | - Michael Ott
- Department of Gastroenterology, Hepatology, Infectious Diseases, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Amar Deep Sharma
- Department of Gastroenterology, Hepatology, Infectious Diseases, and Endocrinology, Hannover Medical School, Hannover, Germany.
- Research Group RNA Therapeutics & Liver Regeneration, REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany.
| | - Asha Balakrishnan
- Department of Gastroenterology, Hepatology, Infectious Diseases, and Endocrinology, Hannover Medical School, Hannover, Germany.
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4
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Wu Z, Ke Q, Jiang L, Hong H, Pan W, Chen W, Abudukeremu X, She F, Chen Y. TGF-β1 facilitates gallbladder carcinoma metastasis by regulating FOXA1 translation efficiency through m 6A modification. Cell Death Dis 2024; 15:422. [PMID: 38886389 PMCID: PMC11183149 DOI: 10.1038/s41419-024-06800-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 05/22/2024] [Accepted: 05/31/2024] [Indexed: 06/20/2024]
Abstract
TGF-β1 plays a pivotal role in the metastatic cascade of malignant neoplasms. N6-methyladenosine (m6A) stands as one of the most abundant modifications on the mRNA transcriptome. However, in the metastasis of gallbladder carcinoma (GBC), the effect of TGF-β1 with mRNA m6A modification, especially the effect of mRNA translation efficiency associated with m6A modification, remains poorly elucidated. Here we demonstrated a negative correlation between FOXA1 and TGF-β1 expression in GBC. Overexpression of FOXA1 inhibited TGF-β1-induced migration and epithelial-mesenchymal transition (EMT) in GBC cells. Mechanistically, we confirmed that TGF-β1 suppressed the translation efficiency of FOXA1 mRNA through polysome profiling analysis. Importantly, both in vivo and in vitro experiments showed that TGF-β1 promoted m6A modification on the coding sequence (CDS) region of FOXA1 mRNA, which was responsible for the inhibition of FOXA1 mRNA translation by TGF-β1. We demonstrated through MeRIP and RIP assays, dual-luciferase reporter assays and site-directed mutagenesis that ALKBH5 promoted FOXA1 protein expression by inhibiting m6A modification on the CDS region of FOXA1 mRNA. Moreover, TGF-β1 inhibited the binding capacity of ALKBH5 to the FOXA1 CDS region. Lastly, our study confirmed that overexpression of FOXA1 suppressed lung metastasis and EMT in a nude mice lung metastasis model. In summary, our research findings underscore the role of TGF-β1 in regulating TGF-β1/FOXA1-induced GBC EMT and metastasis by inhibiting FOXA1 translation efficiency through m6A modification.
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Affiliation(s)
- Zhenheng Wu
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350001, China
- Fujian Medical University Cancer Center, Fuzhou, Fujian, 350122, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fujian Medical University, Fuzhou, Fujian, 350122, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, Fujian, 350122, China
| | - Qiming Ke
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350001, China
- Fujian Medical University Cancer Center, Fuzhou, Fujian, 350122, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fujian Medical University, Fuzhou, Fujian, 350122, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, Fujian, 350122, China
| | - Lei Jiang
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350001, China
- Fujian Medical University Cancer Center, Fuzhou, Fujian, 350122, China
| | - Haijie Hong
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350001, China
- Fujian Medical University Cancer Center, Fuzhou, Fujian, 350122, China
| | - Wei Pan
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350001, China
- Fujian Medical University Cancer Center, Fuzhou, Fujian, 350122, China
| | - Wen Chen
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350001, China
- Fujian Medical University Cancer Center, Fuzhou, Fujian, 350122, China
| | - Xiahenazi Abudukeremu
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350001, China
- Fujian Medical University Cancer Center, Fuzhou, Fujian, 350122, China
| | - Feifei She
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fujian Medical University, Fuzhou, Fujian, 350122, China.
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, Fujian, 350122, China.
| | - Yanling Chen
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350001, China.
- Fujian Medical University Cancer Center, Fuzhou, Fujian, 350122, China.
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fujian Medical University, Fuzhou, Fujian, 350122, China.
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, Fujian, 350122, China.
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5
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Saxena R, Krishnan M P S, Christudass CS, Chauhan A, Malik VS, Gupta A, Gupta S, Anthwal A, Goyal B. Micro-RNAs With Prognostic Significance in Gallbladder Cancer: A Systematic Review and Meta-Analysis. Cureus 2024; 16:e55515. [PMID: 38576631 PMCID: PMC10990876 DOI: 10.7759/cureus.55515] [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: 03/04/2024] [Indexed: 04/06/2024] Open
Abstract
Gallbladder cancer (GBC) stands out as one of the most widespread malignancies impacting the biliary tract globally. Despite increasing interest, to the best of our knowledge, no meta-analysis has been undertaken to amalgamate the existing data concerning the prognostic significance of micro-RNAs (miRNAs) in GBC in comparison to studies on miRNAs in other cancers. Hence, this systematic review and meta-analysis aimed at determining the prognostic significance of miRNAs in GBC patients. Comprehensive literature searches were conducted across PubMed, Cochrane Library, Ovid, Scopus, and Science Direct databases. Studies that evaluated the association between miRNAs and overall survival in GBC patients were included. Random-effect meta-analysis was employed to pool hazard ratios (HRs) and their 95% confidence intervals (CIs) across studies. A total of 15 studies, encompassing 16 miRs, were included for our analysis. The pooled analysis revealed that a high expression of miR-204, miR-7-2-3p, miR-29c-3p, miR-125b, miR-20a, miR-139-5p, miR-141, miR-92b-3p, miR-335, and miR-372 was significantly associated with poor prognosis and increased risk (HR>1 and the upper bound of the 95% CI>1). Additionally, these miRNAs were associated with the overall survival (HR = 1.56, 95% CI = 0.91-2.20, I2 = 91.82%). Significant heterogeneity was observed and could be attributed to the limited number of studies available on the GBC and significant reliance on quantitative real-time PCR for the detection of miRNAs. In conclusion, specific miRNAs exhibit prognostic significance in GBC, with potential implications for patient stratification and targeted therapeutic interventions. However, due to the heterogeneity among studies, these findings should be interpreted cautiously and validated in larger cohorts.
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Affiliation(s)
- Rahul Saxena
- Biochemistry, All India Institute of Medical Sciences, Rishikesh, Rishikesh, IND
| | - Sarath Krishnan M P
- Biochemistry, All India Institute of Medical Sciences, Rishikesh, Rishikesh, IND
| | | | - Anil Chauhan
- Telemedicine, Postgraduate Institute of Medical Education and Research, Chandigarh, IND
| | - Vivek S Malik
- Telemedicine, Centre for Evidence Synthesis and Public Policy, All India Institute of Medical Sciences, Rishikesh, Rishikesh, IND
| | - Amit Gupta
- General Surgery, All India Institute of Medical Sciences, Rishikesh, Rishikesh, IND
| | - Sweety Gupta
- Radiation Oncology, All India Institute of Medical Sciences, Rishikesh, Rishikesh, IND
| | - Akhil Anthwal
- Biochemistry, All India Institute of Medical Sciences, Rishikesh, Rishikesh, IND
| | - Bela Goyal
- Biochemistry, All India Institute of Medical Sciences, Rishikesh, Rishikesh, IND
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6
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Quraishi R, Sanyal S, Dwivedi M, Moitra M, Dwivedi M. Genetic Factors and MicroRNAs in the Development of Gallbladder Cancer: The Prospective Clinical Targets. Curr Drug Targets 2024; 25:375-387. [PMID: 38544392 DOI: 10.2174/0113894501182288240319074330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 01/14/2024] [Accepted: 02/01/2024] [Indexed: 07/19/2024]
Abstract
Gallbladder cancer (GBC) is an uncommon condition in which malignant (cancer) cells are detected in gallbladder tissue. Cancer is often triggered when normal cells turn malignant and begin to spread. Cancer can also be caused by genetic anomalies that result in uncontrolled cell proliferation and tumor development. MicroRNAs (also known as miRNAs or miRs) are a group of small, endogenous, non-coding RNAs of 19-23 nucleotides in length, which play a key role in post-transcriptional gene regulation. These miRNAs serve as negative gene regulators by supervising target genes and regulating biological processes, including cell proliferation, migration, invasion, and apoptosis. Cancer development and progression relate to aberrant miRNA expression. This review demonstrated the implication of various genetic factors and microRNAs in developing and regulating GBC. This suggests the potential of genes and RNAs as the diagnostic, prognostic, and therapeutic targets in gallbladder cancer.
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Affiliation(s)
- Roshni Quraishi
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Gomtinagar Extension, Lucknow-226028, India
| | - Somali Sanyal
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Gomtinagar Extension, Lucknow-226028, India
| | - Medha Dwivedi
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Gomtinagar Extension, Lucknow-226028, India
| | - Monika Moitra
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Gomtinagar Extension, Lucknow-226028, India
| | - Manish Dwivedi
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Gomtinagar Extension, Lucknow-226028, India
- Research Cell, Amity University Uttar Pradesh, Lucknow Campus, Gomtinagar Extension, Lucknow-226028, India
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7
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Shao H, Zhu J, Zhu Y, Liu L, Zhao S, Kang Q, Liu Y, Zou H. Identification of characteristic genes and construction of regulatory network in gallbladder carcinoma. BMC Med Genomics 2023; 16:240. [PMID: 37821907 PMCID: PMC10566037 DOI: 10.1186/s12920-023-01663-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 09/17/2023] [Indexed: 10/13/2023] Open
Abstract
BACKGROUND Gallbladder carcinoma (GBC) is a highly malignant tumor with a poor overall prognosis. This study aimed to identify the characteristic microRNAs (miRNAs) of GBC and the competing endogenous RNA (ceRNA) regulatory mechanisms. METHODS The microarray data of GBC tissue samples and normal gallbladder (NGB) tissue samples from the Gene Expression Omnibus (GEO) database was downloaded. GBC-related differentially expressed miRNAs (DE-miRNAs) were identified by inter-group differential expression analysis and weighted gene co-expression network analysis (WGCNA). Machine learning algorithms were used to screen the characteristic miRNA based on the intersect between least absolute shrinkage and selection operator (LASSO) and Support vector machine-recursive feature elimination (SVM-RFE). Based on the differential expression analysis of GEO database, the ceRNA network of characteristic miRNA was predicted and constructed. The biological functions of the ceRNA network were revealed by carrying out the gene enrichment analysis was implemented. We further screened the key genes of ceRNA network and constructed a protein-protein interaction (PPI) network, and predicted and generated the transcription factors (TFs) network of signature miRNAs. The expression of characteristic miRNA in clinical samples was verified by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS A total of 131 GBC-related DE-miRNAs were obtained. The hsa-miR-4770 was defined as characteristic miRNA for GBC. The ceRNA network containing 211 mRNAs, one miRNA, two lncRNAs, and 48 circRNAs was created. Gene enrichment analysis suggested that the downstream genes were mainly involved in actin filament organization, cell-substrate adhesion, cell-matrix adhesion, reactive oxygen species metabolic process, glutamine metabolic process and extracellular matrix (ECM)-receptor interaction pathway. 10 key genes in the network were found to be most correlated with disease, and involved in cell cycle-related processes, p53, and extrinsic apoptotic signaling pathways. The qRT-PCR result demonstrated that hsa-miR-4770 is down-regulated in GBC, and the expression trend is consistent with the public database. CONCLUSIONS We identified hsa-miR-4770 as the characteristic miRNA for GBC. The ceRNA network of hsa-miR-4770 may play key roles in GBC. This study provided some basis for potential pathogenesis of GBC.
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Affiliation(s)
- Hanrui Shao
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, 374 Dianmian Avenue, Wu Hua District, Kunming, 650106, Yunnan, P.R. China
| | - Jiahai Zhu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, 374 Dianmian Avenue, Wu Hua District, Kunming, 650106, Yunnan, P.R. China
| | - Ya Zhu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, 374 Dianmian Avenue, Wu Hua District, Kunming, 650106, Yunnan, P.R. China
| | - Lixin Liu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, 374 Dianmian Avenue, Wu Hua District, Kunming, 650106, Yunnan, P.R. China
| | - Songling Zhao
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, 374 Dianmian Avenue, Wu Hua District, Kunming, 650106, Yunnan, P.R. China
| | - Qiang Kang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, 374 Dianmian Avenue, Wu Hua District, Kunming, 650106, Yunnan, P.R. China
| | - Yunxia Liu
- Experiment Teaching Center, Basic Medical School, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, P.R. China.
| | - Hao Zou
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, 374 Dianmian Avenue, Wu Hua District, Kunming, 650106, Yunnan, P.R. China.
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8
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Sun Y, Li X, Cheng H, Wang S, Zhou D, Ding J, Ma F. Drug resistance and new therapies in gallbladder cancer. Drug Discov Ther 2023; 17:220-229. [PMID: 37587052 DOI: 10.5582/ddt.2023.01013] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/18/2023]
Abstract
Gallbladder cancer (GBC) is a highly aggressive malignancy, which poses significant challenges for timely diagnosis, resulting in a dismal prognosis. Chemotherapy serves as a primary treatment option in cases where surgery is not feasible. However, the emergence of chemoresistance poses a significant challenge to the effectiveness of chemotherapy, ultimately resulting in a poor prognosis. Despite extensive research on mechanisms of chemotherapeutic resistance in oncology, the underlying mechanisms of chemoresistance in GBC remain poorly understood. In this review, we present the findings from the last decade on the molecular mechanisms of chemotherapeutic resistance in GBC. We hope that these insights may provide novel therapeutic and experimental targets for further investigations into this lethal disease.
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Affiliation(s)
- Yuxin Sun
- Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoxuan Li
- Qingdao University, Qingdao, Shandong, China
| | - Haihong Cheng
- Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shouhua Wang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Di Zhou
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Ding
- Department of Biliary and Pancreatic Surgery, Shanghai Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fei Ma
- Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute for Pediatric Research, Shanghai, China
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9
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Shahin RK, Elkady MA, Abulsoud AI, Abdelmaksoud NM, Abdel Mageed SS, El-Dakroury WA, Zewail MB, Elazazy M, Sobhy MH, Nomier Y, Elazazy O, Elballal MS, Mohammed OA, Midan HM, Elrebehy MA, Ziada BO, Doghish AS. miRNAs orchestration of gallbladder cancer - Particular emphasis on diagnosis, progression and drug resistance. Pathol Res Pract 2023; 248:154684. [PMID: 37454489 DOI: 10.1016/j.prp.2023.154684] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 07/07/2023] [Accepted: 07/10/2023] [Indexed: 07/18/2023]
Abstract
Gallbladder cancer (GBC) is characterized by a highly invasive nature and a poor prognosis, with adenocarcinoma being the main histological subtype. According to statistical data, patients diagnosed with advanced GBC have a survival rate of less than 5% for 5 years. Despite the novel therapeutic techniques, the unsatisfactory results could be related to the underlying biology of tumor cells and resistance to chemotherapy. Early diagnosis is more important than clinical therapy as it assists in determining the pathological stage of cancer and facilitates the selection of appropriate medication. Hence, it is very important to understand the precise pathogenesis of GBC and to discover potential novel biomarkers for early diagnosis of GBC. Non-coding RNAs, such as microRNAs, long non-coding RNAs, and circular RNAs, have been found to influence the transcriptional regulation of target genes associated with cancer, either directly or indirectly. microRNAs are a group of small, non-coding, single-stranded RNAs that are expressed endogenously. miRNAs play significant roles in various fundamental cellular processes. Therefore, miRNAs have the potential to serve as valuable biomarkers and therapeutic targets for GBC.
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Affiliation(s)
- Reem K Shahin
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mohamed A Elkady
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231 Cairo, Egypt
| | - Ahmed I Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231 Cairo, Egypt; Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | | | - Sherif S Abdel Mageed
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Moataz B Zewail
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mahmoud Elazazy
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Mohamed H Sobhy
- Nanomedicine Research Labs, Center for Materials Science, Zewail City of Science and Technology, 6th of October City, Giza, Egypt
| | - Yousra Nomier
- Pharmacology Department, Pharmacy College, Jazan University, Saudi Arabia
| | - Ola Elazazy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Osama A Mohammed
- Department of Clinical Pharmacology, Faculty of Medicine, Bisha University, Bisha 61922, Saudi Arabia; Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Heba M Midan
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt.
| | - Bassant O Ziada
- Research Department, Utopia Pharmaceuticals, Nasr City, 11765 Cairo, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231 Cairo, Egypt.
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10
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Lv Y, Yin W, Zhang Z. Non-coding RNAs as potential biomarkers of gallbladder cancer. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2022; 25:1489-1511. [PMID: 36576705 DOI: 10.1007/s12094-022-03056-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 12/20/2022] [Indexed: 12/29/2022]
Abstract
Gallbladder cancer (GBC) performs strongly invasive and poor prognosis, and adenocarcinoma is the most common histological type in it. Statistically, the 5-year survival rate of patients with advanced GBC is less than 5%. Such dismal outcome might be caused by chemotherapy resistance and native biology of tumor cells, regardless of emerging therapeutic strategies. Early diagnosis, depending on biomarkers, receptors and secretive proteins, is more important than clinical therapy, guiding the pathologic stage of cancer and the choice of medication. Therefore, it is in urgent need to understand the specific pathogenesis of GBC and strive to find promising novel biomarkers for early screening in GBC. Non-coding RNAs (ncRNAs), especially microRNAs (miRNAs, miRs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are confirmed to participate in and regulate the occurrence and development of GBC. Exceptionally, lncRNAs and circRNAs could act as competing endogenous RNAs (ceRNAs) containing binding sites for miRNAs and crosstalk with miRNAs to target regulatory downstream protein-coding messenger RNAs (mRNAs), thus affecting the expression levels of specific proteins to participate in and regulate the development and progression of GBC. It follows that ncRNAs may become promising biomarkers and potential therapeutic targets for GBC. In this review, we mainly summarize the recent research progress of miRNAs and lncRNAs in regulating the development and progression of GBC, chemoresistance, and predicting the prognosis of patients, and highlight the potential applications of the lncRNA/circRNA-miRNA-mRNA cross-regulatory networks in early diagnosis, chemoresistance, and prognostic evaluation, aiming to better understand the pathogenesis of GBC and develop new diagnostic and therapeutic strategies.
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Affiliation(s)
- Yan Lv
- The Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, 443002, China.
- College of Basic Medical Science, China Three Gorges University, Life Science Building, No.8 Daxue Road, Yichang, 443002, China.
| | - Wanyue Yin
- College of Basic Medical Science, China Three Gorges University, Life Science Building, No.8 Daxue Road, Yichang, 443002, China
| | - Zhikai Zhang
- The Third-Grade Pharmacological Laboratory On Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
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11
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Effects of Long Noncoding RNA HOXA-AS2 on the Proliferation and Migration of Gallbladder Cancer Cells. JOURNAL OF ONCOLOGY 2022; 2022:6051512. [PMID: 36299503 PMCID: PMC9592229 DOI: 10.1155/2022/6051512] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 08/29/2022] [Accepted: 09/02/2022] [Indexed: 01/17/2023]
Abstract
To explore the function and mechanism of lncRNA HOXA-AS2 in cancer-associated fibroblasts (CAFs)-derived exosomes in gallbladder cancer metastasis, and provide new research targets for the treatment of gallbladder cancer. At the same time, in order to clarify the early predictive value of lncRNA HOXA-AS2 for gallbladder cancer metastasis, and to provide a theoretical basis for clinical individualized treatment of gallbladder cancer. Methods. In our previous work, we used TCGA database analysis to find that lncRNA HOXA-AS2 was highly expressed in gallbladder cancer tissues compared with normal tissues. In this study, the expression levels of HOXA-AS2 in gallbladder cancer cell lines and control cells were first verified by QPCR and Western blot methods. Then, lentiviral tools were used to construct knockdown vectors (RNAi#1, RNAi#2) and negative control vectors targeting two different sites of HOXA-AS2, and the vectors were transfected into NOZ and OCUG-1 cells, respectively. Real-time PCR was used to detect knockdown efficiency. Then, the effects of silencing HOXA-AS2 on the proliferation, cell viability, cell migration, and invasion ability of gallbladder cancer cells were detected by MTT, plate cloning assay, Transwell migration chamber assay, and Transwell invasion chamber assay. Finally, the interaction between HOXA-AS2 and miR-6867 and the 3′UTR of YAP1 protein was detected by luciferase reporter gene. The results showed that the expression level of HOXA-AS2 in gallbladder cancer cell lines was higher than that in control cells. The expression of HOXA-AS2 in gallbladder carcinoma tissues was significantly higher than that in adjacent tissues (p < 0.05). After successful knockout of HOXA-AS2 by lentiviral transfection, the expression of HOXA-AS2 in gallbladder cancer cell lines was significantly decreased. Through cell proliferation and plate clone detection, it was found that silencing HOXA-AS2 inhibited cell proliferation and invasion. Through software prediction and fluorescein reporter gene detection, it was found that HOXA-AS2 has a binding site with miR-6867, and the two are negatively correlated, that is, the expression of miR-6867 is enhanced after the expression of HOXA-AS2 is downregulated. And the 3′UTR of YAP1 protein in the Hippo signaling pathway binds to miR-6867. Therefore, HOXA-AS2 may affect the expression of YAP1 protein by regulating miR-6867, thereby inhibiting the Hippo signaling pathway and promoting the proliferation and metastasis of gallbladder cancer cells. HOXA-AS2 is abnormally expressed in gallbladder cancer cells. HOXA-AS2 may promote the migration and invasion of gallbladder cancer cells by regulating the Hippo signaling pathway through miR-6867. HOXA-AS2 may serve as a potential diagnostic and therapeutic target for gallbladder cancer in clinic.
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12
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Sulforaphane Enhanced Proliferation of Porcine Satellite Cells via Epigenetic Augmentation of SMAD7. Animals (Basel) 2022; 12:ani12111365. [PMID: 35681828 PMCID: PMC9179638 DOI: 10.3390/ani12111365] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 05/22/2022] [Accepted: 05/24/2022] [Indexed: 12/10/2022] Open
Abstract
Satellite cells take an indispensable place in skeletal muscle regeneration, maintenance, and growth. However, only limited works have investigated effects of dietary compounds on the proliferation of porcine satellite cells (PSCs) and related mechanisms. Sulforaphane (SFN) at multiple levels was applied to PSCs. The PSCs’ viability and HDAC activity were measured with a WST-1 cell proliferation kit and Color-de-Lys® HDAC colorimetric activity assay kit. Gene expression and epigenetics modification were tested with qRT-PCR, Western blot, bisulfite sequencing, and ChIP-qPCR. This study found that SFN enhanced PSC proliferation and altered mRNA expression levels of myogenic regulatory factors. In addition, SFN inhibited histone deacetylase (HDAC) activity, disturbed mRNA levels of HDAC family members, and elevated acetylated histone H3 and H4 abundance in PSCs. Furthermore, both mRNA and protein levels of the Smad family member 7 (SMAD7) in PSCs were upregulated after SFN treatment. Finally, it was found that SFN increased the acetylation level of histone H4 in the SMAD7 promoter, decreased the expression of microRNAs, including ssc-miR-15a, ssc-miR-15b, ssc-miR-92a, ssc-miR-17-5p, ssc-miR-20a-5p, and ssc-miR-106a, targeting SMAD7, but did not impact on the SMAD7 promoter’s methylation status in PSCs. In summary, SFN was found to boost PSC proliferation and epigenetically increase porcine SMAD7 expression, which indicates a potential application of SFN in modulation of skeletal muscle growth.
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Cao J, Shao H, Hu J, Jin R, Feng A, Zhang B, Li S, Chen T, Jeungpanich S, Topatana W, Tian Y, Lu Z, Cai X, Chen M. Identification of invasion-metastasis associated MiRNAs in gallbladder cancer by bioinformatics and experimental validation. J Transl Med 2022; 20:188. [PMID: 35484565 PMCID: PMC9052523 DOI: 10.1186/s12967-022-03394-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 04/15/2022] [Indexed: 01/13/2023] Open
Abstract
Background Recent studies exploring the roles of invasion-metastasis associated miRNAs in gallbladder cancer (GBC) are limited. In the study, we aimed to identify the invasion-metastasis associated miRNAs in GBC by bioinformatics and experimental validation. Methods MiRNAs of different expression were identified by comparing GBC tumor samples with different survival from Gene Expression Omnibus database. MiRTarBase was used for identifying the potential target genes of miRNAs. Then, we performed Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. And miRNA-gene and protein–protein interaction (PPI) network were constructed for hub genes evaluation. We further explored and compared miR-642a-3p and miR-145-5p expression in both The Cancer Genome Atlas database and our hospital data. Finally, quantitative real-time PCR, wound healing assay, and Transwell assay were conducted to validate the invasion-metastasis associated miRNAs in GBC. Results In GSE104165 database, 25 up-regulated and 97 down-regulated miRNAs were detected with significantly different expression in GBC tumor samples. Then, 477 potential target genes were identified from the 2 most up-regulated miRNAs (miR-4430 and miR-642a-3p) and 268 genes from the 2 most down-regulated miRNAs (miR-451a and miR-145-5p). After GO and KEGG analysis, mTOR and PI3K-Akt signaling pathways were found associated with the potential target genes. Based on PPI network, the top 10 highest degree hub nodes were selected for hub genes. Furthermore, the miRNA-hub gene network showed significant miR-642a-3p up-regulation and miR-145-5p down-regulation in both GBC tissues and cell lines. In the experimental validation, miR-145-5p up-regulation and miR-642a-3p down-regulation were confirmed to suppress GBC invasion and metastasis. Conclusions MiR-642a-3p and miR-145-5p were identified as invasion-metastasis associated miRNAs via bioinformatics and experimental validation, and both up-regulation of miR-642a-3p and down-regulation of miR-145-5p would be served as novel treatment options for GBC in the future. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03394-8.
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Affiliation(s)
- Jiasheng Cao
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, No. 3 East Qingchun Road, Hangzhou, 310016, Zhejiang Province, China.,Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China
| | - Huijiang Shao
- Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China.,Department of Hepatobiliary and Pancreatic Surgery, Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang Province, China
| | - Jiahao Hu
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, No. 3 East Qingchun Road, Hangzhou, 310016, Zhejiang Province, China.,Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China
| | - Renan Jin
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, No. 3 East Qingchun Road, Hangzhou, 310016, Zhejiang Province, China.,Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China
| | - Anyun Feng
- Health Management Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310022, China
| | - Bin Zhang
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, No. 3 East Qingchun Road, Hangzhou, 310016, Zhejiang Province, China.,Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China
| | - Shijie Li
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, No. 3 East Qingchun Road, Hangzhou, 310016, Zhejiang Province, China.,Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China
| | - Tianen Chen
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, No. 3 East Qingchun Road, Hangzhou, 310016, Zhejiang Province, China.,Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China
| | - Sarun Jeungpanich
- Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China
| | - Win Topatana
- Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China
| | - Yitong Tian
- Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China
| | - Ziyi Lu
- Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China
| | - Xiujun Cai
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, No. 3 East Qingchun Road, Hangzhou, 310016, Zhejiang Province, China. .,Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China.
| | - Mingyu Chen
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, No. 3 East Qingchun Road, Hangzhou, 310016, Zhejiang Province, China. .,Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang Province, China.
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Hu X, Zhang J, Bu J, Yang K, Xu S, Pan M, Xiang D, Chen W. MiR-4733-5p promotes gallbladder carcinoma progression via directly targeting kruppel like factor 7. Bioengineered 2022; 13:10691-10706. [PMID: 35443866 PMCID: PMC9161844 DOI: 10.1080/21655979.2022.2065951] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
Gallbladder carcinoma (GBC) is highly aggressive with poor prognosis. Accumulating reports show that miRNAs play critical roles in tumor progression. Previous studies have identified several miRNAs that promoted or inhibited GBC cell proliferation and/or metastasis. Here, we used the Gene Expression Omnibus (GEO) dataset to identify dysregulated miRNAs in GBC, followed by validating the upregulation of the miR-4733-5p and downregulation of kruppel-like factor 7 (KLF7) in GBC biopsies by quantitative real-time PCR (RT-qPCR), in situ hybridization (ISH) staining, and immunohistochemistry (IHC) assays. GBC cell proliferation and invasion capacities mediated by miR-4733-5p were evaluated by a series of function assays in vitro, including CCK-8, colony formation assay, wound healing assay and transwell assay. Xenograft tumor model found that miR-4733-5p promoted GBC tumor growth in vivo. This study clarified that miR-4733-5p was upregulated in GBC and promoted GBC cell proliferation via directly binding to 3' untranslated region (UTR) of KLF, which was downregulated and prohibited the proliferation and migration of GBC cells.
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Affiliation(s)
- Xiaoqiang Hu
- Department of Biliary and Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
| | - Junzhe Zhang
- Department of Biliary and Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
| | - Junfeng Bu
- Department of Biliary and Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
| | - Kaini Yang
- Department of Biliary and Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
| | - Sunwang Xu
- Department of Biliary and Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
| | - Mengqiao Pan
- Department of Biliary and Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
| | - Dongxi Xiang
- Department of Biliary and Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
| | - Wei Chen
- Department of Biliary and Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China.,Shanghai Key Laboratory of Biliary Tract Disease, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine; Shanghai 200120, China.,Shanghai Research Center of Biliary Tract Disease, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
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15
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The CBS-H 2S axis promotes liver metastasis of colon cancer by upregulating VEGF through AP-1 activation. Br J Cancer 2022; 126:1055-1066. [PMID: 34952931 PMCID: PMC8979992 DOI: 10.1038/s41416-021-01681-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 12/04/2021] [Accepted: 12/16/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The main therapy for colon cancer with liver metastasis is chemotherapy based on 5-fluorouracil combined with targeted drugs. However, acquired drug resistance and severe adverse reactions limit patients' benefit from standard chemotherapy. Here, we investigate the involvement of endogenous hydrogen sulfide (H2S) in liver metastasis of colon cancer and its potential value as a novel therapeutic target. METHODS We used the CRISPR/Cas9 system to knockdown CBS gene expression in colon cancer cell lines. PCR arrays and proteome arrays were applied to detect the transcription and protein expression levels, respectively, of angiogenesis-related genes after knockdown. The molecular mechanism was investigated by western blot analysis, RT-qPCR, immunofluorescence staining, ChIP assays and dual-luciferase reporter assays. A liver metastasis mouse model was adopted to investigate the effect of targeting CBS on tumour metastasis in vivo. RESULTS Knockdown of CBS decreased the metastasis and invasion of colon cancer cells and inhibited angiogenesis both in vivo and in vitro. Tissue microarray analysis showed a positive correlation between CBS and VEGF expression in colon cancer tissues. Further analysis at the molecular level validated a positive feedback loop between the CBS-H2S axis and VEGF. CONCLUSIONS Endogenous H2S promotes angiogenesis and metastasis in colon cancer, and targeting the positive feedback loop between the CBS-H2S axis and VEGF can effectively intervene in liver metastasis of colon cancer.
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16
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Predicted miRNAs suppressed cell proliferation and migration via FAK/VASP axis; Systems biology approach. INFORMATICS IN MEDICINE UNLOCKED 2022. [DOI: 10.1016/j.imu.2022.100890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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17
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MiR-20a-5p Negatively Regulates NR4A3 to Promote Metastasis in Bladder Cancer. JOURNAL OF ONCOLOGY 2021; 2021:1377989. [PMID: 34925506 PMCID: PMC8677415 DOI: 10.1155/2021/1377989] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/20/2021] [Accepted: 10/22/2021] [Indexed: 02/05/2023]
Abstract
Metastasis is the leading cause of death in cancer patients. Therefore, the prediction and treatment of metastasis are critical in improving the survival of patients with bladder cancer. In this study, we aimed to investigate the role of miR-20a-5p and NR4A3 in bladder cancer and the regulatory relationship between them. The high expression of miR-20a-5p in the bladder cancer (BCa) tissues and cells was determined by qRT-PCR. Exogenous miR-20a-5p overexpression promoted the proliferation, migration, and invasion of BCa cells. MiR-20a-5p inhibition inhibited the BCa cell proliferation, invasion, and migration. NR4A3 was proved to be the target gene of miR-20a-5p by the double luciferase reporter assay. In addition, the reduction of NR4A3 could promote the proliferation, invasion, and clonal formation of the bladder cancer cells 5637 and T24. NR4A3 overexpression could reverse the carcinogenic effect of miR-20a. We further confirmed that the oncogenic effect of miR-20a was achieved by promoting EMT in tumor cells. MiR-20a-5p promoted the growth and metastasis of the bladder cancer cells by inhibiting the expression of the tumor suppressor gene NR4A3 and played a carcinogenic role in BCa. Thus, miR-20a-5p may become a potential therapeutic target for BCa treatment.
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18
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Rana V, Parama D, Khatoon E, Girisa S, Sethi G, Kunnumakkara AB. Reiterating the Emergence of Noncoding RNAs as Regulators of the Critical Hallmarks of Gall Bladder Cancer. Biomolecules 2021; 11:biom11121847. [PMID: 34944491 PMCID: PMC8699045 DOI: 10.3390/biom11121847] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 11/25/2021] [Accepted: 12/04/2021] [Indexed: 01/17/2023] Open
Abstract
Gall bladder cancer (GBC) is a rare and one of the most aggressive types of malignancies, often associated with a poor prognosis and survival. It is a highly metastatic cancer and is often not diagnosed at the initial stages, which contributes to a poor survival rate of patients. The poor diagnosis and chemoresistance associated with the disease limit the scope of the currently available surgical and nonsurgical treatment modalities. Thus, there is a need to explore novel therapeutic targets and biomarkers that will help relieve the severity of the disease and lead to advanced therapeutic strategies. Accumulating evidence has correlated the atypical expression of various noncoding RNAs (ncRNAs), including circular RNAs (circRNAs), long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and small nucleolar RNAs (snoRNA) with the increased cell proliferation, epithelial-mesenchymal transition (EMT), invasion, migration, metastasis, chemoresistance, and decreased apoptosis in GBC. Numerous reports have indicated that the dysregulated expression of ncRNAs is associated with poor prognosis and lower disease-free and overall survival in GBC patients. These reports suggest that ncRNAs might be considered novel diagnostic and prognostic markers for the management of GBC. The present review recapitulates the association of various ncRNAs in the initiation and progression of GBC and the development of novel therapeutic strategies by exploring their functional and regulatory role.
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Affiliation(s)
- Varsha Rana
- Cancer Biology Laboratory & DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India; (V.R.); (D.P.); (E.K.); (S.G.)
| | - Dey Parama
- Cancer Biology Laboratory & DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India; (V.R.); (D.P.); (E.K.); (S.G.)
| | - Elina Khatoon
- Cancer Biology Laboratory & DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India; (V.R.); (D.P.); (E.K.); (S.G.)
| | - Sosmitha Girisa
- Cancer Biology Laboratory & DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India; (V.R.); (D.P.); (E.K.); (S.G.)
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- Correspondence: (G.S.); (A.B.K.)
| | - Ajaikumar B. Kunnumakkara
- Cancer Biology Laboratory & DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India; (V.R.); (D.P.); (E.K.); (S.G.)
- Correspondence: (G.S.); (A.B.K.)
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Tong C, Wang Y, Li J, Cen W, Zhang W, Zhu Z, Yu J, Lu B. Pterostilbene inhibits gallbladder cancer progression by suppressing the PI3K/Akt pathway. Sci Rep 2021; 11:4391. [PMID: 33623100 PMCID: PMC7902850 DOI: 10.1038/s41598-021-83924-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 02/08/2021] [Indexed: 12/20/2022] Open
Abstract
Gallbladder cancer is the most common malignant tumor of the biliary system and is characterized by difficulty to diagnose in early stages, a high degree of malignancy, and poor prognosis. Finding new drugs may improve the prognosis for this dismal cancer. Herein, we investigated the potential application of pterostilbene (PTS) against gallbladder cancer in vivo and in vitro. PTS potently inhibited cell proliferation, migration and invasion of gallbladder cancer cells. Moreover, PTS also had a function of inducing apoptosis in vitro. Meanwhile, PTS reversed EMT with a correlated inhibition of PI3K/Akt activation. Tumor xenograft models showed that PTS inhibited tumor growth and had low toxicity in vivo, which were consistent with the in vitro data. These findings indicate that PTS arrests cell growth through inhibition of PI3K/AKT signaling and is a potential drug for the therapy of gallbladder cancer.
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Affiliation(s)
- Chenhao Tong
- Department of Hepatobiliary Surgery, Shaoxing Hospital, Zhejiang University School of Medicine (Shaoxing People's Hospital), No. 568 Zhongxing North Road, Shaoxing, 312000, Zhejiang, China
| | - Yali Wang
- Department of Hepatobiliary Surgery, Shaoxing Hospital, Zhejiang University School of Medicine (Shaoxing People's Hospital), No. 568 Zhongxing North Road, Shaoxing, 312000, Zhejiang, China
| | - Jiandong Li
- Department of Hepatobiliary Surgery, Shaoxing Hospital, Zhejiang University School of Medicine (Shaoxing People's Hospital), No. 568 Zhongxing North Road, Shaoxing, 312000, Zhejiang, China
| | - Wenda Cen
- Shaoxing University School of Medicine, Shaoxing, China
| | - Weiguang Zhang
- Department of Molecular Medicine and Clinical Laboratory, Shaoxing Second Hospital, Shaoxing, China
| | - Zhiyang Zhu
- Department of Hepatobiliary Surgery, Shaoxing Hospital, Zhejiang University School of Medicine (Shaoxing People's Hospital), No. 568 Zhongxing North Road, Shaoxing, 312000, Zhejiang, China
| | - Jianhua Yu
- Department of Hepatobiliary Surgery, Shaoxing Hospital, Zhejiang University School of Medicine (Shaoxing People's Hospital), No. 568 Zhongxing North Road, Shaoxing, 312000, Zhejiang, China. .,Shaoxing University School of Medicine, Shaoxing, China.
| | - Baochun Lu
- Department of Hepatobiliary Surgery, Shaoxing Hospital, Zhejiang University School of Medicine (Shaoxing People's Hospital), No. 568 Zhongxing North Road, Shaoxing, 312000, Zhejiang, China. .,Shaoxing University School of Medicine, Shaoxing, China.
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DHA Abolishes the Detrimental Effect of Docetaxel on Downregulation of the MICA via Decreasing the Expression Level of MicroRNA-20a in Gastric Cancer. J Gastrointest Cancer 2021; 51:545-551. [PMID: 31368060 DOI: 10.1007/s12029-019-00280-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND MHC class I chain-related protein A (MICA) is a membrane glycoprotein expressed abnormally on some malignant cells including gastric cancer (GC) cell and elicits anti-tumor immune responses. Downregulation of MICA expression could lead to immune-evasion of cancer cells. OBJECTIVE(S) In this study, we aimed to investigate the effect of docosahexaenoic acid (DHA) and docetaxel alone or in combination on the expression level of MICA and its regulating microRNA (miRNA), miR-20a in MKN45 GC cell line. METHOD(S) MKN45 GC cell line was cultured and MTT assay was performed to determine IC50 of docetaxel. Cells were treated by 18.5 μM docetaxel and 100 μM DHA. After that, RNA extraction and cDNA synthesis were done and the expression level of MICA and miR-20a were determined by quantitative real-time PCR for both treated and untreated cell lines. RESULTS Our findings showed less downregulation of the expression level of MICA by the combination of docetaxel/DHA (5.34-fold) compared with docetaxel (45.45-fold) and DHA (55.55-fold). Consistently, combination therapy led to the more downregulation of the expression level of the miR-20a (5.20-fold) in comparison to docetaxel (2.38-fold) and DHA (1.60-fold). CONCLUSION(S) As an unwanted effect of docetaxel therapy in GC, downregulation of MICA expression could lead to weak anti-tumor immune responses. By increasing the expression level of MICA, combination therapy of docetaxel with DHA would be useful to overcome this side effect.
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Ofoeyeno N, Ekpenyong E, Braconi C. Pathogenetic Role and Clinical Implications of Regulatory RNAs in Biliary Tract Cancer. Cancers (Basel) 2020; 13:E12. [PMID: 33375055 PMCID: PMC7792779 DOI: 10.3390/cancers13010012] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/18/2020] [Accepted: 12/19/2020] [Indexed: 02/07/2023] Open
Abstract
Biliary tract cancer (BTC) is characterised by poor prognosis and low overall survival in patients. This is generally due to minimal understanding of its pathogenesis, late diagnosis and limited therapeutics in preventing or treating BTC patients. Non-coding RNA (ncRNA) are small RNAs (mRNA) that are not translated to proteins. ncRNAs were considered to be of no importance in the genome, but recent studies have shown they play essential roles in biology and oncology such as transcriptional repression and degradation, thus regulating mRNA transcriptomes. This has led to investigations into the role of ncRNAs in the pathogenesis of BTC, and their clinical implications. In this review, the mechanisms of action of ncRNA are discussed and the role of microRNAs in BTC is summarised. The scope of this review will be limited to miRNA as they have been shown to play the most significant roles in BTC progression. There is huge potential in miRNA-based biomarkers and therapeutics in BTC, but more studies, research and technological advancements are required before it can be translated into clinical practice for patients.
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Affiliation(s)
- Nduka Ofoeyeno
- The Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK;
| | | | - Chiara Braconi
- The Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK;
- Beatson West of Scotland Cancer Centre, Glasgow G12 Y0N, UK
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22
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Tulsyan S, Hussain S, Mittal B, Saluja SS, Tanwar P, Rath GK, Goodman M, Kaur T, Mehrotra R. A systematic review with in silico analysis on transcriptomic profile of gallbladder carcinoma. Semin Oncol 2020; 47:398-408. [PMID: 33162112 DOI: 10.1053/j.seminoncol.2020.02.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 02/21/2020] [Indexed: 01/17/2023]
Abstract
Gallbladder cancer (GBC) is an aggressive malignancy of the biliary tract. It is asymptomatic in its early stages, and often, characterized by a poor prognosis and worse treatment response. Distribution of GBC shows both geographical as well as ethnic variations. Several studies have elucidated the differential gene expression profile between the normal gallbladder and GBCs, with varied but inconsistent results. Thus, a deep understanding of the expression profile of GBC might aid in the identification of potential biomarkers, which would further help in better disease management and appropriate therapy selection. This review summarizes studies on the transcriptomic profile of GBC with emphasis on studies pertaining to coding (mRNA) and noncoding (micro and long noncoding) RNA along with aberrant promoter methylation studies, ranging from a single gene to global gene to high throughput RNA sequencing approaches, published between 2000 to May, 2019. In addition, data mining of GBC from the available public functional genomics data repository at Gene Expression Omnibus has been done to rule out potentially important dysregulated genes in this malignancy. To the best of our knowledge, this is the first article to shed light on the RNA based gene regulatory network(s) along with bioinformatic analysis. Moreover, this review represents major research challenges and ambiguity, knowledge of which is a must for establishing molecular/ clinical biomarkers for early GBC diagnosis, management, and treatment protocols.
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Affiliation(s)
- Sonam Tulsyan
- Division of Preventive Oncology, National Institute of Cancer Prevention and Research, Noida, India
| | - Showket Hussain
- Division of Molecular Oncology, National Institute of Cancer Prevention and Research, Noida, India.
| | - Balraj Mittal
- Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow, India
| | - Sundeep Singh Saluja
- Department of Surgical Gastroenterology & Hepatology, GB Pant Hospital, New Delhi, India
| | - Pranay Tanwar
- Laboratory Oncology Unit, Rotary Cancer Center, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | - G K Rath
- Laboratory Oncology Unit, Rotary Cancer Center, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | - Michael Goodman
- Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, Georgia, USA
| | | | - Ravi Mehrotra
- India Cancer Research Consortium, Indian Council of Medical Research, New Delhi, India.
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23
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Li XL, Li SZ, Wu CX, Xing XH. miR-188-5p inhibits proliferation, migration, and invasion in gallbladder carcinoma by targeting Wnt2b and Smad2. Kaohsiung J Med Sci 2020; 37:294-304. [PMID: 33236530 DOI: 10.1002/kjm2.12323] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 08/31/2020] [Accepted: 10/19/2020] [Indexed: 12/17/2022] Open
Abstract
Gallbladder carcinoma (GBC) commonly occurs in gastrointestinal malignancy and has the fifth highest mortality rate among gastrointestinal malignancy. Recently, miR-188-5p, a small noncoding RNA, has been implicated in various types of cancer such as nasopharyngeal carcinoma, oral squamous cell carcinoma, liver cancer, and prostate cancer. However, the effect of miR-188-5p on GBC remains unclear. Here, we demonstrated that miR-188-5p was downregulated in GBC tissues, and downregulation of miR-188-5p correlated with larger tumor size, lymph node metastasis, and extensive metastasis. In addition, the overall survival time of patients with higher miR-188-5p expression was significantly longer than that of patients with low-miR-188-5p expression. Moreover, downregulation of miR-188-5p promoted the proliferation, migration, and invasion of GBC cells, while its overexpression inhibited cell invasion and induced cell apoptosis, and arrested GBC growth in vivo. Importantly, miR-188-5p-dependent tumorigenesis was correlated with Wnt/β-catenin signaling and p-38/JNK signaling. In conclusion, miR-188-5p plays a direct role in GBC tumorigenesis. Our study suggests that miR-188-5p could serve as a novel diagnosis marker and therapeutic target in GBC.
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Affiliation(s)
- Xiang-Lu Li
- Department of Ward 1 of Oncology, Hainan General Hospital, Haikou City, China
| | - Shi-Zong Li
- Department of Hepatobiliary and Pancreatic Surgery, Hainan General Hospital, Haikou City, China
| | - Chang-Xiong Wu
- Department of Hepatobiliary and Pancreatic Surgery, Hainan General Hospital, Haikou City, China
| | - Xue-Hua Xing
- Department of Ward 1 of Oncology, Hainan General Hospital, Haikou City, China
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24
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Liao C, Guo Y, Gong Y, Huang X, Liao X, Wang X, Ruan G, Gao F. Clinical implications and nomogram prediction of long noncoding RNA FRGCA as diagnostic and prognostic indicators in colon adenocarcinoma. Medicine (Baltimore) 2020; 99:e22806. [PMID: 33126318 PMCID: PMC7598802 DOI: 10.1097/md.0000000000022806] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer, especially colon adenocarcinoma (COAD), is associated with significant morbidity and mortality worldwide. Long noncoding RNA (lncRNA) has been implicated in tumorigenesis. The aim of the present study was to elucidate the potential diagnostic and prognostic values of lncRNA FRGCA in COAD.The data of 438 COAD patients were retrieved for analysis. Diagnostic significance was evaluated using tumor and nontumor tissues. Prognostic significance was evaluated using a Cox proportional regression model. Stratified analysis was performed to identify associations between clinical factors and lncRNA FRGCA expression. A nomogram was constructed using the clinical factors and lncRNA FRGCA for survival prediction. Enrichment analysis identified gene ontologies and metabolic pathways of mRNAs with high Pearson correlation coefficients with lncRNA FRGCA.lncRNA FRGCA was highly expressed in tumor tissues of COAD and demonstrated diagnostic value (area under curve = 0.763, P < .0001). Prognostic significance analysis indicated that lncRNA FRGCA had prognostic value in COAD [adjusted P < .001, hazard ratio (HR) = 0.444, 95% confidence interval (95% CI) = 0.288-0.685] and high expression of lncRNA FRGCA indicated better survival in COAD. A nomogram was evaluated for prediction of survival at 1, 3, and 5 years. Enrichment analysis revealed many mRNAs involved in the structural constituents of the mitochondrial inner membrane and translational termination, protein binding, translation, ribosome, oxidative phosphorylation, and metabolic pathways, especially the nucleoplasm.Differentially expressed in tumor vs nontumor tissues, lncRNA FRGCA had both diagnostic and prognostic implications in COAD, which may be associated with ribosome metabolism, oxidative phosphorylation, and nucleoplasm-related metabolic pathways.
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Affiliation(s)
- Cun Liao
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning
| | - Yun Guo
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning
| | - Yizhen Gong
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning
| | - Xue Huang
- Department of Gastroenterology, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang, Guangxi
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xiangkun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Guotian Ruan
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning
| | - Feng Gao
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning
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25
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de Ceuninck van Capelle C, Spit M, Ten Dijke P. Current perspectives on inhibitory SMAD7 in health and disease. Crit Rev Biochem Mol Biol 2020; 55:691-715. [PMID: 33081543 DOI: 10.1080/10409238.2020.1828260] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Transforming growth factor β (TGF-β) family members play an extensive role in cellular communication that orchestrates both early development and adult tissue homeostasis. Aberrant TGF-β family signaling is associated with a pathological outcome in numerous diseases, and in-depth understanding of molecular and cellular processes could result in therapeutic benefit for patients. Canonical TGF-β signaling is mediated by receptor-regulated SMADs (R-SMADs), a single co-mediator SMAD (Co-SMAD), and inhibitory SMADs (I-SMADs). SMAD7, one of the I-SMADs, is an essential negative regulator of the pleiotropic TGF-β and bone morphogenetic protein (BMP) signaling pathways. In a negative feedback loop, SMAD7 inhibits TGF-β signaling by providing competition for TGF-β type-1 receptor (TβRI), blocking phosphorylation and activation of SMAD2. Moreover, SMAD7 recruits E3 ubiquitin SMURF ligases to the type I receptor to promote ubiquitin-mediated proteasomal degradation. In addition to its role in TGF-β and BMP signaling, SMAD7 is regulated by and implicated in a variety of other signaling pathways and functions as a mediator of crosstalk. This review is focused on SMAD7, its function in TGF-β and BMP signaling, and its role as a downstream integrator and crosstalk mediator. This crucial signaling molecule is tightly regulated by various mechanisms. We provide an overview of the ways by which SMAD7 is regulated, including noncoding RNAs (ncRNAs) and post-translational modifications (PTMs). Finally, we discuss its role in diseases, such as cancer, fibrosis, and inflammatory bowel disease (IBD).
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Affiliation(s)
| | - Maureen Spit
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Peter Ten Dijke
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
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26
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Ahadi A. The significance of microRNA deregulation in colorectal cancer development and the clinical uses as a diagnostic and prognostic biomarker and therapeutic agent. Noncoding RNA Res 2020; 5:125-134. [PMID: 32954092 PMCID: PMC7476809 DOI: 10.1016/j.ncrna.2020.08.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/19/2020] [Accepted: 08/19/2020] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most widely recognized and deadly malignancies worldwide. Although death rates have declined over the previous decade, mainly because of enhanced screening or potential treatment alternatives, CRC remains the third leading cause of cancer-related mortality globally, with an estimated incidence of over 1 million new cases and approximately 600 000 deaths estimated yearly. Therefore, many scientific efforts are put into the development of new diagnostic biomarkers for CRC. MicroRNAs (miRNAs), one of the epigenetics categories, have demonstrated significant roles in carcinogenesis and progression through regulating epithelial-mesenchymal transition (EMT), oncogenic signaling pathways, and metastasis. Dysregulation of miRNAs expression has been reported in many cancers, including CRC. The expression profile of miRNAs is reproducibly altered in CRC, and their expression patterns are associated with diagnosis, prognosis, and therapeutic outcomes in CRC. Recently, many studies were conducted on the dysregulation of miRNAs as a diagnostic and prognostic biomarker in CRC. Among them, some miRNAs, which include miR-21, miR-34 family, miR-155, miR-224, and miR-378, have been more studied in CRC with more prominent roles in diagnosis, prognosis, and therapy. In the present review, we summarized the latest information regarding the dysregulated miRNAs in CRC and the advantages of using miRNAs as a biomarker for CRC diagnosis, treatment, and their function in different signaling pathways involved in CRC progression. Moreover, we described the translation of miRNA research to potential therapeutic applications in the management of CRC in clinical settings.
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Affiliation(s)
- Alireza Ahadi
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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27
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Gu Z, Wu S, Xu G, Wu W, Mao B, Zhao S. miR-487a performs oncogenic functions in osteosarcoma by targeting BTG2 mRNA. Acta Biochim Biophys Sin (Shanghai) 2020; 52:631-637. [PMID: 32409840 DOI: 10.1093/abbs/gmaa034] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 01/14/2019] [Accepted: 03/06/2020] [Indexed: 11/14/2022] Open
Abstract
Aberrant microRNA (miRNA) expression plays a critical role in osteosarcoma (OS) pathogenesis. In this study, we elucidated the involvement of miR-487a in OS and the underlying molecular mechanisms. We found that miR-487a was upregulated in OS clinical samples and cell lines. Knockdown of miR-487a suppressed OS cell growth and invasion and induced apoptosis; however, overexpression of miR-487a promoted OS cell growth and invasion. Accordingly, downregulation of miR-487a significantly suppressed tumor growth of OS xenografts in vivo. Furthermore, B-cell translocation gene 2 (BTG2) mRNA was found to be a novel target of miR-487a. Knockdown of BTG2 using small interfering RNA (siRNA) recapitulated the oncogenic effects of miR-487a, whereas BTG2 overexpression partially reversed these effects. Finally, miR-487a levels were found to be negatively correlated with BTG2 expression in OS clinical samples. Collectively, our data suggest that miR-487a is an oncogenic miRNA in OS and it lowers BTG2 expression.
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Affiliation(s)
- Zhiqian Gu
- Department of Orthopedics, Hwa Mei Hospital, University of Chinese Academy of Sciences (Ningbo No. 2 Hospital), Ningbo 315000, China
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo 315000, China
| | - Shaokun Wu
- Department of Orthopedics, Hwa Mei Hospital, University of Chinese Academy of Sciences (Ningbo No. 2 Hospital), Ningbo 315000, China
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo 315000, China
| | - Guoxing Xu
- Department of Orthopedics, Third Affiliated Hospital, Naval Medical University, Shanghai 200438, China
| | - Wei Wu
- Department of Orthopedics, Hwa Mei Hospital, University of Chinese Academy of Sciences (Ningbo No. 2 Hospital), Ningbo 315000, China
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo 315000, China
| | - Bo Mao
- Department of Orthopedics, Hwa Mei Hospital, University of Chinese Academy of Sciences (Ningbo No. 2 Hospital), Ningbo 315000, China
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo 315000, China
| | - Shoujun Zhao
- Department of Orthopedics, Hwa Mei Hospital, University of Chinese Academy of Sciences (Ningbo No. 2 Hospital), Ningbo 315000, China
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo 315000, China
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28
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Sun H, Wang Q, Yuan G, Quan J, Dong D, Lun Y, Sun B. Hsa_circ_0001649 restrains gastric carcinoma growth and metastasis by downregulation of miR-20a. J Clin Lab Anal 2020; 34:e23235. [PMID: 32212290 PMCID: PMC7307365 DOI: 10.1002/jcla.23235] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 01/10/2020] [Accepted: 01/17/2020] [Indexed: 12/17/2022] Open
Abstract
Background Gastric carcinoma (GC) is a familiar carcinoma and serious threat to human health. We investigated the efficacy and mechanism of circular RNA hsa_circ_0001649 on the growth, migration, and invasion of GC cells. Methods microRNA (miR)‐20a and hsa_circ_0001649 expression was investigated by RT‐qPCR and was changed by cell transfection. CCK‐8, flow cytometry, and BrdU assays were, respectively, used to investigate the efficacies of hsa_circ_0001649 and miR‐20a on cell viability, apoptosis, and proliferation. Transwell assay was used to investigate the efficacies of hsa_circ_0001649 and miR‐20a on cell migration and invasion. Moreover, the levels of cyclin D1, Bax, cleaved caspase‐3, and signal pathway‐related proteins were investigated by Western blot. Results Hsa_circ_0001649 was downregulated in GC cells and tissues. Upregulation of hsa_circ_0001649 restrained viability, proliferation, migration, and invasion, while promoted apoptosis. Furthermore, miR‐20a was negatively regulated by hsa_circ_0001649 and miR‐20a overexpression reversed the efficacy of hsa_circ_0001649 upregulation. Finally, upregulation of hsa_circ_0001649 restrained ERK and Wnt/β‐catenin pathways while miR‐20a overexpression reversed these progresses. Conclusion Upregulation of hsa_circ_0001649 restrained GC cell growth and metastasis by downregulating miR‐20a and thereby inactivated ERK and Wnt/β‐catenin pathways.
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Affiliation(s)
- Haiyuan Sun
- Department of Gastroenterology, The Chinese People's Liberation Army Navy 971 Hospital, Qingdao, China
| | - Qunying Wang
- Department of Gastroenterology, The Chinese People's Liberation Army Navy 971 Hospital, Qingdao, China
| | - Gang Yuan
- Department of Gastroenterology, The Chinese People's Liberation Army Navy 971 Hospital, Qingdao, China
| | - Jingzi Quan
- Department of Gastroenterology, The Chinese People's Liberation Army Navy 971 Hospital, Qingdao, China
| | - Dongfang Dong
- Department of Gastroenterology, The Chinese People's Liberation Army Navy 971 Hospital, Qingdao, China
| | - Yue Lun
- Department of Gastroenterology, The Chinese People's Liberation Army Navy 971 Hospital, Qingdao, China
| | - Bo Sun
- Department of Gastroenterology, The Chinese People's Liberation Army Navy 971 Hospital, Qingdao, China
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29
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Li S, Hou X, Wu C, Han L, Li Q, Wang J, Luo S. MiR-645 promotes invasiveness, metastasis and tumor growth in colorectal cancer by targeting EFNA5. Biomed Pharmacother 2020; 125:109889. [PMID: 32036212 DOI: 10.1016/j.biopha.2020.109889] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/26/2019] [Accepted: 01/13/2020] [Indexed: 01/04/2023] Open
Abstract
MicroRNA-645 (miR-645) has been implicated in numerous types of human cancers including colon cancer. However, the effects and mechanisms of action of miR-645 dysregulation on the growth and malignancy of colorectal cancer (CRC) remain unclear. In this study, we demonstrated that miR-645 knockdown significantly diminished CRC cell migration and invasion and repressed epithelial-mesenchymal transition (EMT). Conversely, miR-645 overexpression enhanced CRC cell migration, invasion, and EMT. In vivo assays confirmed that miR-645 knockdown substantially reduced CRC growth and metastasis. Regarding the mechanism, ephrin-A5 (EFNA5) was identified as a direct target gene of miR-645. MiR-645 specifically targeted the 3'-untranslated region of EFNA5 mRNA and hindered its expression. EFNA5 knockdown attenuated the effects of miR-645 knockdown on CRC cell migration and invasion. Additionally, we noted a statistically significant inverse correlation between EFNA5 mRNA and miR-645 levels in tumors from 28 patients with CRC. Hence, miR-645 acts as an oncogenic miRNA that may increase CRC cell migration, invasiveness, and metastasis by targeting EFNA5.
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Affiliation(s)
- Shuai Li
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Xinfang Hou
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Chen Wu
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Lili Han
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Qian Li
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Jufeng Wang
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Suxia Luo
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China.
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30
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Xu G, Wei X, Tu Q, Zhou C. Up-regulated microRNA-33b inhibits epithelial-mesenchymal transition in gallbladder cancer through down-regulating CROCC. Biosci Rep 2020; 40:BSR20190108. [PMID: 31799620 PMCID: PMC6954365 DOI: 10.1042/bsr20190108] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 11/17/2019] [Accepted: 12/02/2019] [Indexed: 02/08/2023] Open
Abstract
Gallbladder cancer (GBC) is a relatively rare but fatal gastrointestinal tumor. The microRNA-33b (miR-33b), a member of miR-33 family, is reported to function as a tumor suppressor in various cancers. Notably, miR-33 was predicted to target CROCC based on microarray-based analysis. Hereby, we aimed to characterize the effect of miR-33b on epithelial-mesenchymal transition (EMT) in GBC and the potential mechanism involved with the regulation of CROCC. In GBC cell lines, miR-33b expressed at low levels, and CROCC expressed at high levels, with enhanced EMT process. To further examine the specific mechanism of miR-33b and CROCC in GBC, the GBC cells were treated with the miR-33b mimic/inhibitor or siRNA-CROCC to assess the expression alteration of EMT-related genes and cell proliferation, migration, and invasion. MiR-33b was verified to target and down-regulate the expression of CROCC. The miR-33b up-regulation or CROCC silencing was observed to increase the level of E-cadherin but decrease the levels of N-cadherin and Vimentin, corresponding to impeded cell proliferation, migration, invasion, EMT, and tumor growth. The findings suggest that miR-33b up-regulation hinders GBC development through down-regulating CROCC, which was achieved by inhibition of EMT. The present study may provide an insight on a novel target for GBC treatment.
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Affiliation(s)
- Guohui Xu
- Department of Hepatobiliary Tumor Surgery, Jiangxi Cancer Hospital, Nanchang 330029, P. R. China
| | - Xiaoyong Wei
- Department of Hepatobiliary Tumor Surgery, Jiangxi Cancer Hospital, Nanchang 330029, P. R. China
| | - Qiang Tu
- Department of Hepatobiliary Tumor Surgery, Jiangxi Cancer Hospital, Nanchang 330029, P. R. China
| | - Cuncai Zhou
- Department of Hepatobiliary Tumor Surgery, Jiangxi Cancer Hospital, Nanchang 330029, P. R. China
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Xiao Z, Chen S, Feng S, Li Y, Zou J, Ling H, Zeng Y, Zeng X. Function and mechanisms of microRNA-20a in colorectal cancer. Exp Ther Med 2020; 19:1605-1616. [PMID: 32104211 PMCID: PMC7027132 DOI: 10.3892/etm.2020.8432] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 10/29/2019] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-associated mortality worldwide. CRC currently has no specific biomarkers to promote its diagnosis and treatment and the underlying mechanisms regulating its pathogenesis have not yet been determined. MicroRNAs (miRs) are small, non-coding RNAs that exhibit regulatory functions and have been demonstrated to serve a crucial role in the post-transcriptional regulatory processes of gene expression that is associated with cell physiology and disease progression. Recently, abnormal miR-20a expression has been identified in a number of cancers types and this has become a novel focus within cancer research. High levels of miR-20a expression have been identified in CRC tissues, serum and plasma. In a recent study, miR-20a was indicated to be present in feces and to exhibit a high sensitivity to CRC. Therefore, miR-20a may be used as a marker for CRC and an indicator that can prevent the invasive examination of patients with this disease. Changes in the expression of miR-20a during chemotherapy can be used as a biomarker for monitoring resistance to treatment. In conclusion, miR-20a exhibits the potential for clinical application as a novel diagnostic biomarker and therapeutic target for use in patients with CRC. The present study focused on the role and mechanisms of miR-20a in CRC.
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Affiliation(s)
- Zheng Xiao
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Shi Chen
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Shujun Feng
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yukun Li
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Juan Zou
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Hui Ling
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Ying Zeng
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,School of Nursing, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xi Zeng
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
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Lu K, Feng F, Yang Y, Liu K, Duan J, Liu H, Yang J, Wu M, Liu C, Chang Y. High-throughput screening identified miR-7-2-3p and miR-29c-3p as metastasis suppressors in gallbladder carcinoma. J Gastroenterol 2020; 55:51-66. [PMID: 31562534 DOI: 10.1007/s00535-019-01627-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 09/01/2019] [Indexed: 02/04/2023]
Abstract
BACKGROUND Gallbladder carcinoma (GBC) is one of the most aggressive and lethal tumors, with extremely high metastatic activity and poor prognosis. Previously we have studied miRNAs that promote metastasis and progression of GBC, the aim of present study was to systematically elucidate the metastasis suppressor miRNAs in GBC. METHODS A novel designed high-throughput screening method that combined high content screening (HCS) and miRNA microarray analysis was conducted to filter out anti-metastatic miRNAs of GBC. Frozen samples were analyzed for the expression of goal miRNAs by real-time PCR. The biological functions of miRNAs were studied by transwell, immunoblot. Liver metastasis model via spleen injection was further examined in nude mice. Kaplan-Meier and Cox regression analyses were used to analyze the effect of goal miRNAs on overall survival. The target genes and interaction network of goal miRNAs were determined by whole transcriptome genome sequencing. RESULTS Out of the miRNAs library, a series of prominent metastatic suppressor miRNA candidates were filtered out. Among them, miR-7-2-3p and miR-29c-3p were discovered downregulated in GBC, and upregulation of them could reverse epithelial-mesenchymal transition and decrease the metastasis ability of GBC cells in vitro and in vivo, which was dominated by the miRNA-mRNA-lncRNA co-expression network. And DCLK1 and SLC36A1 are the direct target genes of miR-7-2-3p and miR-29c-3p. Moreover, the deficiency of miR-7-2-3p and miR-29c-3p was closely associated with poor prognosis of GBC patients. CONCLUSIONS Our findings indicate that miR-7-2-3p and miR-29c-3p play crucial roles in the pathogenesis and worse prognosis of GBCs, which may serve as prognosis biomarkers and promise potential therapeutic targets in the future.
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Affiliation(s)
- Kai Lu
- Biliary Tract Surgery Department, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, People's Republic of China
| | - Feiling Feng
- Biliary Tract Surgery Department, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, People's Republic of China
| | - Yingcheng Yang
- Organ Transplantation Department, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, People's Republic of China
| | - Kai Liu
- Biliary Tract Surgery Department, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, People's Republic of China
| | - Jicheng Duan
- Biliary Tract Surgery Department, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, People's Republic of China
| | - Hu Liu
- Biliary Tract Surgery Department, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, People's Republic of China
| | - Jiahe Yang
- Biliary Tract Surgery Department, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, People's Republic of China
| | - Mengchao Wu
- Hepatic Surgery Department, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, People's Republic of China
| | - Chen Liu
- Biliary Tract Surgery Department, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, People's Republic of China.
| | - Yanxin Chang
- Biliary Tract Surgery Department, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, People's Republic of China.
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Montalvo-Jave EE, Rahnemai-Azar AA, Papaconstantinou D, Deloiza ME, Tsilimigras DI, Moris D, Mendoza-Barrera GE, Weber SM, Pawlik TM. Molecular pathways and potential biomarkers in gallbladder cancer: A comprehensive review. Surg Oncol 2019; 31:83-89. [PMID: 31541911 DOI: 10.1016/j.suronc.2019.09.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Accepted: 09/12/2019] [Indexed: 12/13/2022]
Abstract
The most common malignancy of the biliary tract, gallbladder cancer (GBC) often has a dismal prognosis. The aggressive nature of the tumor, delayed diagnosis at advanced stages of the disease, and lack of effective treatment options are some of the factors that contribute to a poor outcome. Early detection and accurate assessment of disease burden is critical to optimize management and improve long-term survival, as well as identify patients for adjuvant therapy and clinical trials. With recent advances in the understanding of the molecular pathogenesis of GBC, several specific diagnostic and biomarkers have been proposed as being of diagnostic and prognostic importance. Indeed, identification of novel diagnostic and prognostic markers has an important role in early diagnosis and development of targeted therapies among patients with GBC. Next-generation sequencing technology and genomewide data analysis have provided novel insight into understanding the molecular pathogenesis of biliary tract cancers, thereby identifying potential biomarkers for clinical use. We herein review available GBC biomarkers and the potential clinical implications in the management of GBC.
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Affiliation(s)
- Eduardo E Montalvo-Jave
- Servicio de Cirugía General, Clínica de Cirugía Hepato-Pancreato-Biliary, Hospital General de México, Mexico; Departamento de Cirugía, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico
| | - Amir A Rahnemai-Azar
- Department of Surgery, Division of Surgical Oncology, Kaiser Permanente School of Medicine, Los Angeles, CA, USA
| | | | - Mariana Espejel Deloiza
- Departamento de Cirugía, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico
| | - Diamantis I Tsilimigras
- Department of Surgery, Division of Surgical Oncology, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Dimitrios Moris
- Department of Surgery, Division of Surgical Oncology, The Ohio State University College of Medicine, Columbus, OH, USA
| | | | - Sharon M Weber
- Department of Surgery, Division of Surgical Oncology, University of Wisconsin Hospital, Madison, WI, USA
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University College of Medicine, Columbus, OH, USA.
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Hu YP, Jin YP, Wu XS, Yang Y, Li YS, Li HF, Xiang SS, Song XL, Jiang L, Zhang YJ, Huang W, Chen SL, Liu FT, Chen C, Zhu Q, Chen HZ, Shao R, Liu YB. LncRNA-HGBC stabilized by HuR promotes gallbladder cancer progression by regulating miR-502-3p/SET/AKT axis. Mol Cancer 2019; 18:167. [PMID: 31752906 PMCID: PMC6868746 DOI: 10.1186/s12943-019-1097-9] [Citation(s) in RCA: 122] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 11/04/2019] [Indexed: 12/28/2022] Open
Abstract
BACKGROUNDS Long non-coding RNAs (lncRNAs) are essential factors that regulate tumor development and metastasis via diverse molecular mechanisms in a broad type of cancers. However, the pathological roles of lncRNAs in gallbladder carcinoma (GBC) remain largely unknown. Here we discovered a novel lncRNA termed lncRNA Highly expressed in GBC (lncRNA-HGBC) which was upregulated in GBC tissue and aimed to investigate its role and regulatory mechanism in the development and progression of GBC. METHODS The expression level of lncRNA-HGBC in GBC tissue and different cell lines was determined by quantitative real-time PCR. The full length of lncRNA-HGBC was obtained by 5' and 3' rapid amplification of the cDNA ends (RACE). Cellular localization of lncRNA-HGBC was detected by fluorescence in situ hybridization (FISH) assays and subcellular fractionation assay. In vitro and in vivo assays were preformed to explore the biological effects of lncRNA-HGBC in GBC cells. RNA pull-down assay, mass spectrometry, and RNA immunoprecipitation (RIP) assay were used to identify lncRNA-HGBC-interacting proteins. Dual luciferase reporter assays, AGO2-RIP, and MS2-RIP assays were performed to verify the interaction between lncRNA-HGBC and miR-502-3p. RESULTS We found that lncRNA-HGBC was upregulated in GBC and its upregulation could predict poor survival. Overexpression or knockdown of lncRNA-HGBC in GBC cell lines resulted in increased or decreased, respectively, cell proliferation and invasion in vitro and in xenografted tumors. LncRNA-HGBC specifically bound to RNA binding protein Hu Antigen R (HuR) that in turn stabilized lncRNA-HGBC. LncRNA-HGBC functioned as a competitive endogenous RNA to bind to miR-502-3p that inhibits target gene SET. Overexpression, knockdown or mutation of lncRNA-HGBC altered the inhibitory effects of miR-502-3p on SET expression and downstream activation of AKT. Clinically, lncRNA-HGBC expression was negatively correlated with miR-502-3p, but positively correlated with SET and HuR in GBC tissue. CONCLUSIONS Our study demonstrates that lncRNA-HGBC promotes GBC metastasis via activation of the miR-502-3p-SET-AKT cascade, pointing to lncRNA-HGBC as a new prognostic predictor and a therapeutic target.
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Affiliation(s)
- Yun-Ping Hu
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Building 25, Room 513, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
- Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, W. Building 3, Room 407, 280 Chongqi Road, Shanghai, 200025, China
| | - Yun-Peng Jin
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Building 25, Room 513, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Xiang-Song Wu
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Building 25, Room 513, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Yang Yang
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Building 25, Room 513, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Yong-Sheng Li
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Building 25, Room 513, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Huai-Feng Li
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Building 25, Room 513, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Shan-Shan Xiang
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Building 25, Room 513, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Xiao-Ling Song
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Building 25, Room 513, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Lin Jiang
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Building 25, Room 513, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Yi-Jian Zhang
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Building 25, Room 513, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Wen Huang
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Building 25, Room 513, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Shi-Li Chen
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Building 25, Room 513, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Fa-Tao Liu
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Building 25, Room 513, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Chen Chen
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Building 25, Room 513, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Qin Zhu
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Building 25, Room 513, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Hong-Zhuan Chen
- Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, W. Building 3, Room 407, 280 Chongqi Road, Shanghai, 200025, China.
| | - Rong Shao
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Building 25, Room 513, 1665 Kongjiang Road, Shanghai, 200092, China.
- Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, W. Building 3, Room 407, 280 Chongqi Road, Shanghai, 200025, China.
| | - Ying-Bin Liu
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Building 25, Room 513, 1665 Kongjiang Road, Shanghai, 200092, China.
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China.
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China.
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35
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Yang H, Li Y, Peng Z, Wang Y. Overexpression of miR-20a promotes the progression of osteosarcoma by directly targeting QKI2. Oncol Lett 2019; 18:87-94. [PMID: 31289476 PMCID: PMC6540454 DOI: 10.3892/ol.2019.10313] [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: 01/31/2018] [Accepted: 01/22/2019] [Indexed: 11/15/2022] Open
Abstract
Osteosarcoma (OS) is the most common type of malignant primary bone neoplasm. Although the application of neoadjuvant chemotherapy has improved the 5-year survival rate of patients suffering from OS, prognosis remains poor. Therefore, it is important to elucidate the molecular mechanisms underlying the occurrence, progression and metastasis of OS. The RNA-binding protein Quaking (QKI) is a member of the STAR family of proteins, and can function as a tumor suppressor gene to suppress the occurrence and progression of a variety of tumors; however, the role of QKI in OS remains to be fully elucidated. In the present study, it was identified that the expression of QKI2 was downregulated in OS using western blot analysis. In addition, subsequent functional investigations, including MTT, Transwell invasion and migration assays, revealed that QKI2 inhibited the proliferation, invasion and migration of an OS cell line in vitro. By implementing a series of experimental techniques in molecular biology, including reverse transcription-quantitative polymerase chain reaction and a double fluorescence reporter assay, it was demonstrated that the expression of miR-20a was high and inhibited the expression of QKI2 in OS. In conclusion, it was revealed that aberrantly upregulated miR-20a inhibited the expression of QKI2 in OS by targeting QKI2 mRNA, subsequently promoting the proliferation, migration and invasion of OS cells.
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Affiliation(s)
- Hongbo Yang
- Department of Orthopedic Surgery, Affiliated Hospital of Chifeng University, Chifeng, Inner Mongolia 024000, P.R. China
| | - Yongli Li
- Department of Tumor Radiotherapy, Heilongjiang Provincial Hospital, Harbin, Heilongjiang 150000, P.R. China
| | - Zhibin Peng
- Department of Orthopedic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yansong Wang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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Mishra SK, Kumari N, Krishnani N. Molecular pathogenesis of gallbladder cancer: An update. Mutat Res 2019; 816-818:111674. [PMID: 31330366 DOI: 10.1016/j.mrfmmm.2019.111674] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 06/17/2019] [Accepted: 06/24/2019] [Indexed: 01/17/2023]
Abstract
Gallbladder carcinoma (GBC) is the most aggressive gastrointestinal malignancy throughout the world, with wide geographical variance. It is the subtype of biliary tract malignancy that has the poorest prognosis and lower survival among all biliary tract malignancies. Various factors are associated with GBC pathogenesis such as environmental, microbial, metabolic and molecular. Chronic inflammation of gallbladder due to presence of gallstone or microbial infection (eg. Salmonella or H. pylori) results in sustained production of inflammatory mediators in the tissue microenvironment, which can cause genomic changes linked to carcinogenesis. Genetic alterations are one of the major factors, associated with aggressiveness and prognosis. Researches have been done to explore suitable biomarker for early diagnosis and identify altered molecular pathways to develop appropriate biomarkers for early diagnosis, therapy and predicting prognosis. Different agents for targeted therapy against actionable mutations of molecules like EGFR, VEGF, mTOR, HER2, PDL-1, PD-1, MET, PI3K, N-cadherin, VEGFR, MEK1 and MEK2 are being tried. Despite these advancements, there is dismal improvement in the survival of GBC patients. Genetic aberrations other than actionable mutations and epigenetic modification including aberrant expressions of micro-RNAs, are also being studied both as diagnostic biomarker and therapeutic targets. Complex pathogenesis of GBC still needs to be unfolded. In this review we focus on the molecular pathogenesis of GBC elucidated till date along with future directions that can be explored to achieve better management of GBC patients.
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Affiliation(s)
- Shravan Kumar Mishra
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226014, India.
| | - Niraj Kumari
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226014, India.
| | - Narendra Krishnani
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226014, India.
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Gai X, Tang B, Liu F, Wu Y, Wang F, Jing Y, Huang F, Jin D, Wang L, Zhang H. mTOR/miR-145-regulated exosomal GOLM1 promotes hepatocellular carcinoma through augmented GSK-3β/MMPs. J Genet Genomics 2019; 46:235-245. [PMID: 31186161 DOI: 10.1016/j.jgg.2019.03.013] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 03/06/2019] [Accepted: 03/06/2019] [Indexed: 12/28/2022]
Abstract
Golgi membrane protein 1 (GOLM1/GP73) is a serum marker of hepatocellular carcinoma (HCC). We have previously shown that mTOR promoted tumorigenesis of HCC through stimulating GOLM1 expression. In this study, we demonstrated that the mammalian target of rapamycin (mTOR) was a negative regulator of microRNA-145 (miR-145) expression. miR-145 inhibited GOLM1 expression by targeting a coding sequence of GOLM1 gene. GOLM1 and miR-145 were inversely correlated in human HCC tissues. GOLM1-enriched exosomes activated the glycogen synthase kinase-3β/matrix metalloproteinases (GSK-3β/MMPs) signaling axis of recipient cells and accelerated cell proliferation and migration. In contrast, miR-145 suppressed tumorigenesis and metastasis. We suggest that mTOR/miR-145/GOLM1 signaling pathway should be targeted for HCC treatment.
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Affiliation(s)
- Xiaochen Gai
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China
| | - Bufu Tang
- First Affiliated Hospital, Dalian Medical University, Dalian, 116011, China; Department of Radiology, Lishui Hospital of Zhejiang University, Lishui, 323000, China; Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 323000, China
| | - Fangming Liu
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China
| | - Yuting Wu
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China
| | - Fang Wang
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China
| | - Yanling Jing
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China
| | - Fuqiang Huang
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China
| | - Di Jin
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China
| | - Ling Wang
- First Affiliated Hospital, Dalian Medical University, Dalian, 116011, China.
| | - Hongbing Zhang
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China; Department of Neurology, Institute of Neural Regeneration and Repair, The First People's Hospital of Yichang, College of Medicine, Three Gorges University, Yichang, 443000, China.
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38
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Goeppert B, Truckenmueller F, Ori A, Fritz V, Albrecht T, Fraas A, Scherer D, Silos RG, Sticht C, Gretz N, Mehrabi A, Bewerunge-Hudler M, Pusch S, Bermejo JL, Dietrich P, Schirmacher P, Renner M, Roessler S. Profiling of gallbladder carcinoma reveals distinct miRNA profiles and activation of STAT1 by the tumor suppressive miRNA-145-5p. Sci Rep 2019; 9:4796. [PMID: 30886199 PMCID: PMC6423323 DOI: 10.1038/s41598-019-40857-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Accepted: 02/25/2019] [Indexed: 12/13/2022] Open
Abstract
Gallbladder carcinoma (GBC) is a biliary tract cancer with few treatment options and poor prognosis. Radical surgery is the only potentially curative treatment option but most patients diagnosed with GBC are unresectable. Thus, there is a great need for the development of new treatment options including targeted therapy. Here, we aimed at identifying deregulated miRNAs and affected pathways involved in GBC development and progression. We performed global miRNA profiling of 40 GBC and 8 normal gallbladder tissues and identified large differences with 30% of miRNAs being differentially expressed (false discovery rate: FDR < 0.001). We found 24 miRNAs to be differentially regulated in GBC with poor outcome (p < 0.05) of which miR-145-5p was the most downregulated miRNA. Overexpression of miR-145-5p significantly reduced cell proliferation and colony formation. Gene expression analysis of cells expressing miR-145-5p mimics revealed activation of the Signal transducer and activator of transcription 1 (STAT1) signaling pathway which is mainly tumor suppressive. Furthermore, the activation of STAT1 by miR-145-5p was specifically observed in gallbladder carcinoma and cholangiocarcinoma but not in hepatocellular carcinoma cells. The Protein Tyrosine Phosphatase Receptor Type F (PTPRF) is downregulated upon miR-145 expression and may be involved in STAT1 regulation. In addition, we found that the STAT1-regulated protein IRF7 is downregulated in GBC compared to normal gallbladder tissue and low IRF7 expression is associated with significantly lower overall survival of GBC patients. Thus, this study identified GBC patient subgroups and provides new mechanistic insights in the tumor suppressive function of miR-145-5p leading to activation of STAT1 signaling.
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Affiliation(s)
- Benjamin Goeppert
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | | | - Alessandro Ori
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany
| | - Valerie Fritz
- Institute of Biochemistry, Emil-Fischer Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Thomas Albrecht
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Angelika Fraas
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Dominique Scherer
- Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg, Germany
| | - Rosa González Silos
- Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg, Germany
| | - Carsten Sticht
- Center of Medical Research, University Hospital Mannheim, Mannheim, Germany
| | - Norbert Gretz
- Center of Medical Research, University Hospital Mannheim, Mannheim, Germany
| | - Arianeb Mehrabi
- Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Melanie Bewerunge-Hudler
- Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Stefan Pusch
- Heidelberg University Hospital, Institute of Pathology, Department of Neuropathology, Heidelberg, Germany and Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Heidelberg, Germany
| | - Justo Lorenzo Bermejo
- Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg, Germany
| | - Peter Dietrich
- Institute of Biochemistry, Emil-Fischer Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.,Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Marcus Renner
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Stephanie Roessler
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
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Zhou JL, Deng S, Fang HS, Yu G, Peng H. Hsa-let-7g promotes osteosarcoma by reducing HOXB1 to activate NF-kB pathway. Biomed Pharmacother 2018; 109:2335-2341. [PMID: 30551492 DOI: 10.1016/j.biopha.2018.11.026] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 11/04/2018] [Accepted: 11/06/2018] [Indexed: 12/17/2022] Open
Abstract
MicroRNA (miRNA) is known to be involved in regulating the proliferation, migration and apoptosis of cancer cells in osteosarcoma. In this study, We aim to explore the expression of hsa-let-7 g and its role in pathogenesis of osteosarcoma. By analyzing clinical data. We found high expression of hsa-let-7 g in patients with osteosarcoma. The patients with higher expression of hsa-let-7 g showed poorer prognosis and lower survival rate. After downregulation of hsa-let-7 g in cell model and animal model, we found that with downregulation of hsa-let-7 g, the proliferation of osteosarcoma cells was significantly reduced, the level of migration and invasion was down-regulated, the cell cycle was inhibited, and cell apoptosis was increased. Through Dual Luciferase Reporter, immunohistochemistry, western blot and other experiments, it was found that hsa-let-7 g down-regulated HOXB1 gene and activated NF-kB pathway to promote the development of osteosarcoma. In conclusion, hsa-let-7 g is highly expressed in osteosarcoma tissues, and high expression of hsa-let-7 g can promote the occurrence of osteosarcoma by down-regulating HOXB1 and activating NF-kB pathway.
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Affiliation(s)
- Jian-Lin Zhou
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, PR China
| | - Shuang Deng
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, PR China.
| | - Hong-Song Fang
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, PR China
| | - Guangyang Yu
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, PR China
| | - Hao Peng
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, PR China
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Change of Circulating and Tissue-Based miR-20a in Human Cancers and Associated Prognostic Implication: A Systematic Review and Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2018; 2018:6124927. [PMID: 30596096 PMCID: PMC6286746 DOI: 10.1155/2018/6124927] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 10/14/2018] [Accepted: 11/14/2018] [Indexed: 12/16/2022]
Abstract
Background Previous literatures have investigated the change of miR-20a expression level in the progression of multiple cancers and its influence on patients' survival outcome, but results of now-available evidence are inconsistent. Objective To elucidate the prognostic value of circulating and tissue-based miR-20a for patients with various cancers. Methods A systematic search and review of eligible publications were carried out in three electronic databases including the Cochrane Library, PubMed, and Embase, and the methodological quality of included studies was assessed according to Newcastle-Ottawa Scale (NOS). Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for overall survival (OS), recurrence-free survival (RFS), disease-free survival (DFS), and progressive-free survival (PFS) of each study were pooled using a random effect model. Results In total, 24 studies involving 4186 samples of multiple cancers published in 20 articles were included in the statistical analysis. As for circulating miR-20a, five kinds of cancers containing gastric cancer, lymphoma, glioblastoma, prostate cancer, and non-small-cell lung cancer reported upregulated level in patients compared with normal healthy control, and overexpressed circulating miR-20a could confer an unfavorable factor for OS (HR = 1.71, 95% CIs: 1.43 -2.04, p < 0.01) and DFS (HR = 1.90, 95% CIs: 1.45-2.49, p < 0.01). As for tissue-based samples, 6 kinds of malignancies including colorectal cancer, salivary adenoid cystic carcinoma, gallbladder carcinoma, colon cancer, gastrointestinal cancer, and alveolar rhabdomyosarcoma revealed upregulated miR-20a expression level compared with paired nontumorous tissue, of which high expression of miR-20a was significantly associated with poor OS (HR = 2.74, 95% CIs: 1.38-5.42, p < 0.01) and DFS (HR = 2.68, 95% CIs: 1.32-5.45, p < 0.01); meanwhile, other 5 tumors containing breast cancer, cutaneous squamous cell carcinoma, hepatocellular carcinoma, oral squamous cell carcinoma, and epithelial ovarian cancer demonstrated downregulated miR-20a expression level compared with benign tissue, of which low miR-20a expression was significantly related to shorter OS (HR = 3.48, 95% CIs: 2.00-6.06, p < 0.01) and PFS/RFS (HR = 4.05, 95% CIs: 2.89-5.66, p < 0.01). Conclusion Change of circulating and tissue-based miR-20a expression possesses vital prognostic implication for human cancers. Augmented expression of circulating miR-20a predicts poor survival outcome for patients with cancers. Tissue-based miR-20a level may be upregulated or downregulated depending on cancer types; in the former condition, high expression of tissue miR-20a is a risk factor for unfavorable prognosis and in the latter condition low expression of tissue miR-20a is associated with shorter survival.
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MicroRNA-340 inhibits squamous cell carcinoma cell proliferation, migration and invasion by downregulating RhoA. J Dermatol Sci 2018; 92:197-206. [PMID: 30262127 DOI: 10.1016/j.jdermsci.2018.09.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 08/23/2018] [Accepted: 09/04/2018] [Indexed: 12/21/2022]
Abstract
BACKGROUND MicroRNAs are reported to play an important role in tumor growth and metastasis, including squamous cell carcinoma (SCC). Accumulative evidence has revealed that dysregulated miR-340 expression contributed to the carcinogenesis and development of various cancers. OBJECTIVE The aim of the current study was to investigate the role and the underlying mechanism of miR-340 in SCC cell proliferation, migration and invasion. METHODS Quantitative real-time PCR was performed to examine the expression of miR-340 in SCC tissues and cell lines. The function of miR-340 in SCC was investigated through Cell Counting Kit-8, wound healing, transwell migration and invasion assays. Bioinformatics analysis, luciferase reporter assay, western blotting and immunohistochemical analysis were conducted to predict and confirm the target gene of miR-340. RESULTS In the present study, we first found that miR-340 was significantly decreased in both SCC tissues and cell lines. Moreover, ectopic expression of miR-340 remarkably attenuated SCC cell proliferation, migration and invasion, whereas inhibition of endogenous miR-340 promoted SCC cell proliferation, migration and invasion in vitro. Our subsequent bioinformatics analysis and luciferase reporter assay showed that RhoA was a novel direct target of miR-340 in SCC cells, and the knockdown of RhoA expression rescued the effects of miR-340 inhibition on SCC cell proliferation, migration and invasion. More importantly, the expression of RhoA and miR-340 was negatively correlated in SCC tissues. CONCLUSION Our findings demonstrate the tumor suppressor role of miR-340 in SCC by directly regulating RhoA. Therefore, restoration of miR-340 expression can be a potential therapeutic approach for SCC treatment.
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Zhang W, Luo P. MicroRNA-29c restores cisplatin sensitivity in liver cancer through direct inhibition of sirtuin 1 expression. Oncol Lett 2018; 16:1543-1550. [PMID: 30008835 DOI: 10.3892/ol.2018.8801] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Accepted: 05/17/2018] [Indexed: 12/19/2022] Open
Abstract
Liver cancer is one of the most prevalent human tumors in the world. Despite recent advances regarding the understanding of the molecular basis of liver cancer and the introduction of novel chemotherapeutic approaches, liver cancer remains associated with a poor prognosis. Sirtuin 1 (SIRT1) was identified to be abnormally upregulated in liver cancer. Dysregulation of microRNAs (miRs/miRNAs) is associated with a variety of types of cancer, and miRNAs may also serve a role in tumorigenesis and progression. The present study demonstrated that following the selection of the cisplatin chemoresistant HepG2 cell line, miR-29c is downregulated using reverse transcription-quantitative polymerase chain reaction. Furthermore, overexpression of miR-29c in cisplatin-resistant cancer cells was demonstrated to inhibit tumor cell proliferation and to promote apoptosis in vitro and in vivo, as well as restoring cisplatin chemosensitivity by using a cell counting assay, colony formation assay, Annexin V-fluorescein isothocyanate/propidium iodide apoptosis analysis, terminal deoxynucleotidyl transferase dUTP nick end labeling and xenograft tumors in nude mice. Mechanistically, according to bioinformatics analysis and a luciferase assay, miR-29c may directly target SIRT1 mRNA and repress SIRT1 expression, which is positively associated with the chemoresistance of liver cancer and may ultimately provide a novel therapeutic method.
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Affiliation(s)
- Wei Zhang
- Department of Geriatric Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
| | - Peng Luo
- Department of Cardiology, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
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Peng W, Liu YN, Zhu SQ, Li WQ, Guo FC. The correlation of circulating pro-angiogenic miRNAs' expressions with disease risk, clinicopathological features, and survival profiles in gastric cancer. Cancer Med 2018; 7:3773-3791. [PMID: 30003708 PMCID: PMC6089172 DOI: 10.1002/cam4.1618] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 05/17/2018] [Accepted: 05/25/2018] [Indexed: 12/27/2022] Open
Abstract
This study aimed to explore the correlation of circulating pro‐angiogenic miRNAs’ expressions with risk, clinicopathological features, and survival profiles in gastric cancer (GC). Three hundred and thirty‐three GC patients underwent radical resection and 117 health controls (HCs) were recruited for this study. Plasma samples were obtained from GC patients before the operation and from HCs after enrollment. Fourteen pro‐angiogenic miRNAs were asseassed by quantitative polymerase chain reaction (qPCR). Disease‐free survival (DFS) and overall survival (OS) of GC patients were calculated and the median follow‐up duration was 36.0 months. Seven out of 14 pro‐angiogenic miRNAs including let‐7f, miR‐17‐5p, miR‐18a, miR‐19b‐1, miR‐20a, miR‐210, and miR‐296 were observed to be elevated in GC patients compared with HCs. MiR‐18a, miR‐20a, and miR‐210 disclosed good predictive values of GC risk. Six pro‐angiogenic miRNAs including miR‐17‐5p, miR‐92a, miR‐210, miR‐20a, miR‐18a, and miR‐296 expressions were positively while 1 pro‐angiogenic miRNA (miR‐130a) was negatively correlated with tumor malignancy degree in GC patients. K‐M curve disclosed that 5 pro‐angiogenic miRNAs including miR‐17‐5p, miR‐18a, miR‐20a, miR‐92a, and miR‐210 correlated with worse DFS, while 4 pro‐angiogenic miRNAs including miR‐17‐5p, miR‐18a, miR‐20a, and miR‐210 associated with shorter OS. Further multivariate Cox's analysis revealed that miR‐17‐5p, miR‐18a, miR‐20a, and miR‐210 were independent predictive factors for unfavorable DFS and OS. In conclusion, circulating pro‐angiogenic miRNAs could serve as novel noninvasive biomarkers for disease risk and malignancy degree, and miR‐17‐5p, miR‐18a, miR‐20a, and miR‐210 are independent factors predicting poor prognosis in GC patients.
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Affiliation(s)
- Wei Peng
- Department of General Surgery, Guangdong General Hospital Zhuhai Hospital (Zhuhai Golden Bay Center Hospital), Zhuhai, China
| | - Ya-Nan Liu
- Department of General Surgery, Guangdong General Hospital Zhuhai Hospital (Zhuhai Golden Bay Center Hospital), Zhuhai, China
| | - Si-Qiang Zhu
- Deparment of General Surgery, No. 211 Hospital of PLA, Harbin, China
| | - Wen-Qiang Li
- Department of General Surgery, Guangdong General Hospital Zhuhai Hospital (Zhuhai Golden Bay Center Hospital), Zhuhai, China
| | - Feng-Cheng Guo
- Deparment of General Surgery, No. 211 Hospital of PLA, Harbin, China
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Zhou L, Li X, Zhou F, Jin Z, Chen D, Wang P, Zhang S, Zhuge Y, Shang Y, Zou X. Downregulation of leucine-rich repeats and immunoglobulin-like domains 1 by microRNA-20a modulates gastric cancer multidrug resistance. Cancer Sci 2018; 109:1044-1054. [PMID: 29450946 PMCID: PMC5891193 DOI: 10.1111/cas.13538] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 01/28/2018] [Accepted: 02/11/2018] [Indexed: 12/13/2022] Open
Abstract
Multidrug resistance (MDR) significantly restricts the clinical efficacy of gastric cancer (GC) chemotherapy, and it is critical to search novel targets to predict and overcome MDR. Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) has been proved to be correlated with drug resistance in several cancers. The present study revealed that LRIG1 was overexpressed in chemosensitive GC tissues and decreased expression of LRIG1 predicted poor survival in GC patients. We observed that upregulation of LRIG1 enhanced chemosensitivity in GC cells. Interestingly, miR-20a, which was overexpressed in GC MDR cell lines and tissues, was identified to regulate LRIG1 expression by directly targeting its 3' untranslated region. We also found that inhibition of miR-20a suppressed GC MDR, and upregulation showed opposite effects. Moreover, we demonstrated that the miR-20a/LRIG1 axis regulated GC cell MDR through epidermal growth factor receptor (EGFR)-mediated PI3K/AKT and MAPK/ERK signaling pathways. Finally, LRIG1 expression in human GC tissues is inversely correlated with miR-20a and EGFR. Taken together, the newly identified miR-20a/LRIG1/EGFR link provides insight into the MDR process of GC, and targeting this axis represents a novel potential therapeutic strategy to block GC chemoresistance.
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Affiliation(s)
- Lin Zhou
- Department of GastroenterologyNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingChina
- Jiangsu Clinical Medical Center of Digestive DiseaseNanjingChina
| | - Xiaowei Li
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive DiseasesXijing HospitalThe Fourth Military Medical UniversityXi'anChina
| | - Fan Zhou
- Department of GastroenterologyNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingChina
- Jiangsu Clinical Medical Center of Digestive DiseaseNanjingChina
| | - Zhi'an Jin
- The Second Outpatient Department of Chengdu Army Region AuthorityChengduChina
| | - Di Chen
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive DiseasesXijing HospitalThe Fourth Military Medical UniversityXi'anChina
| | - Pin Wang
- Department of GastroenterologyNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingChina
- Jiangsu Clinical Medical Center of Digestive DiseaseNanjingChina
| | - Shu Zhang
- Department of GastroenterologyNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingChina
- Jiangsu Clinical Medical Center of Digestive DiseaseNanjingChina
| | - Yuzheng Zhuge
- Department of GastroenterologyNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingChina
- Jiangsu Clinical Medical Center of Digestive DiseaseNanjingChina
| | - Yulong Shang
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive DiseasesXijing HospitalThe Fourth Military Medical UniversityXi'anChina
| | - Xiaoping Zou
- Department of GastroenterologyNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingChina
- Jiangsu Clinical Medical Center of Digestive DiseaseNanjingChina
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Li C, Deng M, Hu J, Li X, Chen L, Ju Y, Hao J, Meng S. Chronic inflammation contributes to the development of hepatocellular carcinoma by decreasing miR-122 levels. Oncotarget 2017; 7:17021-34. [PMID: 26933995 PMCID: PMC4941368 DOI: 10.18632/oncotarget.7740] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 02/05/2016] [Indexed: 12/12/2022] Open
Abstract
Persistent inflammation in chronic hepatitis plays a major role in the development of hepatocellular carcinoma (HCC). In this study, the major inflammatory cytokines expressed in chronic hepatitis, IL-6 and TNF-α, induced a marked decrease in microRNA-122 (miR-122) levels, and miR-122 expression was downregulated in the livers of chronic hepatitis B (CHB) patients. The decrease of miR-122 caused upregulation of the proinflammatory chemokine CCL2. IL-6 and TNF-α suppressed miR-122 both by directly downregulating the transcription factor C/EBPα and indirectly upregulating c-myc, which blocks C/EBPα-mediated miR-122 transcription. In addition, IL-6 and TNF-α levels were elevated and miR-122 levels were decreased in mouse and rat models of diethylnitrosamine (DEN)-induced HCC. Restoration of miR-122 levels through delivery of agomir-122 suppressed DEN-induced hepatocarcinogenesis in mice. Our results show that inflammation-induced miR-122 downregulation in hepatitis contributes to carcinogenesis and suggest that increasing miR-122 may be an effective strategy for preventing HCC development in CHB patients.
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Affiliation(s)
- Changfei Li
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
| | - Mengmeng Deng
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
| | - Jun Hu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
| | - Xin Li
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
| | - Lizhao Chen
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
| | - Ying Ju
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
| | - Junli Hao
- School of Biomedical Sciences, Chengdu Medical College, Chengdu, China
| | - Songdong Meng
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
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Xu S, Zhan M, Wang J. Epithelial-to-mesenchymal transition in gallbladder cancer: from clinical evidence to cellular regulatory networks. Cell Death Discov 2017; 3:17069. [PMID: 29188076 PMCID: PMC5702855 DOI: 10.1038/cddiscovery.2017.69] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 08/19/2017] [Accepted: 08/23/2017] [Indexed: 02/08/2023] Open
Abstract
Gallbladder cancer (GBC), with late diagnosis, rapid disease progression and early metastasis, is a highly aggressive malignant tumor found worldwide. Patients with GBC have poor survival, low curative resection rates and early recurrence. For such a lethal tumor, uncovering the mechanisms and exploring new strategies to prevent tumor progression and metastasis are critically important. Epithelial-to-mesenchymal transition (EMT) has a prominent role in the early steps of tumor progression and metastasis by initiating polarized epithelial cell transition into motile mesenchymal cells. Accumulating evidence suggests that EMT can be modulated by the cooperation of multiple mechanisms affecting common targets. Signaling pathways, transcriptional and post-transcriptional regulation and epigenetic alterations are involved in the stepwise EMT regulatory network in GBC. Loss of epithelial markers, acquisition of mesenchymal markers and dysregulation of EMT-inducing transcription factors (EMT-TFs) have been observed and are associated with the clinicopathology and prognosis of GBC patients. Therefore, EMT may be a detectable and predictable event for predicting GBC progression and metastasis in the clinic. In this review, we will provide an overview of EMT from the clinical evidence to cellular regulatory networks that have been studied thus far in clinical and basic GBC studies.
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Affiliation(s)
- Sunwang Xu
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ming Zhan
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jian Wang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Targeting of NT5E by miR-30b and miR-340 attenuates proliferation, invasion and migration of gallbladder carcinoma. Biochimie 2017; 146:56-67. [PMID: 29155108 DOI: 10.1016/j.biochi.2017.10.027] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 10/31/2017] [Indexed: 01/11/2023]
Abstract
MicroRNAs (miRNAs) have been closely associated with the proliferation, invasion and migration of various cancers, including gallbladder carcinoma (GBC). Previous studies have revealed dysregulation of miR-30b and miR-340 in many types of cancer. However, the role of miR-30b and miR-340 in the development and progression of GBC remains unclear. Moreover, epithelial-to-mesenchymal transition (EMT) has been gradually viewed as a significant contributor to tumor metastasis. In this study, the cell line GBC-SD was used and we explored that EMT promoted GBC cells invasion and migration and inhibited the expression level of miR-30b and miR-340 compared with the control. We showed that overexpression of miR-30b and miR-340 suppressed GBC cells proliferation, invasion and migration, as well as the expression of EMT-associated genes. In addition, we identified ecto-5'-nucleotidase (NT5E) as a common target of miR-30b and miR-340 using bioinformatics analysis and a luciferase assay. Further experiments found that exogenous expression of NT5E in GBC cells could partially reverse the inhibitory effect of miR-30b and miR-340 on cell proliferation, invasion and migration. Our findings suggest that NT5E-targeting miRNAs (miR-30b and miR-340) function as tumor suppressors and may represent promising therapeutic targets for GBC.
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Si W, Shen J, Du C, Chen D, Gu X, Li C, Yao M, Pan J, Cheng J, Jiang D, Xu L, Bao C, Fu P, Fan W. A miR-20a/MAPK1/c-Myc regulatory feedback loop regulates breast carcinogenesis and chemoresistance. Cell Death Differ 2017; 25:406-420. [PMID: 29125598 PMCID: PMC5762853 DOI: 10.1038/cdd.2017.176] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 07/31/2017] [Accepted: 09/13/2017] [Indexed: 12/25/2022] Open
Abstract
Chemoresistance often leads to the failure of breast cancer treatment. MicroRNAs (miRNAs) play an important role in the progression and chemoresistance of cancer. However, because of the complexity of the mechanisms of chemoresistance and the specificity of miRNA regulation in different cell types, the function of miR-20a in breast cancer chemoresistance is still unclear. Here, by using miRNA microarray and high-content screening techniques, we found that miR-20a/b were significantly downregulated in breast cancer tissues compared with normal breast tissues, and low miR-20a/b expression was correlated with poor survival in breast cancer patients. Ectopic overexpression of miR-20a sensitized breast cancer cells to a broad spectrum of chemotherapy drugs and suppress their proliferation both in vitro and in vivo. Further study demonstrated that miR-20a directly targeted the 3'untranslated region of MAPK1, and thus downregulated the expression of P-gp and c-Myc by inhibiting the MAPK/ERK signaling pathway, whereas c-Myc can bind to the promoter region of the miR-20a gene to promote the expression of miR-20a. Together, our study identified a novel miR-20a/MAPK1/c-Myc feedback loop that regulates breast cancer growth and chemoresistance. These findings suggest that miR-20a synergizing with anticancer drugs will be a promising treatment strategy, especially for chemoresistant patients.
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Affiliation(s)
- Wengong Si
- Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310003, China
| | - Jiaying Shen
- Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310003, China
| | - Chengyong Du
- Breast Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310003, China
| | - Danni Chen
- Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310003, China
| | - Xidong Gu
- Department of Breast Surgery, the First Affiliate Hospital of Zhejiang Chinese Medical University, Hangzhou 310014, China
| | - Chenggong Li
- Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310003, China
| | - Minya Yao
- Breast Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310003, China
| | - Jie Pan
- Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310003, China
| | - Junchi Cheng
- Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310003, China
| | - Donghai Jiang
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310003, China
| | - Liang Xu
- Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310003, China.,Clinical Research Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310003, China
| | - Chang Bao
- Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310003, China
| | - Peifen Fu
- Breast Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310003, China
| | - Weimin Fan
- Program of Innovative Cancer Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310003, China.,Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
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Wei L, Ran F. MicroRNA-20a promotes proliferation and invasion by directly targeting early growth response 2 in non-small cell lung carcinoma. Oncol Lett 2017; 15:271-277. [PMID: 29375712 PMCID: PMC5766075 DOI: 10.3892/ol.2017.7299] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 07/14/2017] [Indexed: 12/25/2022] Open
Abstract
MicroRNA-20a (miR-20a) serves a notable role in tumor development and progression; it functions differently in different types of malignant tumor, and its role and mechanism in non-small cell lung carcinoma (NSCLC) remains unclear. In the present study, the effects of miR-20a on the proliferation and invasion of NSCLC cells and the underlying mechanisms behind this were investigated. Reverse transcription-quantitative polymerase chain reaction revealed that the expression level of miR-20a was higher in human NSCLC than in normal tissues. Following this, the effect of miR-20a on the proliferation, apoptosis, migration and invasion of NSCLCA-549 cells was further evaluated. In vitro analysis, including a Cell Counting Kit-8, colony formation and Transwell migration assay, indicated that miR-20a-knockdown inhibited the proliferation, invasion and migration, while promoting the cell apoptosis of the A-549 cells. Early growth response 2 (EGR2) protein and mRNA levels were downregulated or upregulated following the overexpression or knockdown of miR-20a, respectively. Dual-luciferase reporter gene assays implied that EGR2 is a direct target gene of miR-20a. The results of the present study indicated that miR-20a may function as an oncomiR in the development of NSCLC by promoting cell viability and motility. The inhibition of miR-20a could even become a novel therapeutic method for the treatment of NSCLC.
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Affiliation(s)
- Lai Wei
- Department of Chest Radiotherapy, Hubei Cancer Hospital, Wuhan, Hubei 430079, P.R. China
| | - Fengming Ran
- First Department of Thoracic Surgery, Hubei Cancer Hospital, Wuhan, Hubei 430079, P.R. China
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Zhou N, Cheng W, Peng C, Liu Y, Jiang B. Decreased expression of hsa‑miR‑372 predicts poor prognosis in patients with gallbladder cancer by affecting chloride intracellular channel 1. Mol Med Rep 2017; 16:7848-7854. [PMID: 28944858 DOI: 10.3892/mmr.2017.7520] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 07/28/2017] [Indexed: 11/06/2022] Open
Abstract
It has been reported that hsa‑microRNA (miRNA/miR)‑372 functions as a tumor suppressor or oncogene in various digestive system tumors, however, its roles in gallbladder cancer (GBC) are yet to be established. The present study aimed to determine the expression and clinical relevance of hsa‑miR‑372 in GBC. The expression of hsa‑miR‑372 in 80 pairs of human GBC tissues and adjacent normal gallbladder tissues was measured by reverse transcription‑quantitative polymerase chain reaction. Subsequently, the associations between hsa‑miR‑372 expression levels and the clinicopathological characteristics of patients with GBC were determined using χ2 test. Furthermore, Kaplan‑Meier method and Cox regression analysis were performed to evaluate the association between hsa‑miR‑372 expression and the prognosis of patients with GBC. Furthermore, a dual‑luciferase reporter assay and western blot analysis were performed to predict and verify the target gene of hsa‑miR‑372. The results demonstrated that markedly lower hsa‑miR‑372 expression was observed in GBC tissues, which was associated with poor prognosis in patients with GBC. Downregulated expression of hsa‑miR‑372 was negatively associated with tumor histological grade, tumor‑node‑metastasis stage, lymph node metastasis and distant metastasis, however, no association was observed between reduced hsa‑miR‑372 expression and patient gender, age, tumor size and gallbladder stones. Multivariate Cox regression analysis revealed that hsa‑miR‑372 expression, histological grade and lymph node metastasis were independent prognostic factors for overall survival in patients with GBC. Chloride intracellular channel 1 (CLIC1) was previously reported to be an effective biomarker for predicting the prognosis of GBC. Notably, the results of the present study indicated that CLIC1 may be a direct target gene of hsa‑miR‑372. In conclusion, the current study provides the first statistically convincing evidence that downregulation of hsa‑miR‑372 may occur in GBC tissues, which may be associated with aggressive and progressive tumor behavior by affecting CLIC1 expression.
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Affiliation(s)
- Ning Zhou
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan 410011, P.R. China
| | - Wei Cheng
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan 410011, P.R. China
| | - Chuang Peng
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan 410011, P.R. China
| | - Yi Liu
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan 410011, P.R. China
| | - Bo Jiang
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan 410011, P.R. China
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