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Xie H, Wang H, Li RH, Zhang YW, Fan XR, He XX, Guan AR. DNMT1 promotes the proliferation and migration of gastric cancer cells by inducing microRNA-125a-5p methylation to promote SERPINE1 protein. World J Gastrointest Oncol 2025; 17:98703. [PMID: 40092920 PMCID: PMC11866249 DOI: 10.4251/wjgo.v17.i3.98703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 12/11/2024] [Accepted: 12/23/2024] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) is a malignant tumor originating from gastric mucosal epithelial cells that has high morbidity and mortality. microRNAs (miR) are important diagnostic markers and therapeutic targets in this disease. AIM To explore the mechanism of miR-125a-5p in the pathogenesis of GC. METHODS The expression levels of miR-125a-5p, SERPINE1 and DNMT1 in GC cells and tissues were detected by real-time polymerase chain reaction (PCR) and Western blotting. Methylation-specific PCR was used to detect the level of miR-125a-5p methylation. A cell counting kit 8 assay, scratch test, and a Transwell assay were performed to detect the proliferation, migration, and invasiveness of HGC27 cells, respectively. The expression of the epithelial mesenchymal transition (EMT)-related proteins E-cadherin, N-cadherin and vimentin in HGC27 cells was detected by Western blotting, while the expression of vimentin was detected by immunofluorescence. RESULTS This study revealed that miR-125a-5p was expressed at low levels in GC clinical samples and cells and that miR-125a-5p overexpression inhibited the proliferation, migration, invasiveness and EMT of GC cells. Mechanistically, miR-125a-5p can reduce GC cell proliferation, promote E-cadherin expression, inhibit N-cadherin and vimentin expression, and reduce the EMT of GC cells, thus constraining GC cells to a certain extent. Moreover, DNMT1 inhibited miR-125a-5p expression by increasing the methylation of the miR-125a-5p promoter, thereby promoting the expression of SERPINE1, which acts together with miR-125a-5p to exert antagonistic effects on GC. CONCLUSION Our study revealed that DNMT1 promoted SERPINE1 protein expression by inducing miR-125a-5p methylation, which led to the proliferation, migration and occurrence of EMT in GC cells.
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Affiliation(s)
- Hui Xie
- Department of General Surgery, Yan’an Hospital of Kunming City, Kunming 650051, Yunnan Province, China
| | - Hui Wang
- Department of Digestive Internal Medicine, Yan’an Hospital of Kunming City, Kunming 650051, Yunnan Province, China
| | - Ru-Hong Li
- Department of General Surgery, Yan’an Hospital of Kunming City, Kunming 650051, Yunnan Province, China
| | - Yue-Wen Zhang
- Department of General Surgery, Yan’an Hospital of Kunming City, Kunming 650051, Yunnan Province, China
| | - Xi-Rui Fan
- Department of Digestive Internal Medicine, Yan’an Hospital of Kunming City, Kunming 650051, Yunnan Province, China
| | - Xiao-Xue He
- Department of Digestive Internal Medicine, Yan’an Hospital of Kunming City, Kunming 650051, Yunnan Province, China
| | - Ao-Ran Guan
- Department of General Surgery, Yan’an Hospital of Kunming City, Kunming 650051, Yunnan Province, China
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Tang Y, Fahira A, Lin S, Shao Y, Huang Z. Shared and specific competing endogenous RNAs network mining in four digestive system tumors. Comput Struct Biotechnol J 2024; 23:4271-4287. [PMID: 39669749 PMCID: PMC11635987 DOI: 10.1016/j.csbj.2024.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 10/17/2024] [Accepted: 11/02/2024] [Indexed: 12/14/2024] Open
Abstract
Background Digestive system malignancies, including esophageal carcinoma (ESCA), stomach adenocarcinoma (STAD), liver hepatocellular carcinoma (LIHC), and colon adenocarcinoma (COAD), pose significant global health challenges. Identifying shared and distinct regulatory mechanisms across these cancers can lead to improved therapies. This study aims to construct and compare competing endogenous RNA (ceRNA) networks across ESCA, STAD, LIHC, and COAD to identify RNA biomarkers that could serve as precision therapeutic targets to enhance clinical outcomes and advance personalized cancer care. Methods Clinical and transcriptomic data from The Cancer Genome Atlas (TCGA) were analyzed to predict differentially expressed RNAs using the edgeR package. The ceRNA networks were constructed using the miRcode and ENCORI databases. Functional enrichment analysis and prognostic RNA screening were performed with ConsensusPathDB and univariate Cox regression analysis. Results we identified 6, 88, 55, and 41 RNA biomarkers in ESCA, STAD, LIHC, and COAD, respectively. Network analysis revealed shared and specific elements, with shared nodes enriched in cell cycle and mitotic processes. Several biomarkers, including HMGB3 and RGS16 (ESCA), COL4A1 and COL6A3 (STAD), CDCA5 and CDCA8 (LIHC), and LIMK1 and OSBPL3 (COAD), were consistent with prior studies, while novel biomarkers, such as C3P1 (ESCA), P2RY6 (STAD), and N4BP2L1 and PPP1R3B (LIHC), were discovered. Based on RNA correlation analysis, 1, 23, and 2 potential ceRNA regulatory axes were identified in STAD (PVT1/miR-490-3p/HMGA2), LIHC (DLX6-AS1/miR-139-5p/TOP2A, etc.), and COAD (STRCP1 & LINC00488/miR-142-3p/GAB1), respectively. Conclusions This study advances the understanding of ceRNA networks in digestive cancers, highlighting RNA biomarkers with potential as therapeutic targets for personalized treatment strategies.
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Affiliation(s)
- Yulai Tang
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, School of Pharmacy, Guangdong Medical University, Dongguan 523710, China
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan 523808, China
- Dongguan Key Laboratory of Sepsis Translational Medicine, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710
| | - Aamir Fahira
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan 523808, China
| | - Siying Lin
- Dongguan Key Laboratory of Sepsis Translational Medicine, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710
| | - Yiming Shao
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, School of Pharmacy, Guangdong Medical University, Dongguan 523710, China
| | - Zunnan Huang
- Key Laboratory of Computer-Aided Drug Design of Dongguan City, The First Dongguan Affiliated Hospital, School of Pharmacy, Guangdong Medical University, Dongguan 523710, China
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan 523808, China
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Manzoor U, Pandith AA, Amin I, Wani S, Baba SM, Wani UM, Mansoor S, Aein QU, Anwar I, Bahar B, Koul AM, Sanadhya D, Ahmad A. Regulatory role of miR-125a expression with respect to its target genes LIFR, ERBB2 and STAT3 in the pathogenesis of recurrent pregnancy losses. Int J Gynaecol Obstet 2024; 166:1285-1296. [PMID: 38528801 DOI: 10.1002/ijgo.15496] [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: 04/25/2023] [Revised: 12/23/2023] [Accepted: 03/10/2024] [Indexed: 03/27/2024]
Abstract
OBJECTIVES Studies have investigated miR-125a for its predictable role in recurrent pregnancy loss (RPL) cases to regulate many biological events required for the maintenance of pregnancy by regulating its confirmed target genes LIFR, ERBB2 and STAT3. METHODS The present study included 40 cases of women with at least two RPLs in ≤20 weeks of gestation against 40 healthy multiparous women without a previous history of abortion. Expression analysis of ERBB2, LIFR, STAT3 and miR-125a was conducted by quantitative real-time PCR (qPCR). RESULTS The expression of miR-125a was significantly lower in the plasma of RPL cases (P = 0.0001) and showed a significantly increased mean expression level in product of conception (2.56-fold, P < 0.0001). Among the target gene of miR-125a, ERBB2 and STAT3 gene expression level was significantly increased (2.58-fold, P = 0.04; 1.87-fold, P = 0.025), respectively in RPL cases while the LIFR gene revealed comparable expression (P = 0.64). Furthermore, expression analysis of ERBB2 gene with respect to its regulatory miR-125a cases depicted a significant association (P = 0.0005). Kaplan-Meier survival analysis revealed cases with low miR-125a expression had significantly shorter time to miscarriages, (log-rank P = 0.02). Also, decreased expression of miR-125a significantly conferred >2-fold increased risk for RPL (HR = 2.34: P < 0.05). CONCLUSION The overall conclusion of the study was that altered miR-125a expression may cause deregulation in target genes LIFR, ERBB2 and STAT3 resulting in adverse consequence in the outcome of pregnancy.
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Affiliation(s)
- Usma Manzoor
- Advanced Center for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
- School of Life and Basic Sciences, Jaipur National University, Jaipur, Rajasthan, India
| | - Arshad A Pandith
- Advanced Center for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
| | - Ina Amin
- Advanced Center for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
- Department of Clinical Biochemistry, University of Kashmir, Srinagar, India
| | - Saima Wani
- Department of Obstetrics and Gynecology, SKIMS, Srinagar, Jammu and Kashmir, India
| | - Shahid M Baba
- Advanced Center for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
| | - Umer M Wani
- Department of Biotechnology, University of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Sheikh Mansoor
- Advanced Center for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
| | - Qurat Ul Aein
- Advanced Center for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
| | - Iqra Anwar
- Advanced Center for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
| | - Barjista Bahar
- Department of Obstetrics and Gynecology, SKIMS, Srinagar, Jammu and Kashmir, India
| | - Aabid M Koul
- Advanced Center for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
| | - Dheera Sanadhya
- School of Life and Basic Sciences, Jaipur National University, Jaipur, Rajasthan, India
| | - Abida Ahmad
- Department of Obstetrics and Gynecology, SKIMS, Srinagar, Jammu and Kashmir, India
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Liu D, Tang X, Huang Z, Wen J, Zhou Y. Histone deacetylase HDAC2 regulates microRNA-125a expression in neuroblastoma. Brain Behav 2022; 12:e2401. [PMID: 35060363 PMCID: PMC8865159 DOI: 10.1002/brb3.2401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 10/12/2021] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Neuroblastoma (NB) is an infrequent childhood malignancy of the peripheral sympathetic nervous system and is accountable for about 10% of pediatric tumors. microRNA (miR)-125a has been implicated to serve as a tumor suppressor in various cancers. Herein, we set out to ascertain whether miR-125a exerts antitumor effects in NB. METHODS Downregulated miRNAs were identified by miRNA microarray analysis of NB tissues and paracancerous tissues. The expression of miR-125a in NB tissues and cells was detected by reverse transcription-quantitative (RT-q) PCR, followed by prognostic analysis. Gene Ontology (GO) enrichment analysis was performed on target genes of differentially expressed miRNAs. Cell proliferation, apoptosis, and differentiation were detected by cell counting kit-8 (CCK-8), Hoechst staining, immunofluorescence, and western blot. NB cells were injected into nude mice to detect tumorigenic, apoptotic, and differentiation activities in vivo. Dual-luciferase assay and chromatin immunoprecipitation (ChIP) were carried out to verify the binding relationship between miR-125a and PHOX2B or histone deacetylases 2 (HDAC2), respectively. Finally, rescue experiments were conducted. RESULTS miR-125a was downregulated in NB tissues and cells, which was associated with poor prognosis. miR-125a reduced NB cell proliferation and augmented apoptosis and differentiation. NB cells with miR-125a overexpression decreased cell tumorigenesis and increased apoptosis and differentiation in xenograft tumor tissues. miR-125a targeted PHOX2B, which was highly expressed in NB tissues and cells. HDAC2, highly expressed in NB tissues and cells, repressed miR-125a transcription through histone deacetylation. Overexpression of HDAC2 or PHOX2B rescued the effects of miR-125a on NB cell proliferation, apoptosis, and differentiation. CONCLUSION HDAC2 inhibited miR-125a transcription through deacetylation, and miR-125a suppressed NB development through binding to PHOX2B.
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Affiliation(s)
- Denghui Liu
- Department of Pediatric Surgery, Hunan Children's Hospital, Changsha, P.R. China
| | - Xianglian Tang
- Department of Pediatric Surgery, Hunan Children's Hospital, Changsha, P.R. China
| | - Zhao Huang
- Department of Pediatric Surgery, Hunan Children's Hospital, Changsha, P.R. China
| | - Jiabing Wen
- Department of Pediatric Surgery, Hunan Children's Hospital, Changsha, P.R. China
| | - Yuxiang Zhou
- Department of Pediatric Surgery, Hunan Children's Hospital, Changsha, P.R. China
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Li R, Hu Z, Wang Z, Zhu T, Wang G, Gao B, Wang J, Deng X. miR-125a-5p promotes gastric cancer growth and invasion by regulating the Hippo pathway. J Clin Lab Anal 2021; 35:e24078. [PMID: 34708891 PMCID: PMC8649339 DOI: 10.1002/jcla.24078] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 09/22/2021] [Accepted: 10/16/2021] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVE This study was carried out to explore the potential involvement of miR-125a-5p in the oncogenic effects of EphA2, TAZ, and TEAD2 and the activity of the Hippo signaling pathway in gastric cancer progression. METHODS In vitro transfection of miR-125a-5p mimics or inhibitors, qRT-PCR, colony formation assays, and cell invasion assays were used to assess the effect of miR-125a-5p on the growth and invasion in gastric cancer (GC). Male nude mice bearing tumors derived from human GC cells were used for evaluating the effects of miR-125a-5p on tumor growth. Luciferase reporter assay, immunofluorescence, immunohistochemistry, qRT-PCR, and immunoblotting were performed to explore the role of miR-125a-5p in the epithelial-mesenchymal transition (EMT) and association among miR-125a-5p, EphA2, TAZ, and TEAD2 in GC cells. RESULTS MiR-125a-5p enhanced GC cell viability and invasion in vitro, whereas inhibition of miR-125a-5p using a specific inhibitor and antagomir suppressed cancer cell invasion and tumor growth. Moreover, inhibition of miR-125a-5p reversed EMT in vitro. miR-125a-5p upregulated the expression of EphA2, TAZ, and TEAD2, promoted TAZ nuclear translocation, and induced changes in the activity of the Hippo pathway by enhancing the expression of TAZ target genes. Finally, miR-125a-5p was overexpressed in late-stage GCs, and positive correlations were observed with its targets EphA2, TAZ, and TEAD2. CONCLUSION miR-125a-5p can promote GC growth and invasion by upregulating the expression of EphA2, TAZ, and TEAD2.
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Affiliation(s)
- Ruixin Li
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Zhihao Hu
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Zhuoyin Wang
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Tianyu Zhu
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Guojun Wang
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Bulang Gao
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Jingtao Wang
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Xiumei Deng
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
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Bure IV, Nemtsova MV. Methylation and Noncoding RNAs in Gastric Cancer: Everything Is Connected. Int J Mol Sci 2021; 22:ijms22115683. [PMID: 34073603 PMCID: PMC8199097 DOI: 10.3390/ijms22115683] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 05/19/2021] [Accepted: 05/25/2021] [Indexed: 12/18/2022] Open
Abstract
Despite recent progress, gastric cancer remains one of the most common cancers and has a high mortality rate worldwide. Aberrant DNA methylation pattern and deregulation of noncoding RNA expression appear in the early stages of gastric cancer. Numerous investigations have confirmed their significant role in gastric cancer tumorigenesis and their high potential as diagnostic and prognostic biomarkers. Currently, it is clear that these epigenetic regulators do not work alone but interact with each other, generating a complex network. The aim of our review was to summarize the current knowledge of this interaction in gastric cancer and estimate its clinical potential for the diagnosis, prognosis, and treatment of the disease.
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Affiliation(s)
- Irina V. Bure
- Laboratory of Medical Genetics, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia;
- Correspondence: ; Tel.: +49-915-069-2721
| | - Marina V. Nemtsova
- Laboratory of Medical Genetics, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia;
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115522 Moscow, Russia
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Zheng W, Wu F, Fu K, Sun G, Sun G, Li X, Jiang W, Cao H, Wang H, Tang W. Emerging Mechanisms and Treatment Progress on Liver Metastasis of Colorectal Cancer. Onco Targets Ther 2021; 14:3013-3036. [PMID: 33986602 PMCID: PMC8110277 DOI: 10.2147/ott.s301371] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 03/24/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer is currently the third largest malignant tumor in the world, with high new cases and high mortality. Metastasis is one of the most common causes of death of colorectal cancer, of which liver metastasis is the most fatal. Since the beginning of the Human Genome Project in 2001, people have gradually recognized the 3 billion base pairs that make up the human genome, of which only about 1.5% of the nucleic acid sequences are used for protein coding, including proto-oncogenes and tumor suppressor genes. A large number of differences in the expression of proto-oncogenes and tumor suppressor genes have also been found in the study of colorectal cancer, which proves that they are also actively involved in the progression of colorectal cancer and promote the occurrence of liver metastasis. Except for 1.5% of the coding sequence, the rest of the nucleic acid sequence does not encode any protein, which is called non-coding RNA. With the deepening of research, genome sequences without protein coding potential that were originally considered “junk sequences” may have important biological functions. Many years of studies have found that a large number of abnormal expression of ncRNA in colorectal cancer liver metastasis, indicating that ncRNA plays an important role in it. To explore the role and mechanism of these coding sequences and non-coding RNA in liver metastasis of colorectal cancer is very important for the early diagnosis and treatment of liver metastasis of colorectal cancer. This article reviews the coding genes and ncRNA that have been found in the study of liver metastasis of colorectal cancer in recent years, as well as the mechanisms that have been identified or are still under study, as well as the clinical treatment of liver metastasis of colorectal cancer.
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Affiliation(s)
- Wubin Zheng
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Fan Wu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Kai Fu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Guangshun Sun
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Guoqiang Sun
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Xiao Li
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Wei Jiang
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Hongyong Cao
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Hanjin Wang
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Weiwei Tang
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, People's Republic of China
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Ahadi A. Dysregulation of miRNAs as a signature for diagnosis and prognosis of gastric cancer and their involvement in the mechanism underlying gastric carcinogenesis and progression. IUBMB Life 2020; 72:884-898. [DOI: 10.1002/iub.2259] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 02/08/2020] [Indexed: 02/06/2023]
Affiliation(s)
- Alireza Ahadi
- Department of Medical Genetics, School of MedicineShahid Beheshti University of Medical Sciences Tehran Iran
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Cao Q, Wang N, Ren L, Tian J, Yang S, Cheng H. miR-125a-5p post-transcriptionally suppresses GALNT7 to inhibit proliferation and invasion in cervical cancer cells via the EGFR/PI3K/AKT pathway. Cancer Cell Int 2020; 20:117. [PMID: 32308562 PMCID: PMC7147043 DOI: 10.1186/s12935-020-01209-8] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 04/06/2020] [Indexed: 02/08/2023] Open
Abstract
Background The carcinogenesis and progression of cervical cancer is a complex process in which numerous microRNAs are involved. The purpose of this study is to investigate the role of miR-125a-5p in progression of cervical cancer. Methods RT-qPCR was used to detect the expression of miR-125a-5p and GALNT7 in cervical cancer tissues and cell lines. Then, the miR-125a-5p mimic, miR-125a-5p inhibitor, GALNT7 siRNA, or/and pcDNA-GALNT7 were respectively transfected into HeLa and Caski cervical cancer cells, and Cell Counting kit-8 assay, Transwell assay and flow cytometry analysis were respectively used to observe cell proliferation, invasion and apoptosis. Subsequently, luciferase reporter gene assay was employed in confirming the target relationship between miR-125a-5p and GALNT7. MiR-125a-5p mimic or/and pcDNA-GALNT7 were transfected into the cervical cancer cells at the absence of epidermal growth factor (EGF) or not, and the pcDNA-GALNT7 was transfected into the cervical cancer cells at the absence of inhibitors of multiple kinases or not. Furthermore, the effect of miR-125a-5p on tumor growth was also studied using a xenograft model of nude mice. Results MiR-125a-5p was down-regulated in both cervical cancer tissues and cell lines and it inhibited cell proliferation and invasion of cervical cancer cells. MiR-125a-5p directly targeted and post-transcriptionally downregulated GALNT7 that was strongly upregulated in cervical cancer tissues and cell lines. Similar to the effect of miR-125a-5p mimic, silencing GALNT7 inhibited proliferation and invasion of cervical cancer cells. In addition, miR-125a-5p overexpression could counteract both GALNT7- and EGF-induced cell proliferation and invasion. GALNT7 promoted cell proliferation and invasion by activating the EGFR/PI3K/AKT kinase pathway, which could be abated by the inhibitors of the kinases. Moreover, the role of miR-125a-5p inhibited tumor formation in cervical cancer by suppressing the expression of GALNT7 in vivo. Conclusion In conclusion, miR-125a-5p suppressed cervical cancer progression by post-transcriptionally downregulating GALNT7 and inactivating the EGFR/PI3K/AKT pathway.
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Affiliation(s)
- Qinxue Cao
- Department Gynecology, Huaihe Hospital of Henan University, No.8 Baobei Road, Kaifeng, 475000 Henan Province China
| | - Ning Wang
- Department Gynecology, Huaihe Hospital of Henan University, No.8 Baobei Road, Kaifeng, 475000 Henan Province China
| | - Lu Ren
- Department Gynecology, Huaihe Hospital of Henan University, No.8 Baobei Road, Kaifeng, 475000 Henan Province China
| | - Jun Tian
- Department Gynecology, Huaihe Hospital of Henan University, No.8 Baobei Road, Kaifeng, 475000 Henan Province China
| | - Shaoqin Yang
- Department Gynecology, Huaihe Hospital of Henan University, No.8 Baobei Road, Kaifeng, 475000 Henan Province China
| | - Hailing Cheng
- Department Gynecology, Huaihe Hospital of Henan University, No.8 Baobei Road, Kaifeng, 475000 Henan Province China
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Abstract
The aim of the study was to estimate the prognostic and clinicopathologic significance of miR-125a-5p in human cancers. Eligible studies were obtained from PubMed, Embase, and the Cochrane Library. Combined hazard ratios (HRs) and odds ratios (ORs) were used to evaluate the prognostic and clinicopathologic value of miR-125a-5p. In pan-cancer, high miR-125a-5p expression was associated with better overall survival (OS) (HR = 0.459, 95% confidence interval [CI]: 0.369-0.57, P < .001), and disease-free survival (HR = 0.343, 95% CI: 0.237-0.496, P < .001). Furthermore, favorable OS was also found in lung cancer (HR = 0.343, 95% CI: 0.228-0.517, P < .001) and gastric cancer (HR = 0.341, 95% CI: 0.160-0.725, P = .005) patients with high miR-125a-5p expression. Besides, high miR-125a-5p expression was correlated with early stage (OR = 0.413, 95% CI: 0.228-0.749, P = .004) and negative lymph node metastasis (OR = 0.262, 95% CI: 0.073-0.941, P = .04) in gastric cancer, and was linked with better tumor differentiation in pan-cancer (OR = 1.623, 95% CI: 1.064-2.476, P = .025) and lung cancer (OR = 2.371, 95% CI: 1.358-4.141, P = .002). In conclusion, miR-125a-5p is a tumor suppressor with prognostic and clinicopathologic values for human cancer, and miR-125a-5p overexpression predicted favorable prognosis, early stage, negative lymph node metastasis, and better tumor differentiation. More research should be conducted to test these results.
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Affiliation(s)
- Haidong Ye
- Department of Surgery of Traditional Chinese Medicine, Zhejiang University of Traditional Chinese Medicine Affiliated Wenzhou Hospital, Wenzhou
| | - Wei Zhu
- Department of General Surgery, The First Hospital of Huzhou
| | - Lina Mei
- Department of Internal Medicine, Huzhou Maternity & Child Health Care Hospital
| | - Zhouxiang Lu
- Department of internal medicine, Huzhou Traditional Chinese Medicine Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Huzhou, Zhejiang, China
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Liu J, Tao C. Overexpression of miRNA-125a-5p inhibits the growth and angiogenesis of hepatocellular carcinoma by regulating the expression of VEGF-A. BIOTECHNOL BIOTEC EQ 2019. [DOI: 10.1080/13102818.2019.1640073] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Affiliation(s)
- Jingjing Liu
- Department of Infectious Diseases, Liaocheng People’s Hospital, Liaocheng, Shandong Province, People’s Republic of China
| | - Changming Tao
- Department of Infectious Diseases, Liaocheng People’s Hospital, Liaocheng, Shandong Province, People’s Republic of China
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12
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Li G, Ao S, Hou J, Lyu G. Low expression of miR-125a-5p is associated with poor prognosis in patients with gastric cancer. Oncol Lett 2019; 18:1483-1490. [PMID: 31423214 PMCID: PMC6607383 DOI: 10.3892/ol.2019.10423] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 04/16/2019] [Indexed: 12/19/2022] Open
Abstract
microRNAs (miRs) serve critical roles in tumor progression. Low expression of miR-125a in gastric carcinoma (GC) may promote tumor development. In the present study, low expression of miR-125a was confirmed in cancer tissues using The Cancer Genome Atlas database. Additionally, the expression and clinical significance of miR-125a-5p was investigated using reverse transcription-quantitative PCR in 150 cases of GC. The results of the present study demonstrated that the level of miR-125a-5p expression was decreased in GC biopsies compared with that in matched adjacent normal tissues. Low expression of miR-125a-5p was associated with increased tumor diameter, high Ki67 expression and poor overall survival of patients with GC. Multivariate survival analysis demonstrated that low miR-125a-5p expression may be used as an independent prognostic factor for patients with GC. However, no effects on the cell viability in a Cell Counting kit-8 assay, and cell migration and invasion in Transwell assays were detected in response to treatment using miR-125a-5p mimics or inhibitors in vitro. Therefore, the results of the present study provide evidence that low expression of miR-125a-5p may be associated with a poor prognosis, suggesting its value as a tumor biomarker for patients with GC.
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Affiliation(s)
- Guan Li
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Sheng Ao
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Jianing Hou
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Guoqing Lyu
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
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13
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Cao K, Fang Y, Wang H, Jiang Z, Guo L, Hu Y. The lncRNA HOXA11-AS regulates Rab3D expression by sponging miR-125a-5p promoting metastasis of osteosarcoma. Cancer Manag Res 2019; 11:4505-4518. [PMID: 31191012 PMCID: PMC6529177 DOI: 10.2147/cmar.s196025] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 04/22/2019] [Indexed: 12/22/2022] Open
Abstract
Objective: Many studies have shown that long non-coding RNAs (lncRNAs) are closely related to various cancers. This study aims to explore the roles of lncRNA HOXA11-AS in the development and progression of osteosarcoma (OS). Methods: The expression levels of HOXA11-AS and miR-125a-5p in tumor tissues and the adjacent tissues were detected by RT-PCR method. The proliferation, migration and invasion of MG-63 and KHOS cells were determined. Results: It was found that HOXA11-AS expression levels in OS tissues and OS cell lines were higher than those in OS adjacent tissues and normal human osteoblast cell lines. The higher expression level of HOXA11-AS was positively correlated with more severe clinical stage, distant metastasis and poor prognosis of OS. Inhibition of HOXA11-AS expression could reduce metastasis and invasion of OS cell lines. In addition, HOXA11-AS was found to be an endogenous inhibitor of miR-125a-5p, it down regulated the expression level of miR-125a-5p, and this process could promote the expression of Rab3D, the target gene of miR-125a-5p. Conclusion: Our study elucidated the role of a new HOXA11-AS/miR-125a-5p/Rab3D regulatory pathway in promoting OS metastasis.
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Affiliation(s)
- Kun Cao
- Department of Orthopaedics, The First Hospital Of Anhui Medical University, Hefei, People's Republic of China
| | - Yueyang Fang
- Department of Orthopaedics, The First Hospital Of Anhui Medical University, Hefei, People's Republic of China
| | - Hao Wang
- Department of Orthopaedics, The First Hospital Of Anhui Medical University, Hefei, People's Republic of China
| | - Zheng Jiang
- Department of Orthopaedics, The First Hospital Of Anhui Medical University, Hefei, People's Republic of China
| | - Li Guo
- Department of Orthopaedics, The Second Hospital Of Shanxi Medical University, Taiyuan, People's Republic of China
| | - Yong Hu
- Department of Orthopaedics, The First Hospital Of Anhui Medical University, Hefei, People's Republic of China
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14
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Wang JK, Wang Z, Li G. MicroRNA-125 in immunity and cancer. Cancer Lett 2019; 454:134-145. [PMID: 30981762 DOI: 10.1016/j.canlet.2019.04.015] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 04/09/2019] [Accepted: 04/09/2019] [Indexed: 12/31/2022]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that play a wide variety of critical roles in different biological processes by post-transcriptionally regulating gene expression. They access diverse regulatory pathways during various stages of cellular differentiation, growth, and apoptosis, and can contribute to both normal and diseased functions. One important family of miRNAs involved in these functions is the miR-125 family (miR-125a and miR-125b). Investigations have been made to increasingly uncover the mechanisms by which the miR-125 family regulates normal homeostasis and growth in a variety of cell types including immune cells, and how dysregulation of miR-125a and miR-125b can lead to disease pathogenesis and tumorigenesis. In this review, we summarize what is currently known about miR-125a and miR-125b, mainly focusing on their roles in immune cell development and function as well as tumor suppression and promotion.
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Affiliation(s)
- Jessica K Wang
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, United States
| | - Zhe Wang
- Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, China; Suzhou Institute of Systems Medicine, Suzhou, 215123, China
| | - Guideng Li
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, United States; Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, China; Suzhou Institute of Systems Medicine, Suzhou, 215123, China.
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15
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Yang L, Zhang S, Guo K, Huang H, Qi S, Yao J, Zhang Z. miR-125a restrains cell migration and invasion by targeting STAT3 in gastric cancer cells. Onco Targets Ther 2018; 12:205-215. [PMID: 30636883 PMCID: PMC6309784 DOI: 10.2147/ott.s168454] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Recently, many microRNAs have been found to be involved in the cancer progression including miR-125a. However, the underlying mechanisms of miR-125a in gastric cancer (GC) remain to be completely elucidated. OBJECTIVE The study was to investigate the functional role of miR-125a and the expression relevance of signal transducer and activator of transcription 3 (STAT3) and hyaluronan synthase 1 (HAS1). METHOD CCK-8 assay, scratch wound healing and transwell assay were conducted to identify the functional role of miR-125a in GC. In addition, using bioinformatics analysis, the target regulation relationship was found in STAT3 and miR-125a. To confirm the relationship, luciferase reporter assay was performed. More importantly, quantitative polymerase chain reaction and western blot assay were carried out to determine the association among miR-125a, STAT3 and HAS1 in GC cells. RESULTS Overexpressed miR-125a inhibited the migration and invasion of GC cells through scratch wound healing and transwell assay, and its knockdown displayed adverse effects, but the viability of GC cells did not show significant difference using CCK-8 assay. In addition, we identified that the knockdown of STAT3 or HAS1 remarkably suppressed the migration and invasion abilities of GC cells. Using bioinformatics analysis, miRTar, in particular, indicated that the 3'-untranslated region of STAT3 binds to miR-125a with a high score. Subsequently, we also verified that STAT3 was a target of miR-125a via luciferase reporter assay. Furthermore, we found that upregulated miR-125a expression could conspicuously constrain STAT3 expression at both protein and mRNA levels in MKN45 and NCI-N87 cells using quantitative polymerase chain reaction and Western blot assay, but no significant difference had been found in SGC 7901 cells. To further identify the regulatory relationship between miR-125a and STAT3, downregulation of miR-125a in MKN45 and NCI-N87 cells was carried out, which showed that the protein and mRNA expression levels of STAT3 were declined in two cell lines. Finally, we observed that upregulated miR-125a could lead to the decrease of HAS1 at protein and mRNA levels, whereas its knockdown revealed opposite effects. Meanwhile, we noticed that overexpression of STAT3 could induce the escalation of HAS1 at protein and mRNA expression levels and its knockdown exhibited the adverse outcomes. CONCLUSION These findings indicated that miR-125a may control the HAS1 expression in GC progression by targeting STAT3, which is likely to facilitate a better understanding of the regulation mechanisms of miR-125a in GC.
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Affiliation(s)
- Liu Yang
- Department of Cancer Biotherapy Center, Hubei Cancer Hospital, Wuhan, Hubei 430079, China
| | - Shuguang Zhang
- Department of Clinical Laboratory, Liaocheng People's Hospital, Liaocheng, Shandong 252000, China
| | - Kai Guo
- Department of Gastroenterology, The 161th Hospital of PLA, Wuhan, Hubei 430010, China
| | - Hu Huang
- Department of Oncology, The 161th Hospital of PLA, Wuhan, Hubei 430010, China
| | - Shuai Qi
- Department of Pharmacy, The 161th Hospital of PLA, Wuhan, Hubei 430010, China
| | - Jie Yao
- Department of Urological Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China,
| | - Zhihong Zhang
- Department of Oncology, Gong'an County People's Hospital, Jingzhou, Hubei 434000, China,
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16
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Identification of small molecule inhibitors for differentially expressed miRNAs in gastric cancer. Comput Biol Chem 2018; 77:442-454. [DOI: 10.1016/j.compbiolchem.2018.07.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 06/26/2018] [Accepted: 07/16/2018] [Indexed: 12/19/2022]
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17
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Russo A, Potenza N. Antiproliferative Activity of microRNA-125a and its Molecular Targets. Microrna 2018; 8:173-179. [PMID: 30394225 DOI: 10.2174/2211536608666181105114739] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 10/18/2018] [Accepted: 10/29/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND MicroRNA-125a is present in all animals with bilateral symmetry and displays a conserved nucleotide sequence with a section of 11 bases including the seed region that is identical in all considered species. It primarily downregulates the expression of LIN28, thereby promoting cell differentiation and larval phase transitions in nematodes, mammals and insects. OBJECTIVE In this review, we focus on the cellular control of miR-125a expression and its antiproliferative activity. RESULTS In mammalians, microRNA-125a is present in most adult organs and tissues in which it targets proteins involved in the mitogenic response, such as membrane receptors, intracellular signal transducers, or transcription factors, with the overall effect of inhibiting cell proliferation. Tissue levels of miR-125a generally raise during differentiation but it is often downregulated in cancers, e.g. colon, cervical, gastric, ovarian, lung, and breast cancers, osteosarcoma, neuroblastoma, glioblastoma, medulloblastoma, retinoblastoma and hepatocellular carcinoma. CONCLUSION The antiproliferative activity of miR-125a, demonstrated in many cell types, together with the notion that this miRNA is downregulated in several kinds of cancers, give a substantial support to the concept that miR-125a plays an oncosuppressive role.
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Affiliation(s)
- Aniello Russo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
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18
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Chen J, Ouyang H, An X, Liu S. miR-125a is upregulated in cancer stem-like cells derived from TW01 and is responsible for maintaining stemness by inhibiting p53. Oncol Lett 2018; 17:87-94. [PMID: 30655742 DOI: 10.3892/ol.2018.9587] [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: 11/16/2016] [Accepted: 04/27/2018] [Indexed: 02/05/2023] Open
Abstract
microRNA (miR)-125a and miR-125b were demonstrated to translationally and transcriptionally inhibit the mRNA level of p53 following the induction of chemo-reagents in our previous report. As a small subpopulation of nasopharyngeal carcinoma (NPC), cancer stem-like cells (CSCs) function critically in multi-malignant behaviors, including tumorigenesis and metastasis; however, the expression pattern and regulatory role of miR-125a, miR-125b and p53 in CSCs derived from NPC remain unclear. In order to investigate the potential regulatory role of miR-125 on p53, firstly CSCs was isolated from TW01 by culturing in serum-free medium. The stemness of isolated CSCs was examined via self-renewal capacity and side population assays. Following this, the miR-125a, miR-125b and p53 mRNA levels were evaluated via reverse-transcription quantitative polymerase chain reaction. Following the transfections of wild-type p53 or p53 without DNA binding activity (p53-mutR248Q) into TW01 or CSCs, Chromatin Immunoprecipitation (ChIP), and cell cycle analyses using flow cytometry or Cell Counting Kit-8 assays were performed. Notably, it was determined that miR-125a was significantly upregulated in CSCs derived from TW01, but not miR-125b, and the mRNA and protein levels of p53 were downregulated. The transfection of p53 significantly decreased the cell viability and stopped cell cycle at the G0/G1 phases in TW01 and CSCs. The ChIP assay confirmed that the ectopic expression of wild-type p53 transcriptionally regulates its downstream gene, p21, but not B-cell lymphoma 2 nor Sco2. Taken together, the results of the present study indicated that p53 regulates CSCs via its DNA binding activity and potentially, in CSCs, miR-125a regulates the expression of p53, maintaining stemness.
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Affiliation(s)
- Jianjun Chen
- Department of E.N.T., The First People's Hospital of Neijiang, Neijiang, Sichuan 641000, P.R. China
| | - Hui Ouyang
- Department of E.N.T., The First People's Hospital of Neijiang, Neijiang, Sichuan 641000, P.R. China
| | - Xuemei An
- Department of Neurology, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610000, P.R. China
| | - Shixi Liu
- Department of E.N.T., West China Hospital, Sichuan University, Chengdu, Sichuan 610000, P.R. China
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Liu H, Ma Y, Liu C, Li P, Yu T. Reduced miR-125a-5p level in non-small-cell lung cancer is associated with tumour progression. Open Biol 2018; 8:180118. [PMID: 30305431 PMCID: PMC6223209 DOI: 10.1098/rsob.180118] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 09/03/2018] [Indexed: 02/06/2023] Open
Abstract
Emerging evidence suggests that microRNAs (miRNAs) serve an important role in tumourigenesis and development. Although the low expression of miR-125a-5p in non-small-cell lung cancer (NSCLC) has been reported, the underlying mechanism remains unknown. In the current study, the low expression of miR-125a-5p in NSCLC was verified in paired cancer tissues and adjacent non-tumour tissues. Furthermore, the CpG island in the miR-125a-5p region was hypermethylated in the tumour tissues, and the hypermethylation was negatively correlated with miR-125a-5p expression. Target gene screening showed that the histone methyltransferase Suv39H1 was one of the potential target genes. In vitro studies showed that miR-125a-5p could directly suppress Suv39H1 expression and decrease the H3K9me3 levels. On the other hand, Suv39H1 could induce demethylation of miR-125a-5p, resulting in re-activation of miR-125a-5p. What is more, overexpessing miR-125a-5p could also self-activate the silenced miR-125a-5p in NSCLC cells, which suppressed cell migration, invasion and proliferation in vitro and inhibited cancer progression in vivo Thus, we found that the epigenetic silenced miR-125a-5p could be self-activated through targeting Suv39H1 in NSCLC, suggesting that miR-125a-5p might not only have the potential prognostic value as a tumour biomarker but also be a potential therapeutic target in NSCLC.
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Affiliation(s)
- Hongxu Liu
- Department of Thoracic Surgery, Cancer Hospital of China Medical University, Shenyang 110042, Liaoning Province, People's Republic of China
- Department of Thoracic Surgery, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, People's Republic of China
| | - Yegang Ma
- Department of Thoracic Surgery, Cancer Hospital of China Medical University, Shenyang 110042, Liaoning Province, People's Republic of China
- Department of Thoracic Surgery, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, People's Republic of China
| | - Changhao Liu
- Department of Thoracic Surgery, Cancer Hospital of China Medical University, Shenyang 110042, Liaoning Province, People's Republic of China
- Department of Thoracic Surgery, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, People's Republic of China
| | - Pengfei Li
- Department of Thoracic Surgery, Cancer Hospital of China Medical University, Shenyang 110042, Liaoning Province, People's Republic of China
- Department of Thoracic Surgery, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, People's Republic of China
| | - Tao Yu
- Department of Medical Imaging, Cancer Hospital of China Medical University, Shenyang 110042, Liaoning Province, People's Republic of China
- Department of Medical Imaging, Liaoning Cancer Hospital and Institute, Shenyang 110042, Liaoning Province, People's Republic of China
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20
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Cai M, Chen Q, Shen J, Lv C, Cai L. Epigenetic silenced miR-125a-5p could be self-activated through targeting Suv39H1 in gastric cancer. J Cell Mol Med 2018; 22:4721-4731. [PMID: 30117667 PMCID: PMC6156292 DOI: 10.1111/jcmm.13716] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Accepted: 05/08/2018] [Indexed: 01/22/2023] Open
Abstract
Emerging evidence suggests that microRNAs (miRNAs) serve an important role in tumorigenesis and development. Although the low expression of miR‐125a‐5p in gastric cancer has been reported, the underlying mechanism remains unknown. In the current study, the low expression of miR‐125a‐5p in gastric cancer was verified in paired cancer tissues and adjacent non‐tumour tissues. Furthermore, the GC islands in the miR‐125a‐5p region were hypermethylated in the tumour tissues. And the hypermethylation was negatively correlated with the miR‐125a‐5p expression. Target gene screening showed that the histone methyltransferase Suv39H1 was one of the potential target genes. In vitro studies showed that miR‐125a‐5p could directly suppress the Suv39H1 expression and decrease the H3K9me3 levels. On the other hand, the Suv39H1 could induce demethylation of miR‐125a‐5p, resulting in re‐activation of miR‐125a‐5p. What is more, overexpessing miR‐125a‐5p could also self‐activate the silenced miR‐125a‐5p in gastric cancer cells, which suppressed cell migration, invasion and proliferation in vitro and inhibited cancer progression in vivo. Thus, we uncovered here that the epigenetic silenced miR‐125a‐5p could be self‐activated through targeting Suv39H1 in gastric cancer, suggesting that miR‐125a‐5p might be not only the potential prognostic value as a tumour biomarker but also potential therapeutic targets in gastric cancer.
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Affiliation(s)
- Mingzhi Cai
- Department of General Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou City, China
| | - Qiuxian Chen
- Department of General Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou City, China
| | - Juntao Shen
- Department of General Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou City, China
| | - Chenbing Lv
- Department of General Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou City, China
| | - Lisheng Cai
- Department of General Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou City, China
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21
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Alessandrini L, Manchi M, De Re V, Dolcetti R, Canzonieri V. Proposed Molecular and miRNA Classification of Gastric Cancer. Int J Mol Sci 2018; 19:E1683. [PMID: 29882766 PMCID: PMC6032377 DOI: 10.3390/ijms19061683] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 05/30/2018] [Accepted: 06/01/2018] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is a common malignant neoplasm worldwide and one of the main cause of cancer-related deaths. Despite some advances in therapies, long-term survival of patients with advanced disease remains poor. Different types of classification have been used to stratify patients with GC for shaping prognosis and treatment planning. Based on new knowledge of molecular pathways associated with different aspect of GC, new pathogenetic classifications for GC have been and continue to be proposed. These novel classifications create a new paradigm in the definition of cancer biology and allow the identification of relevant GC genomic subsets by using different techniques such as genomic screenings, functional studies and molecular or epigenetic characterization. An improved prognostic classification for GC is essential for the development of a proper therapy for a proper patient population. The aim of this review is to discuss the state-of-the-art on combining histological and molecular classifications of GC to give an overview of the emerging therapeutic possibilities connected to the latest discoveries regarding GC.
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Affiliation(s)
- Lara Alessandrini
- Pathology, IRCCS CRO National Cancer Institute, 33081 Aviano, Italy.
| | - Melissa Manchi
- Pathology, IRCCS CRO National Cancer Institute, 33081 Aviano, Italy.
| | - Valli De Re
- Immunopathology and Cancer Biomarkers, IRCCS CRO National Cancer Institute, 33081 Aviano, Italy.
| | - Riccardo Dolcetti
- The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, QLD 4102, Australia.
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22
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Panella M, Mosca N, Di Palo A, Potenza N, Russo A. Mutual suppression of miR-125a and Lin28b in human hepatocellular carcinoma cells. Biochem Biophys Res Commun 2018; 500:824-827. [PMID: 29689270 DOI: 10.1016/j.bbrc.2018.04.167] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 04/20/2018] [Indexed: 12/15/2022]
Abstract
MicroRNA-125a exhibits an antiproliferative activity and is downregulated in several types of tumors, including hepatocellular carcinoma where it targets sirtuin-7, matrix metalloproteinase-11, and c-Raf. Another target of miR-125a is Lin28, a pluripotency factor that is generally undetectable in differentiated cells but is often upregulated/reactivated in tumors where it acts as an oncogenic factor promoting cell proliferation and tumor progression. In this study we show that downregulation of Lin28b by miR-125a partially accounts for its antiproliferative activity toward hepatocellular carcinoma cells. We also found that Lin28b is able to bind a conserved GGAG motif of pre-miR-125a and to inhibit its maturation in hepatocellular carcinoma cells. Reciprocal inhibition between miR-125a and Lin28b reasonably generates a positive feedback loop where reactivation of Lin-28b inhibits the expression of both miR-125a and let-7, reinforcing its own expression and leading to a marked overexpression of the mitogenic targets of the two miRNAs. On the other hand, perturbation of these circuits by overexpression of miR-125a suppresses Lin28b leading to a decreased cell proliferation. Overall, these data support a tumor suppressive role for miR-125a and contribute to the elucidation of its molecular targets.
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Affiliation(s)
- Marta Panella
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Nicola Mosca
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Armando Di Palo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Aniello Russo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy.
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23
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Coppola N, de Stefano G, Panella M, Onorato L, Iodice V, Minichini C, Mosca N, Desiato L, Farella N, Starace M, Liorre G, Potenza N, Sagnelli E, Russo A. Lowered expression of microRNA-125a-5p in human hepatocellular carcinoma and up-regulation of its oncogenic targets sirtuin-7, matrix metalloproteinase-11, and c-Raf. Oncotarget 2018; 8:25289-25299. [PMID: 28445974 PMCID: PMC5421930 DOI: 10.18632/oncotarget.15809] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 02/07/2017] [Indexed: 12/12/2022] Open
Abstract
Human microRNA-125a-5p (miR-125a) is expressed in most tissues where it downregulates the expression of membrane receptors or intracellular transductors of mitogenic signals, thus limiting cell proliferation. Expression of this miRNA generally increases with cell differentiation whereas it is downregulated in several types of tumors, such as breast, lung, ovarian, gastric, colon, and cervical cancers, neuroblastoma, medulloblastoma, glioblastoma, and retinoblastoma. In this study, we focused on hepatocellular carcinoma and used real-time quantitative PCR to measure miR-125a expression in 55 tumor biopsies and in matched adjacent non-tumor liver tissues. This analysis showed a downregulation of miR-125a in 80 % of patients, with a mean decrease of 4.7-fold. Comparison of miRNA downregulation with clinicopathological parameters of patients didn't yield significant correlations except for serum bilirubin. We then evaluated the expression of known targets of miR-125a and found that sirtuin-7, matrix metalloproteinase-11, and c-Raf were up-regulated in tumor tissue by 2.2-, 3-, and 1.7-fold, respectively. Overall, these data support a tumor suppressor role for miR-125a and encourage further studies aimed at the comprehension of the molecular mechanisms governing its expression, eventually leading to treatments to restore its expression in tumor cells.
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Affiliation(s)
- Nicola Coppola
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Giorgio de Stefano
- IX Interventional Ultrasound Unit for Infectious Diseases, AORN dei Colli, P.O. Cotugno, Naples, Italy
| | - Marta Panella
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Naples, Italy
| | - Lorenzo Onorato
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Valentina Iodice
- IX Interventional Ultrasound Unit for Infectious Diseases, AORN dei Colli, P.O. Cotugno, Naples, Italy
| | - Carmine Minichini
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Nicola Mosca
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Naples, Italy
| | - Luisa Desiato
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Naples, Italy
| | - Nunzia Farella
- IX Interventional Ultrasound Unit for Infectious Diseases, AORN dei Colli, P.O. Cotugno, Naples, Italy
| | - Mario Starace
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Giulia Liorre
- IX Interventional Ultrasound Unit for Infectious Diseases, AORN dei Colli, P.O. Cotugno, Naples, Italy
| | - Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Naples, Italy
| | - Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Aniello Russo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Naples, Italy
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24
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Huang WT, Tsai YH, Chen SH, Kuo CW, Kuo YL, Lee KT, Chen WC, Wu PC, Chuang CY, Cheng SM, Lin CH, Leung EY, Chang YC, Cheung CHA. HDAC2 and HDAC5 Up-Regulations Modulate Survivin and miR-125a-5p Expressions and Promote Hormone Therapy Resistance in Estrogen Receptor Positive Breast Cancer Cells. Front Pharmacol 2017; 8:902. [PMID: 29326587 PMCID: PMC5736991 DOI: 10.3389/fphar.2017.00902] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Accepted: 11/27/2017] [Indexed: 12/18/2022] Open
Abstract
Intrinsic or acquired resistance to hormone therapy is frequently reported in estrogen receptor positive (ER+) breast cancer patients. Even though dysregulations of histone deacetylases (HDACs) are known to promote cancer cells survival, the role of different HDACs in the induction of hormone therapy resistance in ER+ breast cancer remains unclear. Survivin is a well-known pro-tumor survival molecule and miR-125a-5p is a recently discovered tumor suppressor. In this study, we found that ER+, hormone-independent, tamoxifen-resistant MCF7-TamC3 cells exhibit increased expression of HDAC2, HDAC5, and survivin, but show decreased expression of miR-125a-5p, as compared to the parental tamoxifen-sensitive MCF7 breast cancer cells. Molecular down-regulations of HDAC2, HDAC5, and survivin, and ectopic over-expression of miR-125a-5p, increased the sensitivity of MCF7-TamC3 cells to estrogen deprivation and restored the sensitivity to tamoxifen. The same treatments also further increased the sensitivity to estrogen-deprivation in the ER+ hormone-dependent ZR-75-1 breast cancer cells in vitro. Kaplan-Meier analysis and receiver operating characteristic curve analysis of expression cohorts of breast tumor showed that high HDAC2 and survivin, and low miR-125a-5p, expression levels correlate with poor relapse-free survival in endocrine therapy and tamoxifen-treated ER+ breast cancer patients. Further molecular analysis revealed that HDAC2 and HDAC5 positively modulates the expression of survivin, and negatively regulates the expression miR-125a-5p, in ER+ MCF7, MCF7-TamC3, and ZR-75-1 breast cancer cells. These findings indicate that dysregulations of HDAC2 and HDAC5 promote the development of hormone independency and tamoxifen resistance in ERC breast cancer cells in part through expression regulation of survivin and miR-125a-5p.
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Affiliation(s)
- Wen-Tsung Huang
- Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Liouying, Tainan, Taiwan
| | - Yu-Hsuan Tsai
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Shang-Hung Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.,Division of Oncology and Hematology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ching-Wen Kuo
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yao-Lung Kuo
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Kuo-Ting Lee
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wen-Chung Chen
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Pei Chih Wu
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan
| | - Chun-Yu Chuang
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan
| | - Siao Muk Cheng
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chun-Hui Lin
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Euphemia Yee Leung
- Auckland Cancer Society Research Centre and Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
| | - Yung-Chieh Chang
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chun Hei Antonio Cheung
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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25
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Sun Z, Zhang W, Li Q. miR-125a suppresses viability and glycolysis and induces apoptosis by targeting Hexokinase 2 in laryngeal squamous cell carcinoma. Cell Biosci 2017; 7:51. [PMID: 29043013 PMCID: PMC5629811 DOI: 10.1186/s13578-017-0178-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 09/28/2017] [Indexed: 01/23/2023] Open
Abstract
Background miR-125a usually functions as a tumor suppressor in cancers. However, the role of miR-125a in laryngeal squamous cell carcinoma (LSCC) has not been determined. Methods qRT-PCR was applied to measure the expression of miR-125a and HK2 mRNA in LSCC tissues and cells. CCK-8 kit and flow cytometry analysis were performed to detect cell viability and apoptosis. Luciferase reporter assay and RNA immunoprecipitation (RIP) were conducted to confirm the relationship between miR-125a and HK2. Commercial test kits were used to determine the concentrations of glucose and l-lactate. Xenograft in mice was constructed to validate the function and mechanism of miR-125a in LSCC tumor growth. Results A negative correlation was found between miR-125a expression and the level of Hexokinase 2 (HK2) mRNA in LSCC tissues. Functional experiments found that miR-125a inhibited viability and glycolysis and induced apoptosis in LSCC cells. Similarly, HK2 downregulation led to viability and glycolysis inhibition and induction of apoptosis in LSCC cells in vitro. Moreover, miR-125a overexpression suppressed LSCC xenograft growth in vivo. Mechanically, HK2 was verified to be a target of miR-125a by luciferase reporter assays and RNA immunoprecipitation (RIP) assays. Furthermore, restored HK2 expression reversed miR-125a-mediated proliferation and glycolysis inhibition and induction of apoptosis in LSCC cells. Conclusions miR-125a suppressed LSCC progression by targeting HK2 in vitro and in vivo, suggesting that miR-125a may be a potential molecular target for LSCC treatment. Electronic supplementary material The online version of this article (doi:10.1186/s13578-017-0178-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Zhanwei Sun
- Department of Otolaryngology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450000 China
| | - Wenqi Zhang
- Department of Otolaryngology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450000 China.,Department of Otolaryngology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, No. 7 Weiwu Road, Zhengzhou, 450003 People's Republic of China
| | - Qian Li
- Department of Otolaryngology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450000 China
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26
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Chen D, Sun Q, Zhang L, Zhou X, Cheng X, Zhou D, Ye F, Lin J, Wang W. The lncRNA HOXA11-AS functions as a competing endogenous RNA to regulate PADI2 expression by sponging miR-125a-5p in liver metastasis of colorectal cancer. Oncotarget 2017; 8:70642-70652. [PMID: 29050308 PMCID: PMC5642583 DOI: 10.18632/oncotarget.19956] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 06/27/2017] [Indexed: 12/12/2022] Open
Abstract
Several long non-coding RNAs (lncRNAs) play important roles in the regulation of liver metastasis in colorectal cancer (CRC) patients. We previously described the potential involvement of HOMEOBOX A11 (HOXA11) antisense RNA (HOXA11-AS), miR-125a-5p, and peptidyl arginine deiminase 2 (PADI2) in promoting liver metastasis in CRC patients. In the present study, we verified the significant upregulation of HOXA11-AS and PADI2, as well as the downregulation of miR-125a-5p, in CRC patients with liver metastasis. Overexpression and knockdown studies of HOXA11-AS or PADI2, as well as gain-/loss-of-function studies of miR-125a-5p, revealed a positive correlation between HOXA11-AS and PADI2 and a negative correlation with miR-125a-5p in the regulation of liver metastasis in CRC cell lines. Overall, we conclude that HOXA11-AS promotes liver metastasis in CRC by functioning as a miR-125a-5p sponge and describe a novel HOXA11-AS-miR-125a-5p-PADI2 regulatory network involved in CRC liver metastasis.
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Affiliation(s)
- Dong Chen
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiang Sun
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lufei Zhang
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaohu Zhou
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaofei Cheng
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dongkai Zhou
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Feng Ye
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianjiang Lin
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Weilin Wang
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China
- State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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27
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Potenza N, Panella M, Castiello F, Mosca N, Amendola E, Russo A. Molecular mechanisms governing microRNA-125a expression in human hepatocellular carcinoma cells. Sci Rep 2017; 7:10712. [PMID: 28878257 PMCID: PMC5587745 DOI: 10.1038/s41598-017-11418-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 08/24/2017] [Indexed: 12/13/2022] Open
Abstract
MicroRNA-125a-5p (miR-125a) is a vertebrate homolog of lin-4, the first discovered microRNA, and plays a fundamental role in embryo development by downregulating Lin-28 protein. MiR-125a is also expressed in differentiated cells where it generally acts as an antiproliferative factor by targeting membrane receptors or intracellular transductors of mitogenic signals. MiR-125a expression is downregulated in several tumors, including hepatocellular carcinoma (HCC) where it targets sirtuin-7, matrix metalloproteinase-11, VEGF-A, Zbtb7a, and c-Raf. In this study, we have isolated the transcription promoter of human miR-125a and characterized its activity in HCC cells. It is a TATA-less Pol II promoter provided with an initiator element and a downstream promoter element, located 3939 bp upstream the genomic sequence of the miRNA. The activity of the promoter is increased by the transcription factor NF-kB, a master regulator of inflammatory response, and miR-125a itself was found to strengthen this activation through inhibition of TNFAIP3, a negative regulator of NF-kB. This finding contributes to explain the increased levels of miR-125a observed in the liver of patients with chronic hepatitis B.
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Affiliation(s)
- Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100, Caserta, Italy
| | - Marta Panella
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100, Caserta, Italy
| | - Filomena Castiello
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100, Caserta, Italy
| | - Nicola Mosca
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100, Caserta, Italy
| | - Elena Amendola
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, 80131, Napoli, Italy
| | - Aniello Russo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100, Caserta, Italy.
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28
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Polymorphisms of miR-196a2 (rs11614913) and miR-605 (rs2043556) confer susceptibility to gastric cancer. GENE REPORTS 2017. [DOI: 10.1016/j.genrep.2017.04.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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29
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Kiss I, Mlčochová J, Součková K, Fabian P, Poprach A, Halamkova J, Svoboda M, Vyzula R, Slaby O. MicroRNAs as outcome predictors in patients with metastatic colorectal cancer treated with bevacizumab in combination with FOLFOX. Oncol Lett 2017; 14:743-750. [PMID: 28693229 PMCID: PMC5494676 DOI: 10.3892/ol.2017.6255] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 03/30/2017] [Indexed: 12/13/2022] Open
Abstract
Bevacizumab is a humanized anti-vascular endothelial growth factor monoclonal antibody, used in combination with a oxaliplatin-based chemotherapy in the treatment of metastatic colorectal cancer (mCRC). The aim of the present study was to identify microRNA (miRNA)-based predictive biomarkers of therapy response in order to avoid unnecessary and costly therapy to non-responding patients. High-throughput miRNA microarray profiling (Affymetrix miRNA array) was performed on a discovery cohort of patients with mCRC. The discovery cohort was (n=20) divided into either responding (n=10) or non-responding (n=10) groups of bevacizumab/5-flourouracil, leucovorin, oxaliplatin (FOLFOX) treatment according to Response Evaluation Criteria in Solid Tumors criteria. Validation of candidate miRNAs was performed on an independent cohort of 41 patients with mCRC using quantitative reverse transcription polymerase chain reaction. Normalized data were subjected to receiver operating characteristic and Kaplan-Meier analyses. In total, 67 miRNAs were identified to be differentially expressed when miRNA expression was compared between responding and non-responding patients to bevacizumab/FOLFOX treatment (P<0.05). A total of 7 miRNAs were chosen for independent validation, which confirmed significantly higher expression of miR-92b-3p, miR-3156-5p, miR-10a-5p and miR-125a-5p (P<0.005) in tumor tissue of responding patients compared with non-reponding patients. Using the combination of miRNAs, the present study identified responders to the therapy with sensitivity 82% and specificity 64% (area under the curve = 0.8015). In conclusion, 4 predictive miRNAs associated with progression-free survival (PFS) were identified in patients with mCRC treated with bevacizumab/FOLFOX. Following further independent validations, detection of these miRNA may enable identification of patients with mCRC who may potentially benefit from the therapy.
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Affiliation(s)
- I Kiss
- Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| | - J Mlčochová
- Department of Molecular Medicine, Central European Institute of Technology, Masaryk University, 625 00 Brno, Czech Republic
| | - K Součková
- Department of Molecular Medicine, Central European Institute of Technology, Masaryk University, 625 00 Brno, Czech Republic
| | - P Fabian
- Department of Clinical and Experimental Pahology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| | - A Poprach
- Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| | - J Halamkova
- Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| | - M Svoboda
- Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| | - R Vyzula
- Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
| | - O Slaby
- Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic.,Department of Molecular Medicine, Central European Institute of Technology, Masaryk University, 625 00 Brno, Czech Republic
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30
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Xu M, Sizova O, Wang L, Su DM. A Fine-Tune Role of Mir-125a-5p on Foxn1 During Age-Associated Changes in the Thymus. Aging Dis 2017; 8:277-286. [PMID: 28580184 PMCID: PMC5440108 DOI: 10.14336/ad.2016.1109] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 11/09/2016] [Indexed: 12/19/2022] Open
Abstract
Decline of transcription factor FoxN1, which predominantly regulates thymic epithelial cell (TEC) differentiation and homeostasis lifelong, is demonstrated to be casually related to age-related thymic involution. Whereas, a global role of microRNAs (miRNAs) has also been demonstrated to control and maintain TEC-constituting thymic microenvironment and to be changed in expression profile in the aged thymus. Therefore, it is urgently necessary to build knowledge regarding whether and which miRNAs regulate FoxN1 gene in the aged thymus. We primarily compared changes in miRNA expression profile between young and aged murine TECs with Mus musculus miRBase-V20 arrays (containing 1892 unique probes), and clearly identified and validated that at least one miRNA, miR-125a-5p, was increased in aged thymus. Applying miR-125a-5p mimics was able to inhibit FoxN1 3′UTR luciferase activity in a 293T cell line and to suppress FoxN1 expression in murine TEC Z210 cells. Since a single miRNA can play a fine-tuning role to regulate expression of multiple genes and a single gene can be regulated by multiple miRNAs, our result adds a single miRNA, miR-125a-5p, into the panel of FoxN1-regulating miRNAs associated with thymic aging.
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Affiliation(s)
- Minwen Xu
- 1First Affiliated Hospital, Gannan Medical University, Ganzhou 341000, China
| | - Olga Sizova
- 3Institute of Molecular Medicine, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Liefeng Wang
- 2Department of Biotechnology, Gannan Medical University, Ganzhou 341000, China.,3Institute of Molecular Medicine, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Dong-Ming Su
- 3Institute of Molecular Medicine, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
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31
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Gao Y, Feng B, Lu L, Han S, Chu X, Chen L, Wang R. MiRNAs and E2F3: a complex network of reciprocal regulations in human cancers. Oncotarget 2017; 8:60624-60639. [PMID: 28947999 PMCID: PMC5601167 DOI: 10.18632/oncotarget.17364] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Accepted: 04/03/2017] [Indexed: 12/14/2022] Open
Abstract
E2F transcription factor 3 (E2F3) is oncogenic in tumorigenesis. Alterations in E2F3 functions correspond with poor prognosis in various cancers, underscoring their status for the clinical cancer phenotype. Latest reports discovered intricate networks between microRNAs (miRNAs) and E2F3 in regulating the balance of these events, including proliferation, apoptosis, metastasis, as well as drug resistance. miRNAs are non-coding small RNAs which negatively regulate gene expressions post-transcriptionally mainly through 3′-UTR binding of target mRNAs. Increasing evidence shows that E2F3 can be activated/inhibited by numerous miRNAs whose dysregulation has been implicated in malignancy. In turn, miRNAs themselves can be transcriptionally regulated by E2F3, thus forming a negative feedback loop. These findings add a new challenging layer of complexity to E2F3 network. Current understanding of the reciprocal link between E2F3 and miRNAs in human cancers were summarized, which could help to develop potential therapeutic strategies.
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Affiliation(s)
- Yanping Gao
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, PR China
| | - Bing Feng
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, PR China
| | - Lu Lu
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, PR China
| | - Siqi Han
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, PR China
| | - Xiaoyuan Chu
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, PR China
| | - Longbang Chen
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, PR China
| | - Rui Wang
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, PR China
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32
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Guo Y, Qi Y, Guo A, Du C, Zhang R, Chu X. miR-564 is downregulated in gastric carcinoma and targets E2F3. Oncol Lett 2017; 13:4155-4160. [PMID: 28588702 DOI: 10.3892/ol.2017.5964] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 02/27/2017] [Indexed: 12/17/2022] Open
Abstract
Numerous aberrantly expressed microRNAs (miRNAs/miRs) have been identified in gastric cancer (GC); however, only a fraction of these have been functionally investigated and novel deregulated miRNAs in GC remain to be explored. Through examining two public miRNA expression profile datasets, the present study identified aberrantly expressed miRNAs in GC. One of these miRNA, miR-564, was identified to be downregulated in GC, which was validated in tissue samples from patients with GC by reverse transcription-quantitative polymerase chain reaction analysis. Targets of miR-564 were then predicted bioinformatically, including transcription factor E2F3 (E2F3), which was identified to be functionally enriched in several cancer signaling pathways. Furthermore, overexpression of miR-564 decreased the activity of a luciferase reporter carrying the 3'-untranslated region of E2F3, in addition to the mRNA and protein level of E2F3, indicating that miR-564 directly targets E2F3. These data suggest that by targeting E2F3, miR-564 may act as a tumor suppressor gene in gastric carcinogenesis.
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Affiliation(s)
- Yong Guo
- Department of Pathology, No. 161 Hospital of the People's Liberation Army, Wuhan, Hubei 430010, P.R. China
| | - Yong Qi
- Outpatient Department, The People's Liberation Army Naval University of Engineering, Wuhan, Hubei 430033, P.R. China
| | - Aitao Guo
- Department of Pathology, The General Hospital of the People's Liberation Army, Beijing 100853, P.R. China
| | - Chengxiong Du
- Department of General Surgery, No. 161 Hospital of the People's Liberation Army, Wuhan, Hubei 430010, P.R. China
| | - Rong Zhang
- Clinical Laboratory, Liuhuaqiao Hospital, Guangzhou, Guangdong 510010, P.R. China
| | - Xiaoyong Chu
- Medical Clinic of Military Economy Academy of the People's Liberation Army, Wuhan, Hubei 430035, P.R. China
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33
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Pan Q, Liao X, Liu H, Wang Y, Chen Y, Zhao B, Lazartigues E, Yang Y, Ma X. MicroRNA-125a-5p alleviates the deleterious effects of ox-LDL on multiple functions of human brain microvessel endothelial cells. Am J Physiol Cell Physiol 2016; 312:C119-C130. [PMID: 27903586 DOI: 10.1152/ajpcell.00296.2016] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 11/16/2016] [Accepted: 11/29/2016] [Indexed: 01/23/2023]
Abstract
MicroRNA-125a-5p (miR-125a-5p) could participate in the pathogenesis of vascular diseases. In this study, we investigated the role of miR-125a-5p in oxidized low-density lipoprotein (ox-LDL)-induced functional changes in human brain microvessel endothelial cells (HBMEC). The reactive oxygen species (ROS) production, nitric oxide (NO) generation, senescence, apoptosis, and functions of HBMEC were analyzed. For mechanism study, the epidermal growth factor receptor (EGFR)/extracellular signal-regulated protein kinase (ERK)/p38 mitogen-activated protein kinase (p38 MAPK) pathway and phosphatidylinositol-3-kinase (PI3K)/serine/threonine kinase (Akt)/endothelial nitric oxide synthase (eNOS) pathway were analyzed. Results showed the following: 1) Expression of miR-125a-5p was reduced in ox-LDL-treated HBMEC. 2) Overexpression of miR-125a-5p protected HBMEC from ox-LDL-induced apoptosis, senescence, ROS production, and NO reduction. 3) Overexpression of miR-125a-5p increased HBMEC proliferation, migration, and tube formation, while decreasing HBMEC adhesion to leukocytes, as well as counteracting the effects of ox-LDL on those functions. 4) The levels of EGFR/ERK/p38 MAPK pathway, PI3K/Akt/eNOS pathway, cleaved caspase-3, and adherent molecular ICAM-1 and VCAM-1 were associated with the effects of ox-LDL on these HBMEC functions. In conclusion, miR-125a-5p could counteract the effects of ox-LDL on various HBMEC functions via regulating the EGFR/ERK/p38 MAPK and PI3K/Akt/eNOS pathways and cleaved caspase-3, ICAM-1, and VCAM-1 expression.
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Affiliation(s)
- Qunwen Pan
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Xiaorong Liao
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Hua Liu
- College of Health Science, Wuhan Sports University, Wuhan, China
| | - Yan Wang
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Yanfang Chen
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.,Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio; and
| | - Bin Zhao
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Eric Lazartigues
- Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Yi Yang
- College of Health Science, Wuhan Sports University, Wuhan, China
| | - Xiaotang Ma
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China;
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Fan Z, Cui H, Xu X, Lin Z, Zhang X, Kang L, Han B, Meng J, Yan Z, Yan X, Jiao S. MiR-125a suppresses tumor growth, invasion and metastasis in cervical cancer by targeting STAT3. Oncotarget 2016; 6:25266-80. [PMID: 26389681 PMCID: PMC4694830 DOI: 10.18632/oncotarget.4457] [Citation(s) in RCA: 127] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 06/30/2015] [Indexed: 12/15/2022] Open
Abstract
MiR-125a has been characterized as a tumor suppressor in several cancers. However, the role of miR-125a in cervical cancer is unknown. In this study, we found the expression of miR-125a was downregulated in cervical cancer patients, and negatively correlated with the tumor size, FIGO stage, and preoperative metastasis. Kaplan-Meier analysis showed that miR-125a expression predicted favorable outcome for cervical cancer patients. Dual luciferase assays identified the STAT3 gene as a novel direct target of miR-125a. Functional studies showed that miR-125a overexpression significantly suppressed the growth, invasion and epithelial-mesenchymal transition (EMT) of cervical cancer cells both in vitro and in vivo via decreasing STAT3 expression. Moreover, miR-125a conferred to G2/M cell cycle arrest, accompanied by inhibition of several G2/M checkpoint proteins. Mechanistically, inactivation of miR-125a during cervical carcinogenesis was caused by HPV suppression of p53 expression. Clinically, STAT3, the expression of which, predicted poorer outcome, was inversely correlated with miR-125a in cervical cancer. These data highlight the importance of miR-125a in the cell proliferation and progression of cervical cancer, and indicate that miR-125a may be a useful therapeutic target for cervical cancer.
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Affiliation(s)
- Zhongyi Fan
- Department of Oncology, PLA General Hospital, Beijing, China
| | - Hanzhi Cui
- Department of Oncology, 309th Hospital of PLA, Beijing, China
| | - Xiaojie Xu
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, China
| | - Zhi Lin
- Department of Oncology, PLA General Hospital, Beijing, China
| | - Xuelin Zhang
- Department of Oncology, PLA General Hospital, Beijing, China
| | - Lei Kang
- Department of Nuclear Medicine, Peking University First Hospital, Beijing, China
| | - Baiyu Han
- Department of Endocrinology and Metablism, 264th Hospital of PLA, Shanxi, China
| | - Jing Meng
- Department of Oncology, PLA General Hospital, Beijing, China
| | - Zhifeng Yan
- Department of Oncology, PLA General Hospital, Beijing, China
| | - Xiang Yan
- Department of Oncology, PLA General Hospital, Beijing, China
| | - Shunchang Jiao
- Department of Oncology, PLA General Hospital, Beijing, China
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Tsai MM, Wang CS, Tsai CY, Huang HW, Chi HC, Lin YH, Lu PH, Lin KH. Potential Diagnostic, Prognostic and Therapeutic Targets of MicroRNAs in Human Gastric Cancer. Int J Mol Sci 2016; 17:945. [PMID: 27322246 PMCID: PMC4926478 DOI: 10.3390/ijms17060945] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Revised: 06/01/2016] [Accepted: 06/07/2016] [Indexed: 12/11/2022] Open
Abstract
Human gastric cancer (GC) is characterized by a high incidence and mortality rate, largely because it is normally not identified until a relatively advanced stage owing to a lack of early diagnostic biomarkers. Gastroscopy with biopsy is the routine method for screening, and gastrectomy is the major therapeutic strategy for GC. However, in more than 30% of GC surgical patients, cancer has progressed too far for effective medical resection. Thus, useful biomarkers for early screening or detection of GC are essential for improving patients' survival rate. MicroRNAs (miRNAs) play an important role in tumorigenesis. They contribute to gastric carcinogenesis by altering the expression of oncogenes and tumor suppressors. Because of their stability in tissues, serum/plasma and other body fluids, miRNAs have been suggested as novel tumor biomarkers with suitable clinical potential. Recently, aberrantly expressed miRNAs have been identified and tested for clinical application in the management of GC. Aberrant miRNA expression profiles determined with miRNA microarrays, quantitative reverse transcription-polymerase chain reaction and next-generation sequencing approaches could be used to establish sample specificity and to identify tumor type. Here, we provide an up-to-date summary of tissue-based GC-associated miRNAs, describing their involvement and that of their downstream targets in tumorigenic and biological processes. We examine correlations among significant clinical parameters and prognostic indicators, and discuss recurrence monitoring and therapeutic options in GC. We also review plasma/serum-based, GC-associated, circulating miRNAs and their clinical applications, focusing especially on early diagnosis. By providing insights into the mechanisms of miRNA-related tumor progression, this review will hopefully aid in the identification of novel potential therapeutic targets.
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Affiliation(s)
- Ming-Ming Tsai
- Department of Nursing, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan.
- Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan.
| | - Chia-Siu Wang
- Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan.
| | - Chung-Ying Tsai
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
| | - Hsiang-Wei Huang
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
| | - Hsiang-Cheng Chi
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
| | - Yang-Hsiang Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
| | - Pei-Hsuan Lu
- Department of Dermatology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 333, Taiwan.
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan.
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Li J, Qiu D, Chen Z, Du W, Liu J, Mo X. Altered expression of miR-125a-5p in thymoma-associated myasthenia gravis and its down-regulation of foxp3 expression in Jurkat cells. Immunol Lett 2016; 172:47-55. [PMID: 26875774 DOI: 10.1016/j.imlet.2016.02.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2015] [Revised: 02/03/2016] [Accepted: 02/05/2016] [Indexed: 11/24/2022]
Abstract
Myasthenia gravis is an autoantibody-mediated and T cell-dependent autoimmune disease of neuromuscular junctions. Thymomas may play a crucial role in the pathogenesis of thymoma-associated myasthenia gravis (TAMG), but the thymic pathogenesis of TAMG is unknown. MicroRNAs (miRNAs) are non-coding RNA molecules 21-24 nt in length that regulate the expression of their target genes in a post-transcriptional manner. In this study, we used a miRNA microarray chip to identify, for the first time, 137 miRNAs in normal tissue adjacent to the thymoma from TAMG patients that were significantly dysregulated compared with normal thymus controls. We confirmed the differential expression of miR-125a-5p in larger samples using quantitative real-time polymerase chain reaction (qRT-PCR). Using bioinformatics analysis, we identified the foxp3 3' untranslated region (UTR) as a target of miR-125a-5p. Importantly, miR-125a-5p expression exhibited a negative correlation with foxp3 expression in normal tissue adjacent to the thymoma from TAMG patients. Furthermore, we demonstrated that the expression of the foxp3 gene was modulated by miR-125a-5p in Jurkat cells. Taken together, our results suggest that the abnormal expression of miR-125a-5p and its effect on foxp3 expression are likely involved in the pathogenesis of TAMG.
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Affiliation(s)
- Jinpin Li
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning 530021, China.
| | - Di Qiu
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning 530021, China.
| | - Zezhi Chen
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning 530021, China
| | - Weiwei Du
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning 530021, China
| | - Jingli Liu
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning 530021, China
| | - Xuean Mo
- Department of Neurology, the First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning 530021, China
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Guo LL, Song CH, Wang P, Dai LP, Zhang JY, Wang KJ. Competing endogenous RNA networks and gastric cancer. World J Gastroenterol 2015; 21:11680-11687. [PMID: 26556995 PMCID: PMC4631969 DOI: 10.3748/wjg.v21.i41.11680] [Citation(s) in RCA: 153] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 08/12/2015] [Accepted: 09/15/2015] [Indexed: 02/06/2023] Open
Abstract
Recent studies have showed that RNAs regulate each other with microRNA (miRNA) response elements (MREs) and this mechanism is known as "competing endogenous RNA (ceRNA)" hypothesis. Long non-coding RNAs (lncRNAs) are supposed to play important roles in cancer. Compelling evidence suggests that lncRNAs can interact with miRNAs and regulate the expression of miRNAs as ceRNAs. Several lncRNAs such as H19, HOTAIR and MEG3 have been found to be associated with miRNAs in gastric cancer (GC), generating regulatory crosstalk across the transcriptome. These MRE sharing elements implicated in the ceRNA networks (ceRNETs) are able to regulate mRNA expression. The ceRNA regulatory networks including mRNAs, miRNAs, lncRNAs and circular RNAs may play critical roles in tumorigenesis, and the perturbations of ceRNETs may contribute to the pathogenesis of GC.
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NIE GUOHUI, DUAN HONGFANG, LI XIAOQING, YU ZHENDONG, LUO LIANG, LU RUIJING, JI ZILIANG, ZHANG WEI. MicroRNA‑205 promotes the tumorigenesis of nasopharyngeal carcinoma through targeting tumor protein p53-inducible nuclear protein 1. Mol Med Rep 2015; 12:5715-22. [PMID: 26252115 PMCID: PMC4581759 DOI: 10.3892/mmr.2015.4181] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 07/07/2015] [Indexed: 02/05/2023] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a common type of cancer in southern China, miRNAs have been shown to be involved in the tumorigenesis of multiple cancer types. The present study aimed to explore the potential role of miR‑205 in NPC. Reverse transcription quantitative polymerase chain reaction was used to determine the expression levels of miR‑205 in 20 fresh NPC specimens and 20 normal nasopharyngeal tissues. The function of miR‑205 in the proliferation, migration, invasion and apoptosis of NPC‑derived cells was detected by MTT assay, colony formation assay, wound healing assay, Transwell assay and flow cytometry. Furthermore, a target gene of miR‑205 was identified using the luciferase reporter assay. The expression of miR‑205 was increased in NPC tissues compared with that in normal tissues. Overexpression of miR‑205 was found to promote the proliferation, migration and invasion of NPC‑derived cells, while apoptosis was suppressed. Tumor protein p53-inducible nuclear protein 1 was identified as a target gene of miR‑205. Overall, the present study demonstrated that miR‑205 may function as an oncogene in NPC tumorigenesis.
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Affiliation(s)
- GUOHUI NIE
- Department of Otolaryngology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- Correspondence to: Dr Guohui Nie, Department of Otolaryngology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, Guangdong 518036, P.R. China, E-mail:
| | - HONGFANG DUAN
- Department of Otolaryngology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- Department of Clinical Medicine, Guangzhou Medical University, Guangzhou, Guangdong 510000, P.R. China
| | - XIAOQING LI
- Department of Clinical Laboratory, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- Department of Clinical Medicine, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - ZHENDONG YU
- Central Laboratory, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - LIANG LUO
- Department of Otolaryngology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- Department of Clinical Medicine, Guangzhou Medical University, Guangzhou, Guangdong 510000, P.R. China
| | - RUIJING LU
- Department of Clinical Laboratory, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- Department of Clinical Medicine, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - ZILIANG JI
- Department of Clinical Medicine, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - WEI ZHANG
- Shenzhen Key Laboratory for Translational Medicine of Dermatology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong 518036, P.R. China
- Dr Wei Zhang, Shenzhen Key Laboratory for Translational Medicine of Dermatology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center, 1120 Lianhua Road, Shenzhen, Guangdong 518036, P.R. China, E-mail:
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Zhu J, Liu F, Wu Q, Liu X. MiR-221 increases osteosarcoma cell proliferation, invasion and migration partly through the downregulation of PTEN. Int J Mol Med 2015; 36:1377-83. [PMID: 26397386 DOI: 10.3892/ijmm.2015.2352] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2015] [Accepted: 08/25/2015] [Indexed: 11/06/2022] Open
Abstract
Increasing evidence has demonstrated that microRNAs (miRNAs or miRs) are involved in cancer initiation and progression. Previous studies have indicated that miR-221 is one of the most consistently overexpressed miRNAs in multiple types of cancer. However, the role of miR-221 in osteosarcoma carcinogenesis and progression is not yet fully understood. Thus, the aim of the present study was to examine the expression of miR-221 in osteosarcoma and to determine the effects of miR-221 on the biological behavior of osteosarcoma cells. RT-qPCR revealed that the expression of miR-221 was significantly upregulated in the osteosarcoma tissues and osteosarcoma cell lines (p<0.05). In order to explore the role of miR-221 in osteosarcoma, the expression of miR-221 in the human osteosarcoma cell line MG‑63 was upregulated or downregulated by transfection with miR-221 mimic or miR-221 inhibitor, respectively. The results from RT-qPCR revealed that we had successfully generated MG‑63 cells in which miR-221 was either overexpressed or depleted. To investigate the effects of miR-221 on osteosarcoma cell proliferation, invasion and migration, a tetrazolium-based colorimetric assay, propidium iodide (PI) staining, a transwell migration assay and a wound healing assay were used in the present study. The results revealed that the proliferation, invasion and migration ability of the MG‑63 cells in which miR-221 was overexpressed was enhanced, and the proliferation, invasion and migration ability of the MG‑63 cells in which miR-221 was depleted was suppressed. The correlation between miR-221 and phosphatase and tensin homolog (PTEN) expression was investigated by RT-qPCR and western blot analysis. The results revealed that the downregulation of miR-221 significantly increased the expression of PTEN, whereas the upregulation of miR-221 significantly reduced the expression of PTEN. Taken together, our results suggest that miR-221 enhances the proliferation, invasion and migration ability of osteosarcoma cells partly by suppressing PTEN.
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Affiliation(s)
- Jianwei Zhu
- Department of Orthopedics, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Fan Liu
- Department of Orthopedics, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Quanming Wu
- Department of Orthopedics, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Xiancheng Liu
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
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40
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Dai J, Wang J, Yang L, Xiao Y, Ruan Q. miR-125a regulates angiogenesis of gastric cancer by targeting vascular endothelial growth factor A. Int J Oncol 2015; 47:1801-10. [PMID: 26398444 DOI: 10.3892/ijo.2015.3171] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 08/17/2015] [Indexed: 11/05/2022] Open
Abstract
A recent discovery revealed that microRNAs (miRNAs) have an essential effect in the development and progression of gastric cancer (GC). It has already been shown that miR‑125a may inhibit tumor development by targeting human epidermal growth factor receptor-2 (Her-2) in GC; however, the other roles of miR‑125a in gastric cancer remained to be explored. Our study confirmed that miR‑125a was indeed capable of modulating the expression of VEGF-A in gastric cancer cells. In vitro, low expression of miR‑125a was able to maintain the secretion of VEGF-A, while the latter increased Akt phosphorylation level in endothelial cells and thereby promoted the proliferation, migration and angiogenesis of human umbilical vein endothelial cells (HUVECs). Our investigation showed that miR‑125a expression decreased significantly in gastric cancer comparing with normal gastric tissue and was negatively correlated with the expression of VEGF-A (P<0.05). In vivo, the expression of miR‑125a was inversely proportional to microvessel density (MVD) (r=-0.5382, P<0.001). The results of this study suggested that low expression of miR‑125a predict a worse survival in gastric cancer patients. Collectively, our results indicated that miR‑125a regulated the paracrine of VEGF-A in gastric cancer and thereby controlled the angiogenesis of the tumor.
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Affiliation(s)
- Jun Dai
- Institute of Pathology of Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
| | - Jinyu Wang
- Department of Pediatrics, The Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou 310009, P.R. China
| | - Lili Yang
- Institute of Pathology of Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
| | - Ying Xiao
- Institute of Pathology of Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
| | - Qiurong Ruan
- Institute of Pathology of Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
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41
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Zhang H, Zhu X, Li N, Li D, Sha Z, Zheng X, Wang H. miR-125a-3p targets MTA1 to suppress NSCLC cell proliferation, migration, and invasion. Acta Biochim Biophys Sin (Shanghai) 2015; 47:496-503. [PMID: 25998575 DOI: 10.1093/abbs/gmv039] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2015] [Accepted: 03/13/2015] [Indexed: 12/18/2022] Open
Abstract
Metastasis-associated gene 1 (MTA1) is associated with cell growth, metastasis, and survival in non-small-cell lung cancer (NSCLC). Several previous reports have demonstrated that microRNAs affect gene expression through interaction between their seed region and the 3'-untranslated region of the target mRNA, resulting in post-transcriptional regulation. The aim of this study was to identify miRNAs that suppress malignancy in NSCLC cells by targeting MTA1. Two human NSCLC cell lines were analyzed for the expression of MTA1 by quantitative RT-PCR and western blotting after transfection with MTA1 mimics. A luciferase reporter assay was established to test the direct connection between MTA1 and its upstream miRNAs. Cell proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, 5-ethynyl-2'-deoxyuridine analysis, and colony formation assay. Cell migration and invasive capacity were evaluated by wound-healing assay and transwell assay. The miRNA/MTA1 axis was also probed by quantitative RT-PCR and western blotting in samples from eight NSCLC patients. Among the candidate miRNAs, miR-125a-3p was shown to post-transcriptionally regulate MTA1 in NSCLC cells. These data were reinforced by the luciferase reporter assay, in addition to the demonstration that MTA1 is inversely correlated with miR-125a-3p in NSCLC tissues. Furthermore, miR-125a-3p was found to inhibit NSCLC cell proliferation, migration, and invasion, through the same mechanisms of down-regulated MTA1. Our report demonstrates that miR-125a-3p inhibits the proliferation, migration, and invasion of NSCLC cells through down-regulation of MTA1, indicating the role of the miR-125a-3p/MTA1 axis in NSCLC, and may provide novel insight into the molecular mechanisms underpinning the disease and potential therapeutic targets.
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Affiliation(s)
- Hong Zhang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xiaoxia Zhu
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Na Li
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Dianhe Li
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zhou Sha
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xiaokang Zheng
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Haofei Wang
- Department of Cardiothoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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Song C, Wu G, Xiang A, Zhang Q, Li W, Yang G, Shi X, Sun S, Li X. Over-expression of miR-125a-5p inhibits proliferation in C2C12 myoblasts by targeting E2F3. Acta Biochim Biophys Sin (Shanghai) 2015; 47:244-9. [PMID: 25733534 DOI: 10.1093/abbs/gmv006] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of small non-coding RNAs of 20-25 nucleotides in length. It has been shown that miRNAs play important roles in the proliferation of many types of cells, including myoblasts. In this study, we used real-time quantitative polymerase chain reaction, western blotting, EdU, flow cytometry, and CCK-8 assay to explore the role of miR-125a-5p during the proliferation of C2C12 myoblasts. It was found that the expression of miR-125a-5p was decreased during C2C12 myoblast proliferation. Over-expression of miR-125a-5p inhibited C2C12 myoblast proliferation as indicated by EdU staining, flow cytometry, and CCK8 assay. It was also found that miR-125a-5p could negatively regulate E2F3 expression at posttranscriptional level, via a specific target site in the 3' untranslated region. Knockdown of E2F3 showed a similar inhibitory effect on C2C12 myoblast proliferation. Thus, our findings suggest that miR-125a-5p may act as a negative regulator of C2C12 myoblast proliferation by targeting E2F3.
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Affiliation(s)
- Chengchuang Song
- Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China
| | - Guofang Wu
- Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China
| | - Aoqi Xiang
- Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China
| | - Qiangling Zhang
- Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China
| | - Wanhua Li
- Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China
| | - Gongshe Yang
- Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China
| | - Xin'e Shi
- Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China
| | - Shiduo Sun
- Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China
| | - Xiao Li
- Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China
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Gattolliat CH, Uguen A, Pesson M, Trillet K, Simon B, Doucet L, Robaszkiewicz M, Corcos L. MicroRNA and targeted mRNA expression profiling analysis in human colorectal adenomas and adenocarcinomas. Eur J Cancer 2015; 51:409-20. [PMID: 25586944 DOI: 10.1016/j.ejca.2014.12.007] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Revised: 10/21/2014] [Accepted: 12/11/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Colorectal cancer (CRC) mainly develops from colorectal adenomas (CRAs). MicroRNAs (miRs) are short non-coding transcripts that regulate gene expression by binding to target mRNAs, preventing their expression. It was suggested that miRs were involved in cancer as tumour suppressors or oncogenes, thereby being also potential cancer biomarkers. We conducted an expression analysis of miRNAs and several of their target mRNAs, by using microarrays and quantitative Reverse Transcription-Polymerase Chain Reaction (RT-PCR) (RT-qPCR), in CRA and CRC, as compared to normal mucosa (NOR), in order to identify candidate miRNAs involved in CRC progression. RESULTS Microarray, together with confirmatory RT-qPCR analyses, showed 17 significantly deregulated miRNAs in colorectal lesions. While, as expected, some miRNAs have been previously reported to be associated with CRC, including miR-21 and miR-145, others were new (miR-125a-5p and miR-320 family). Some miRNAs were specific for the CRC versus NOR comparison (miR-320b), or for the CRA versus NOR comparison (miR-15b or miR-16), but several of them (miR-21, miR-24, miR-145, mir-150, miR-378) were deregulated in both CRAs and CRCs, as compared to NOR. The impact of these changes in miR expression on target genes is suggested by the associated deregulation of these genes in CRA and CRC. CONCLUSIONS We confirmed that several miRNAs were abnormally expressed in colorectal lesions, identified new deregulated miRs, and showed that several miRNAs could mark the transition from NOR to CRA, thereby marking progression from the early steps of cancer.
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Affiliation(s)
- Charles-Henry Gattolliat
- INSERM U1078-ECLA, Université de Bretagne Occidentale, SFR ScInBioS, Faculté de Médecine, 22, Avenue Camille Desmoulins, 29200 Brest, France
| | - Arnaud Uguen
- INSERM U1078-ECLA, Université de Bretagne Occidentale, SFR ScInBioS, Faculté de Médecine, 22, Avenue Camille Desmoulins, 29200 Brest, France; CHRU de Brest, 5, Avenue Foch, 29200 Brest, France
| | - Marine Pesson
- INSERM U1078-ECLA, Université de Bretagne Occidentale, SFR ScInBioS, Faculté de Médecine, 22, Avenue Camille Desmoulins, 29200 Brest, France
| | - Kilian Trillet
- INSERM U1078-ECLA, Université de Bretagne Occidentale, SFR ScInBioS, Faculté de Médecine, 22, Avenue Camille Desmoulins, 29200 Brest, France
| | - Brigitte Simon
- INSERM U1078-ECLA, Université de Bretagne Occidentale, SFR ScInBioS, Faculté de Médecine, 22, Avenue Camille Desmoulins, 29200 Brest, France
| | | | | | - Laurent Corcos
- INSERM U1078-ECLA, Université de Bretagne Occidentale, SFR ScInBioS, Faculté de Médecine, 22, Avenue Camille Desmoulins, 29200 Brest, France; CHRU de Brest, 5, Avenue Foch, 29200 Brest, France
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Zhang X, Ni Z, Duan Z, Xin Z, Wang H, Tan J, Wang G, Li F. Overexpression of E2F mRNAs associated with gastric cancer progression identified by the transcription factor and miRNA co-regulatory network analysis. PLoS One 2015; 10:e0116979. [PMID: 25646628 PMCID: PMC4315469 DOI: 10.1371/journal.pone.0116979] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 12/17/2014] [Indexed: 12/19/2022] Open
Abstract
Gene expression is regulated at the transcription and translation levels; thus, both transcription factors (TFs) and microRNAs (miRNA) play roles in regulation of gene expression. This study profiled differentially expressed mRNAs and miRNAs in gastric cancer tissues to construct a TF and miRNA co-regulatory network in order to identify altered genes in gastric cancer progression. A total of 70 cases gastric cancer and paired adjacent normal tissues were subjected to cDNA and miRNA microarray analyses. We obtained 887 up-regulated and 93 down-regulated genes and 41 down-regulated and 4 up-regulated miRNAs in gastric cancer tissues. Using the Transcriptional Regulatory Element Database, we obtained 105 genes that are regulated by the E2F family of genes and using Targetscan, miRanda, miRDB and miRWalk tools, we predicted potential targeting genes of these 45 miRNAs. We then built up the E2F-related TF and miRNA co-regulatory gene network and identified 9 hub-genes. Furthermore, we found that levels of E2F1, 2, 3, 4, 5, and 7 mRNAs associated with gastric cancer cell invasion capacity, and has associated with tumor differentiation. These data showed Overexpression of E2F mRNAs associated with gastric cancer progression.
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Affiliation(s)
- XiaoTian Zhang
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medicine, Jilin University, Changchun, Jilin, China
| | - ZhaoHui Ni
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medicine, Jilin University, Changchun, Jilin, China
| | - ZiPeng Duan
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medicine, Jilin University, Changchun, Jilin, China
| | - ZhuoYuan Xin
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medicine, Jilin University, Changchun, Jilin, China
| | - HuaiDong Wang
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medicine, Jilin University, Changchun, Jilin, China
| | - JiaYi Tan
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medicine, Jilin University, Changchun, Jilin, China
| | - GuoQing Wang
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medicine, Jilin University, Changchun, Jilin, China
- * E-mail: (GW); (FL)
| | - Fan Li
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medicine, Jilin University, Changchun, Jilin, China
- * E-mail: (GW); (FL)
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Mu YP, Sun WJ, Lu CW, Su XL. MicroRNAs May Serve as Emerging Molecular Biomarkers for Diagnosis and Prognostic Assessment or as Targets for Therapy in Gastric Cancer. Asian Pac J Cancer Prev 2015; 16:4813-4820. [PMID: 26163596 DOI: 10.7314/apjcp.2015.16.12.4813] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Gastric cancer (GC) is one of the most common cancers, with high incidences in East Asia countries. Most GC patients have been reported with low early diagnosis rate and show extremely poor prognosis. Therefore, it is necessary to develop novel and more sensitive biomarkers to improve early diagnosis and therapy in order to provide longer survival and better quality of life for gastric cancer patients. MicroRNAs (miRNAs) play crucial roles in GC development and progression. miRNAs have emerged as a novel molecular biomarker for cancer diagnosis, prognosis and therapy with surprising stability in tissues, serum or other body fluids. This review summarizes major advances in our current knowledge about potential miRNA biomarkers for GC that have been reported in the past two years.
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Affiliation(s)
- Yong-Ping Mu
- Department of Clinical Laboratory Center, The Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China E-mail : ;
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