Suppressing miR-199a-3p by promoter methylation contributes to tumor aggressiveness and cisplatin resistance of ovarian cancer through promoting DDR1 expression

Deng, Yuao; Zhao, Fang; Liu, Hui; Liu, Xiuyun; Zhang, Danyu; Wang, Lin; Chen, Zhiqiang; Ning, Yingxia

doi:10.1186/s13048-017-0333-4

Cited by 73 publications

(59 citation statements)

References 34 publications

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“…Furthermore, in wt-p53 containing cells, cyclooxygenase 2 is upregulated under genotoxic stress and DDR1 activated cyclooxygenase 2 expression by NFKB pathway, leading to the resistance of breast cancer cells to etoposide [54]. Several studies demonstrated that DDR1 expression at protein level promotes the resistance of tumor cells to chemotherapeutic drugs like etoposide in lymphoma [55, cisplastine in ovarian cancer [56] and gefitinib in glioblastoma cells (both at the protein but also at RNA level) [57]. However, molecular mechanisms by which DDR1 leads to chemotherapy resistance remain unknown.…”

Section: Ddr1mentioning

confidence: 99%

Multitasking discoidin domain receptors are involved in several and specific hallmarks of cancer

Henriet

Sala

Hammoud

et al. 2018

Cell Adhesion & Migration

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Discoidin domain receptors, DDR1 and DDR2, are two members of collagen receptor family that belong to tyrosine kinase receptor subgroup. Unlike other matrix receptor-like integrins, these collagen receptors have not been extensively studied. However, more and more studies are focusing on their involvement in cancer. These two receptors are present in several subcellular localizations such as intercellular junction or along type I collagen fibers. Consequently, they are involved in multiple cellular functions, for instance, cell cohesion, proliferation, adhesion, migration and invasion. Furthermore, various signaling pathways are associated with these multiple functions. In this review, we highlight and characterize hallmarks of cancer in which DDRs play crucial roles. We discuss recent data from studies that demonstrate the involvement of DDRs in tumor proliferation, cancer mutations, drug resistance, inflammation, neo-angiogenesis and metastasis. DDRs could be potential targets in cancer and we conclude this review by discussing the different ways to inhibits them.

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Section: Ddr1mentioning

confidence: 99%

Multitasking discoidin domain receptors are involved in several and specific hallmarks of cancer

Henriet

Sala

Hammoud

et al. 2018

Cell Adhesion & Migration

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“…chen et al (14) demonstrated that the deregulation of miR-199a-3p expression in testicular germ cell tumors may be due to hypermethylation of its promoter. The similar phenomenon was also investigated in ovarian cancer (15). In addition, miR-199a-3p was identified to improve cisplatin sensitivity in cholangiocarcinoma cells or breast cancer cells (16,17).…”

Section: Introductionmentioning

confidence: 79%

miR‑199a‑3p/Sp1/LDHA axis controls aerobic glycolysis in testicular tumor cells

et al. 2018

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Aerobic glycolysis is one of the characteristics of tumor metabolism and contributes to the development of tumors. Studies have identified that microRNA (miRNA/miR) serves an important role in glucose metabolism of tumors. miR‑199a‑3p is a member of the miR‑199a family that controls the outcomes of cell survival and death processes, and previous studies have indicated that the expression of miR‑199a‑3p is low and may be an inhibitor in several cancer types, including testicular tumors. The present study discussed the role and underlying mechanism of miR‑199a‑3p in aerobic glycolysis of Ntera‑2 cells and identified its downstream factors. Firstly, miR‑199a‑3p exhibited an inhibitory effect on lactic acid production, glucose intake, and reactive oxygen species (ROS) and adenosine 5'‑triphosphate (ATP) levels in Ntera‑2 cells. Then, using bioinformatics, recombinant construction and a dual luciferase reporter gene system, transcription factor Specificity protein 1 (Sp1) was determined as the direct target of miR‑199a‑3p. Also, downregulation of Sp1 by RNA interference decreased lactic acid production, glucose intake, and ROS and ATP levels in Ntera‑2 cells. Subsequently, through a functional rescue experiment, it was identified that the overexpression of Sp1 may abate the inhibition of miR‑199a‑3p on glucose metabolism, with the exception of ATP level, suggesting a reciprocal association between Sp1 and miR‑199a‑3p. Finally, it was determined that miR‑199a‑3p overexpression and Sp1 knockdown decreased lactate dehydrogenase A (LDHA) protein expression, which indicated that LDHA is a downstream target of the miR‑199a‑3p/Sp1 signaling pathway. To additionally verify the regulation of LDHA expression by 199a‑3p/Sp1, a LDHA promoter reporter plasmid was generated and the high activity of the promoter, which contained 3 potential Sp1 binding elements, was confirmed. In addition, the overexpression of Sp1 led to the increased activity of the LDHA promoter, whereas knockdown of Sp1 exhibited the opposite effect. Therefore, the results of the present study demonstrated that miR‑199a‑3p can inhibit LDHA expression by downregulating Sp1, and provided mechanistic evidence supporting the existence of a novel miR‑199a‑3p/Sp1/LDHA axis and its critical contribution to aerobic glycolysis in testicular cancer cells.

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“…Vispé et al 44 found that DNA methyltransferase family (DNMT1, DNMT3A, and DNMT3B) were the major protein that maintains DNA methylation in cells, and 5‐aza‐2′‐deoxycytidine could consume DNMT1, resulting in DNA demethylation, re‐expression of tumor suppressor genes and DNA damage. Deng et al 45 verified that knockdown of DNMT3A significantly attenuated the expression level of miR‐199a‐3p. Therefore, miR‐199a‐3p is at a low expression level in HCC cells which is related to the maintenance of DNA methylation by DNMT family.…”

Section: Discussionmentioning

confidence: 99%

Screening and verification of microRNA promoter methylation sites in hepatocellular carcinoma

Lin

Dai

et al. 2020

J of Cellular Biochemistry

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The promoter methylation mode of microribonucleic acid (miRNA) plays a crucial role in the process of hepatocellular carcinoma (HCC). Therefore, the primary purpose of this study was to screen and verify the miRNA methylation sites associated with the overall survival (OS) and clinical characteristics of HCC patients. Methylation-related data were from the Cancer Genome Atlas (TCGA). R software was utilized to screen the methylation sites. The least absolute shrinkage and selection operator algorithm was utilized to develop the miRNA promoter methylation models. Then, methylation-specific polymerase chain reaction was performed with 146 HCC tissues to verify the accuracy of the vascular infiltrationrelated model. Additionally, we verified the functions of vascular infiltration-related miRNA by utilizing cells transfected with miR-199a-3p mimic. The model for predicting OS of HCC patients contained eight methylation sites. The Kaplan-Meier analysis suggested that the model could divide HCC patients into high-and low-risk groups (P < .0001). COX regression analysis suggested that the model (P < .001; 95% CI, 1.264-2.709) and T category (P < .001; 95% CI, 1.472-3.119) were independent risk factors for affecting OS of HCC patients. The model for predicting vascular infiltration, pathological grade, and clinical stage contained 7, 10, and 9 methylation sites respectively, with their area under the receiver operating characteristic curve (AUC) values 0.667, 0.745, and 0.725, respectively. The functional analysis suggested that miRNA methylation is involved in various biological processes such as WNT, MAPK, and mTOR signaling pathways. The accuracy of the vascular infiltration-related model was consistent with our previous bioinformatics assay.And upregulation of miR-199a-3p decreased migration and invasion abilities. The screened miRNA promoter methylation sites can be served as biomarkers for judging OS, vascular infiltration, pathology grade, and clinical stage. It can also provide new targets for improving the treatment and prognosis of HCC patients. K E Y W O R D Sbioinformatics, hepatocellular carcinoma, miRNA, overall survival, promoter methylation, vascular infiltration Xiaofeng Ni, Zhuo Lin, and Shengjie Dai contributed equally to this study. SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section.How to cite this article: Ni X, Lin Z, Dai S, et al. Screening and verification of microRNA promoter methylation sites in hepatocellular carcinoma.

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Suppressing miR-199a-3p by promoter methylation contributes to tumor aggressiveness and cisplatin resistance of ovarian cancer through promoting DDR1 expression

Cited by 73 publications

References 34 publications

Multitasking discoidin domain receptors are involved in several and specific hallmarks of cancer

Multitasking discoidin domain receptors are involved in several and specific hallmarks of cancer

miR‑199a‑3p/Sp1/LDHA axis controls aerobic glycolysis in testicular tumor cells

Screening and verification of microRNA promoter methylation sites in hepatocellular carcinoma

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