Epigenetic silencing of miR-493 increases the resistance to cisplatin in lung cancer by targeting tongue cancer resistance-related protein 1(TCRP1)

Abstract

BackgroundThe potential mechanisms regarding how methylation of microRNA(miRNA) CpG Island could regulate cancer cell chemo-resistance remains unclear. This study aims to explore the epigenetic dysregulation mechanism of miRNA-493 and the ability to modulate lung cancer cell chemotherapy resistance.MethodsReal-time quantitative PCR (qRT-PCR) and In situ hybridization (ISH) were used to analyze the expression of miR-493 in lung cancer cell lines and tumor tissue, respectively. Bisulfite sequencing PCR (BSP) was used to exam the promoter CpG Island of miR-493. The effect of miR-493 on chemosensitivity was evaluated by cell viability assays, apoptosis assays and in vivo experiment. The DNA damage was measured by γ-H2AX immunofluorescence. Luciferase reporter assay was used to assess the target genes of miR-493. Expression of target proteins and downstream molecules were analyzed by Western blot.ResultsmiR-493 is silenced in resistant lung cancer cell due to the aberrant DNA methylation. Enforced expression of miR-493 in lung cancer cells promotes chemotherapy sensitivity to cisplatin through impairing the DNA damage repair and increasing the cells apoptosis in vitro and in vivo. Furthermore, we identify that TCRP1 is a direct functional target of miR-493. Ectopic expression of TCRP1 attenuated increased apoptosis in miR-493-overexpressing lung cancer cells upon cisplatin treatment. Meanwhile, miR-493 level is negatively correlated with TCRP1 expression in lung cancer patients and TCRP1 expression were correlated with poor survival.ConclusionsOur results highlight that hyper-methylation of miR-493CpG island might play important roles in the development of lung cancer chemo-resistance by targeting TCRP1, which might be used as a potential therapeutic target in preventing the chemo-resistance of lung cancer.

MicroRNA‐493‐5p‐mediated repression of the MYCN oncogene inhibits hepatic cancer cell growth and invasion

“…Notably, this second work reported that miR‐493‐5p suppressed the migration of hepatic cancer cells by negatively regulating the expression of vesicle‐associated membrane protein 2 ( VAMP2 ), an oncogenic protein. The tumor suppressor role of miR‐493‐5p has been described in other types of solid tumors . We previously characterized miR‐493‐5p anticancer activity and described a miRNA‐dependent regulatory mechanism between two distinct imprinted loci: (i) the MEG3 ‐miR‐493 locus, which was found to be epigenetically silenced by MEG3 ‐differentially regulated region hypermethylation in liver cancer cell lines and hepatic tumors from patients; and (ii) the IGF2 ‐miR‐483 locus, which was found to be overexpressed in hepatic cancer cells exhibiting IGF2 loss of imprinting .…”

“…The tumor suppressor role of miR-493-5p has been described in other types of solid tumors. [26][27][28][29][30] We previously characterized miR-493-5p anticancer activity and described a miRNA-dependent regulatory mechanism between two distinct imprinted loci: (i) the MEG3-miR-493 locus, which was found to be epigenetically silenced by MEG3-differentially regulated region hypermethylation in liver cancer cell lines and hepatic tumors from patients; and (ii) the IGF2-miR-483 locus, which was found to be overexpressed in hepatic cancer cells exhibiting IGF2 loss of imprinting. 17 In addition, we reported the epigenetic silencing of miR-148a and miR-122, 2 other major tumor suppressor miRNAs, through CpG hypermethylation in HCC cells and tissues.…”

Identification of the Expression Signature and Potential Mechanisms of miR-493-3p in NSCLC using Bioinformatics Strategy: A Comprehensive Study from TCGA and GEO Datasets

“…5A). Moreover, we screened literatures relevant to miR-493-3p targeted genes in the PubMed, and indenti ed 13 target genes of miR-493-3P including: AKT2, STK38L, HMGA2, E2F5, ETS1, FAM168A, PHLPP2, RSPO2, SP1, ANTXR1, STMN-1, KCNH2, ZFX [19][20][21][26][27][28][29][30]. Ultimately, a total of 46 potential target genes of miR-493-3p were identi ed for further analysis.…”

“…However, other studies reported that up-regulated expression of miR-493-3p portend a poor prognosis [25]. Likewise, previous researches have showed silencing miR-493-3p expression increases the chemotherapy resistance in lung cancer [26]. However, the expression and speci c role of miR-493-3p, as well as clinical parameters in NSCLC has not yet been elucidated.…”

MiR-107 confers chemoresistance to colorectal cancer by targeting calcium-binding protein 39

“…10 MicroRNAs (miRNAs) are a family of small, noncoding RNA molecules that play important roles in multiple biological processes, including cell proliferation, apoptosis and organ development, in different cancers. 11 A large body of evidence suggests that miRNAs are closely associated with the development of chemoresistance in cancer cells, [12][13][14][15][16][17] indicating that miRNAs might be potential targets for cancer treatment. Previous studies showed that miR-107 expression is significantly higher in gastric cancer tissues than in adjacent normal tissues, and downregulation of miR-107 expression suppresses tumour cell proliferation, migration and invasion.…”