Epigenetic silencing of miR-493 increases the resistance to cisplatin in lung cancer by targeting tongue cancer resistance-related protein 1(TCRP1).
Epigenetic silencing of miR-493 increases the resistance to cisplatin in lung cancer by targeting tongue cancer resistance-related protein 1(TCRP1).
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miR-493的表观遗传沉默通过靶向舌癌耐药相关蛋白1（TCRP1）增加肺癌对顺铂的耐药性
DOI：
10.1186/s13046-017-0582-5
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发表时间：
2017-08-31
期刊：
影响因子：
--
通讯作者：
He Z
中科院分区：
文献类型：
--
作者：
Gu Y;Zhang Z;Yin J;Ye J;Song Y;Liu H;Xiong Y;Lu M;Zheng G;He Z
背景：microRNA（microRNA，miRNA）CpG岛甲基化调控肿瘤细胞化疗耐药性的机制尚不清楚。方法：采用实时荧光定量PCR（qRT-PCR）和原位杂交（ISH）技术，分别检测肺癌细胞株和肿瘤组织中miR-493的表达，分析miR-493的表观遗传学调控机制及其调控肺癌细胞化疗耐药性的能力。亚硫酸氢盐测序PCR（BSP）检测miR-493启动子CpG岛。通过细胞活力测定、凋亡测定和体内实验评估miR-493对化疗敏感性的影响。用γ-H2 AX免疫荧光法检测DNA损伤。采用荧光素酶报告基因分析法检测miR-493的靶基因。结果：miR-493在耐药肺癌细胞中由于DNA异常甲基化而被沉默。miR-493在肺癌细胞中的高表达可通过损伤DNA损伤修复和增加细胞凋亡来提高顺铂的化疗敏感性。此外，我们确定TCRP 1是miR-493的直接功能靶标。TCRP 1的异位表达减弱了顺铂治疗后miR-493过表达肺癌细胞的凋亡增加。结论：miR-493 CpG岛高甲基化可能通过靶向TCRP 1在肺癌化疗耐药的发生中发挥重要作用，有望成为预防肺癌化疗耐药的潜在治疗靶点。
Background:The 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.Methods:Real-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.Results:miR-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.Conclusions:Our 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.
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影响因子：
3.7
作者：
Gu Y;Cheng Y;Song Y;Zhang Z;Deng M;Wang C;Zheng G;He Z
通讯作者：
He Z
影响因子：
5.7
作者：
Sakai H;Sato A;Aihara Y;Ikarashi Y;Midorikawa Y;Kracht M;Nakagama H;Okamoto K
通讯作者：
Okamoto K
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影响因子：
4.3
作者：
Gu, Yixue;Fan, Shasha;He, Zhimin
通讯作者：
He, Zhimin
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影响因子：
15.9
作者：
Xi, Sichuan;Xu, Hong;Schrump, David S.
通讯作者：
Schrump, David S.
影响因子：
15.9
作者：
Wang, YC;Lu, YP;Chen, CY
通讯作者：
Chen, CY