Department of Nephrology , Yulin No. 2 Hospital, Yulin City, Shaanxi Province, China.
Cell Cycle. 2020 Aug;19(16):2054-2062. doi: 10.1080/15384101.2020.1792667. Epub 2020 Jul 14.
Long non-coding RNA metastasis associated with lung adenocarcinoma transcript 1 (MALAT1) contributes to chemotherapy resistance in some cancers, but the role of MALAT1 in sunitinib (SU) chemoresistance of carcinoma (RCC) is still unknown. In this study, MALAT1 expression in SU-resistance tumor tissues and cells was tested by qRT-PCR. Then, CCK-8, Annexin V-FITC/PI, transwell, and Western blotting assays were used to evaluate cell viability and IC50, apoptosis, cell invasion, and resistance of SU-resistance RCC cells after transfected with small interfering RNA against MALAT1. Further, RNA pull-down and luciferase reporter assay were applied to investigate the underlying mechanism of MALAT1 in SU resistance. The results showed that MALAT1 expression was dramatically upregulated in SU-resistance RCC tissues and cell lines. Knockdown of MALAT1 inhibited proliferation, invasion, and SU chemoresistance, but induced apoptosis in RCC cells. The results of RNA pull-down and luciferase reporter assay indicated that MALAT1 could interact with miR-362-3p and miR-362-3p interact with RasGAP SH3-domain-Binding Protein 1 (G3BP1). Moreover, G3BP1 also played a role in SU chemoresistance of RCC cells, and MALAT1 could perform as a miR-362-3p sponge to modulate G3BP1 expression. Rescue experiments suggested that downregulation of miR-362-3p and overexpression of G3BP1 can reverse the SU chemosensitivity of MALAT1 knockdown in RCC cells. In conclusion, depletion of LncRNA MALAT1 inhibited SU chemoresistance through modulating G3BP1 via sponging miR-362-3p in RCC cells, suggesting that targeting MALAT1 may be a potential therapeutic strategy for SU-resistance RCC.
长链非编码 RNA 肺癌腺癌转移相关转录物 1（MALAT1）在一些癌症中有助于化疗耐药，但 MALAT1 在舒尼替尼（SU）耐药肾细胞癌（RCC）中的作用尚不清楚。在这项研究中，通过 qRT-PCR 检测了 SU 耐药肿瘤组织和细胞中 MALAT1 的表达。然后，通过 CCK-8、Annexin V-FITC/PI、Transwell 和 Western blot 检测，评估了转染 MALAT1 小干扰 RNA 后 SU 耐药 RCC 细胞的细胞活力和 IC50、细胞凋亡、细胞侵袭和对 SU 的耐药性。进一步，应用 RNA 下拉和荧光素酶报告基因检测来研究 MALAT1 在 SU 耐药中的潜在机制。结果表明，MALAT1 在 SU 耐药 RCC 组织和细胞系中表达明显上调。敲低 MALAT1 抑制了 RCC 细胞的增殖、侵袭和 SU 耐药性，但诱导了细胞凋亡。RNA 下拉和荧光素酶报告基因检测结果表明，MALAT1 可以与 miR-362-3p 相互作用，miR-362-3p 与 RasGAP SH3 结构域结合蛋白 1（G3BP1）相互作用。此外，G3BP1 在 RCC 细胞的 SU 耐药中也发挥作用，MALAT1 可以作为 miR-362-3p 的海绵来调节 G3BP1 的表达。挽救实验表明，下调 miR-362-3p 和过表达 G3BP1 可以逆转 RCC 细胞中 MALAT1 敲低对 SU 化疗敏感性的影响。总之，通过调节 G3BP1 抑制 LncRNA MALAT1 抑制了 SU 耐药，表明靶向 MALAT1 可能是治疗 SU 耐药 RCC 的潜在策略。
