Tongji University School of Medicine, Shanghai, 200092, China.
Department of Interventional Radiology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
Arch Biochem Biophys. 2019 Mar 15;663:183-191. doi: 10.1016/j.abb.2019.01.005. Epub 2019 Jan 9.
Increasing evidence suggests that long non-coding RNAs (lncRNAs) are implicated with chemoresistance of cancers. However, their functional role and molecular mechanisms in colorectal cancer (CRC) chemoresistance are still largely unclear. In this work, we aimed to investigate the functional role of lncRNA cancer susceptibility candidate 15 (CASC15) in oxaliplatin (OXA) resistance of CRC and reveal the underlying molecular mechanism. Our results discovered that CASC15 was up-regulated in OXA-resistant CRC tissues and cells. Patients with high CASC15 expression level had a poor prognosis. CASC15 knockdown re-sensitized HT29/OXA and HCT116/OXA cells to OXA. Moreover, CASC15 could act as a competing endogenous RNA (ceRNA) to de-repress ABCC1 expression through sponging miR-145. miR-145 overexpression or ABCC1 knockdown could mimic the functional role of down-regulated CACS15 in OXA resistance, which was counteracted by CASC15 overexpression. Furthermore, CASC15 knockdown facilitated OXA sensitivity of OXA-resistant CRC cells in vivo. In summary, CASC15 silencing overcame OXA resistance of CRC by regulating miR-145/ABCC1 axis, providing a potential therapeutic target for CRC chemoresistance.
越来越多的证据表明，长非编码 RNA（lncRNA）与癌症的化疗耐药性有关。然而，lncRNA 在结直肠癌（CRC）化疗耐药中的功能作用和分子机制仍很大程度上不清楚。在这项工作中，我们旨在研究 lncRNA 癌症易感性候选基因 15（CASC15）在 CRC 奥沙利铂（OXA）耐药中的功能作用，并揭示其潜在的分子机制。我们的研究结果发现，CASC15 在 OXA 耐药的 CRC 组织和细胞中上调。CASC15 高表达的患者预后不良。CASC15 敲低可使 HT29/OXA 和 HCT116/OXA 细胞对 OXA 重新敏感。此外，CASC15 可作为竞争性内源性 RNA（ceRNA）通过海绵吸附 miR-145 来解除 ABCC1 的表达抑制。miR-145 过表达或 ABCC1 敲低可模拟下调 CACS15 在 OXA 耐药中的功能作用，而过表达 CASC15 可拮抗该作用。此外，CASC15 敲低可促进体内 OXA 耐药 CRC 细胞对 OXA 的敏感性。综上所述，CASC15 沉默通过调节 miR-145/ABCC1 轴克服 CRC 的 OXA 耐药性，为 CRC 化疗耐药提供了一个潜在的治疗靶点。
