Linc00152 Functions as a Competing Endogenous RNA to Confer Oxaliplatin Resistance and Holds Prognostic Values in Colon Cancer
Linc00152 Functions as a Competing Endogenous RNA to Confer Oxaliplatin Resistance and Holds Prognostic Values in Colon Cancer
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DOI：
10.1038/mt.2016.180
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发表时间：
2016-12-01
影响因子：
12.4
通讯作者：
Yan, Dongwang
中科院分区：
文献类型：
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作者：
Yue, Ben;Cai, Donglan;Yan, Dongwang
长的非编码RNA在许多人类癌症中起着关键的调节作用，但它们在化疗耐药中的潜在作用和分子机制却知之甚少。本研究表明，一种新的非编码LncRNA-Linc00152(Linc00152)能够促进肿瘤进展并对奥沙利铂(OHP)诱导的细胞凋亡产生体内和体外的耐药。它通过作为竞争内源性RNA调节miR-193a-3p的表达，进而调节erb-b2受体酪氨酸激酶4(ERBB4)的表达，从而拮抗化疗敏感性。结肠癌细胞中ERBB4基因的敲除降低了AKT的磷酸化，从而降低了对L-OHP的耐药性。与上述发现一致的是，分别使用了特异性的AKT信号抑制剂和激活剂，这表明Linc00152至少部分地通过激活AKT途径参与了对L-OHP的抗性。进一步的研究表明，Linc00152基因的增加似乎是II期和III期结肠癌患者术后接受以L为基础的化疗的患者生存率下降和疾病复发增加的独立预后因素。总之，我们的发现确立了Linc00152作为结肠癌患者预后和药物反应的候选预后指标，Linc00152/miR-193a-3p/ERBB4/AKT信号轴上竞争的内源性RNAs机制的参与可能为研究耐药提供了新的选择。
Long noncoding RNAs act as crucial regulators in plenty of human cancers, yet their potential roles and molecular mechanisms in chemoresistance are poorly understood. This study showed that a novel lncRNA, long intergenic noncoding RNA 152 (Linc00152), promoted tumor progression and conferred resistance to oxaliplatin (L-OHP)induced apoptosis in vitro and in vivo. It antagonized chemosensitivity through acting as a competing endogenous RNA to modulate the expression of miR-193a-3p, and then erb-b2 receptor tyrosine kinase 4 (ERBB4). Knockdown of ERBB4 in colon cancer cells decreased AKT phosphorylation, which resulted in decreased L-OHP resistance. Consistent with above findings, the specific AKT signaling inhibitor and activator were used, respectively, which demonstrated that Linc00152 contributed to L-OHP resistance at least partly through activating AKT pathway. Further studies indicated that Linc00152 was increased and appeared to be an independent prognostic factor for decreased survival and increased disease recurrence in stage II and III colon cancer patients undergoing L-OHP-based chemotherapy after surgery. Collectively, our findings established Linc00152 as a candidate prognostic indicator of outcome and drug responsiveness in colon cancer patients, and the involvement of competing endogenous RNAs mechanism in Linc00152/ miR-193a-3p/ERBB4/AKT signaling axis may provide a novel choice in the investigation of drug resistance.