Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
Oncogene. 2021 Jul;40(28):4695-4708. doi: 10.1038/s41388-021-01898-z. Epub 2021 Jun 17.
Oxaliplatin (oxa) is widely used in the treatment of colorectal cancer (CRC), but the development of oxaliplatin resistance is a major obstacle to the therapeutic efficacy in patients. MicroRNAs (miRNAs), endogenous noncoding RNAs measuring between 22 and 24 nucleotides, have been shown to be involved in the development of CRC drug resistance. However, the mechanism by which differentially expressed miRNAs induce chemotherapy resistance in CRC has not been fully elucidated to date. Here, we showed the differentially expressed miRNAs in oxaliplatin-sensitive and oxaliplatin-resistant CRC cells through miRNA microarray technology and found that miR-135b-5p was significantly increased in oxaliplatin-resistant cells. And miR-135b-5p was increased in the serum of colorectal cancer patients. More importantly, the miR-135b-5p level in the serum of oxaliplatin-resistant patients was further increased compared to that of oxaliplatin-sensitive patients. Recent studies have shown that protective autophagy is an important mechanism that promotes drug resistance in tumors. The potential role of miR-135b-5p in inducing protective autophagy and promoting oxaliplatin resistance was evaluated in two stable oxaliplatin-resistant CRC cell lines and their parental cells. We further identified MUL1 as a direct downstream target of miR-135b-5p and showed that MUL1 could degrade the key molecule of autophagy, ULK1, through ubiquitination. Mouse xenograft models were adopted to evaluate the correlation between miR-135b-5p and oxaliplatin-induced autophagy in vivo. Furthermore, we also investigated the regulatory factors for the upregulation of miR-135b-5p in CRC cells under oxaliplatin chemotoxicity. These results indicated that miR-135b-5p upregulation in colorectal cancer could induce protective autophagy through the MUL1/ULK1 signaling pathway and promote oxaliplatin resistance. Targeting miR-135b-5p may provide a new treatment strategy for reversing oxaliplatin resistance in CRC.
奥沙利铂（Oxa）广泛用于结直肠癌（CRC）的治疗，但奥沙利铂耐药的发展是患者治疗效果的主要障碍。microRNAs（miRNAs）是一种内源性的非编码 RNA，长度在 22 到 24 个核苷酸之间，已被证明参与了 CRC 耐药的发展。然而，迄今为止，差异表达的 miRNAs 如何诱导 CRC 化疗耐药的机制尚未完全阐明。在这里，我们通过 miRNA 微阵列技术显示了奥沙利铂敏感和奥沙利铂耐药 CRC 细胞中的差异表达 miRNAs，并发现 miR-135b-5p 在奥沙利铂耐药细胞中显著增加。并且 miR-135b-5p 在结直肠癌患者的血清中增加。更重要的是，与奥沙利铂敏感患者相比，奥沙利铂耐药患者血清中的 miR-135b-5p 水平进一步增加。最近的研究表明，保护性自噬是促进肿瘤耐药的重要机制。在两个稳定的奥沙利铂耐药 CRC 细胞系及其亲本细胞中，评估了 miR-135b-5p 在诱导保护性自噬和促进奥沙利铂耐药中的潜在作用。我们进一步确定 MUL1 是 miR-135b-5p 的直接下游靶标，并表明 MUL1 可以通过泛素化降解自噬的关键分子 ULK1。采用小鼠异种移植模型来评估 miR-135b-5p 与体内奥沙利铂诱导自噬之间的相关性。此外，我们还研究了 CRC 细胞在奥沙利铂化学毒性下 miR-135b-5p 上调的调节因子。这些结果表明，结直肠癌细胞中 miR-135b-5p 的上调可以通过 MUL1/ULK1 信号通路诱导保护性自噬，并促进奥沙利铂耐药。靶向 miR-135b-5p 可能为逆转 CRC 中的奥沙利铂耐药提供新的治疗策略。
