The HSF1/miR-135b-5p axis induces protective autophagy to promote oxaliplatin resistance through the MUL1/ULK1 pathway in colorectal cancer
The HSF1/miR-135b-5p axis induces protective autophagy to promote oxaliplatin resistance through the MUL1/ULK1 pathway in colorectal cancer
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HSF1/miR-135b-5p 轴通过 MUL1/ULK1 通路诱导结直肠癌保护性自噬促进奥沙利铂耐药
DOI：
10.1038/s41388-021-01898-z
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发表时间：
2021-06
期刊：
影响因子：
8
通讯作者：
Yi Ba
中科院分区：
文献类型：
--
作者：
Huiya Wang;Xia Wang;Haiyang Zhang;Ting Deng;Rui Liu;Ying Liu;Hongli Li;Ming Bai;Tao Ning;Junyi Wang;Shaohua Ge;Yi Ba
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。微小RNA（miRNAs），测量22和24个核苷酸之间的内源性非编码RNA，已被证明参与CRC耐药性的发展。然而，差异表达的miRNAs诱导CRC化疗耐药的机制至今尚未完全阐明。在此，我们通过miRNA微阵列技术展示了奥沙利铂敏感和奥沙利铂耐药CRC细胞中差异表达的miRNA，发现miR-135 b-5 p在奥沙利铂耐药细胞中显著增加。miR-135 b-5 p在结直肠癌患者血清中表达增高。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-135 b-5 p水平进一步升高。近年来的研究表明，保护性自噬是促进肿瘤耐药的重要机制。在两种稳定的奥沙利铂耐药CRC细胞系及其亲本细胞中评价了miR-135 b-5 p在诱导保护性自噬和促进奥沙利铂耐药中的潜在作用。我们进一步鉴定了MUL 1作为miR-135 b-5 p的直接下游靶标，并表明MUL 1可以通过泛素化降解自噬的关键分子ULK 1。采用小鼠异种移植模型来评估miR-135 b-5 p与奥沙利铂诱导的体内自噬之间的相关性。此外，我们还研究了奥沙利铂化疗毒性下CRC细胞中miR-135 b-5 p上调的调控因素。这些结果表明，miR-135 b-5 p在结直肠癌中的上调可以通过MUL 1/ULK 1信号通路诱导保护性自噬并促进奥沙利铂耐药。 靶向miR-135 b-5 p可能为逆转CRC奥沙利铂耐药提供新的治疗策略。
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.
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影响因子：
3.8
作者：
Magalhães L;Quintana LG;Lopes DCF;Vidal AF;Pereira AL;D'Araujo Pinto LC;de Jesus Viana Pinheiro J;Khayat AS;Goulart LR;Burbano R;de Assumpção PP;Ribeiro-Dos-Santos Â
通讯作者：
Ribeiro-Dos-Santos Â
DOI：
10.1146/annurev.pathol.4.110807.092222
发表时间：
2009
期刊：
Annual review of pathology
影响因子：
--
作者：
Lee YS;Dutta A
通讯作者：
Dutta A
胃肿瘤外泌体递送的 miR-135b 抑制内皮细胞中 FOXO1 的表达并促进血管生成
影响因子：
12.4
作者：
Bai Ming;Li Jialu;Yang Haiou;Zhang Haiyang;Zhou Zhengyang;Deng Ting;Zhu Kegan;Ning Tao;Fan Qian;Ying Guoguang;Ba Yi
通讯作者：
Ba Yi
影响因子：
3.7
作者：
Li W;Bengtson MH;Ulbrich A;Matsuda A;Reddy VA;Orth A;Chanda SK;Batalov S;Joazeiro CA
通讯作者：
Joazeiro CA
影响因子：
20.3
作者：
Umezu, Tomohiro;Tadokoro, Hiroko;Ohyashiki, Junko H.
通讯作者：
Ohyashiki, Junko H.