文献类型：期刊文献

英文题名：Hypoxia Induces Drug Resistance in Colorectal Cancer through the HIF-1α/miR-338-5p/IL-6 Feedback Loop

作者：Xu, Ke[1,2,4];Zhan, Yueping[2];Yuan, Zeting[1,4];Qiu, Yanyan[1];Wang, Haijing[1];Fan, Guohua[1];Wang, Jie[3];Li, Wei[3];Cao, Yijun[3];Shen, Xian[6];Zhang, Jun[5];Liang, Xin[7,8];Yin, Peihao[1,3,4]

机构：[1]Shanghai Univ Tradit Chinese Med, Intervent Canc Inst Chinese Integrat Med, Putuo Hosp, Shanghai 200062, Peoples R China;[2]Shanghai Univ Tradit Chinese Med, Putuo Hosp, Cent Lab, Shanghai 200062, Peoples R China;[3]Shanghai Univ Tradit Chinese Med, Putuo Hosp, Dept Gen Surg, Shanghai 200062, Peoples R China;[4]Anhui Med Univ, Shanghai Putuo Cent Sch Clin Med, Hefei 230032, Anhui, Peoples R China;[5]Univ Iowa, Holden Comprehens Canc Ctr, Div Hematol Oncol & Blood & Marrow Transplantat, Dept Internal Med,Carver Coll Med, Iowa City, IA 52242 USA;[6]Wenzhou Med Univ, Affiliated Hosp 2, Wenzhou 325035, Zhejiang, Peoples R China;[7]East China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, 130 Meilong Rd, Shanghai 200237, Peoples R China;[8]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, 130 Meilong Rd, Shanghai 200237, Peoples R China

年份：2019

卷号：27

期号：10

起止页码：1810

外文期刊名：MOLECULAR THERAPY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000488532100012)】；

基金：Special thanks to Dr. Teng Chen and Dr. Jianhua Xu for the help during the study. This project was sponsored by the National Nature Science Foundation of China (81873137), the Shanghai Rising-Star Program (17QA1403400), and the Shanghai Committee of Science and Technology (16411972600). This project was also sponsored by "the twelfth five year" key subject (Integrated Chinese and Western Medicine and General practice training of Traditional Chinese Medicine) of traditional Chinese medicine of State Administration of Traditional Chinese medicine and the Action Plan of Shanghai Municipality for Further Accelerating the Development of Traditional Chinese Medicine (ZY[2018-2020]-RCPY-2016).

语种：英文

摘要：Hypoxia is associated with poor prognosis and therapeutic resistance in cancer patients. Accumulating evidence has shown that microRNA (miRNA) plays an important role in the acquired drug resistance in colorectal carcinoma (CRC). However, the role of miRNA in hypoxia-induced CRC drug resistance remains to be elucidated. Here, we identified a hypoxia-triggered feedback loop that involves hypoxia-inducible transcription factor 1 alpha (HIF-1 alpha)-mediated repression of miR-338-5p and confers drug resistance in CRC. In this study, the unbiased miRNA array screening revealed that miR-338-5p is downregulated in both hypoxic CRC cell lines tested. Repression of miR-338-5p was required for hypoxia-induced CRC drug resistance. Furthermore, we identified interleukin-6 (IL-6), which mediates STAT3/Bcl2 activation under hypoxic conditions, as a direct miR-338-5p target. The resulting HIF-1 alpha/miR-338-5p/IL-6 feedback loop was necessary for drug resistance in colon cancer cell lines. Using CRC patient samples, we found miR-338-5p has a negative correlation with HIF-1 alpha and IL-6. Finally, in a xenograft model, overexpressing miR-338-5p in CRC cells and HIF-1 alpha inhibitor PX-478 were able to enhance the sensitivity of CRC to oxaliplatin (OXA) via suppressing the HIF-1 alpha/miR-338-5p/IL-6 feedback loop in vivo. Taken together, our results uncovered an HIF-1 alpha/miR-338-5p/IL-6 feedback circuit that is critical in hypoxia-mediated drug resistance in CRC; targeting each member of this feedback loop could potentially reverse hypoxia-induced drug resistance in CRC.