miR-34a and IRE1A/XBP-1(S) Form a Double-Negative Feedback Loop to Regulate Hypoxia-Induced EMT, Metastasis, Chemo-Resistance and Autophagy

Author:

Bouznad Nassim1ORCID,Rokavec Matjaz1,Öner Meryem Gülfem1,Hermeking Heiko123

Affiliation:

1. Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-Universität, Thalkirchner Strasse 36, 80337 Munich, Germany

2. German Cancer Consortium (DKTK), Partner Site Munich, 80336 Munich, Germany

3. German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

Abstract

Tumor-associated hypoxia, i.e., decreased availability of oxygen, results in a poor clinical outcome since it promotes EMT, metastasis, and chemotherapy-resistance. We have previously identified p53 and its target miR-34a, as critical determinants of the effect of hypoxia on colorectal cancer (CRC). Here, we aimed to characterize mechanisms that contribute to the selective advantage of cells with loss of p53/miR-34a function in a hypoxic environment. Using in silico prediction, we identified XBP-1 and IRE1A as potential miR-34a targets. IRE1A and XBP-1 are central components of the unfolded protein response that is activated by ER stress, which is also induced in tumor cells as a response to harsh conditions surrounding tumors such as hypoxia and a limited supply of nutrients. Here we characterized the XBP-1(S) transcription factor and its regulator IRE1A as direct, conserved miR-34a targets in CRC cells. After hypoxia and DNA damage, IRE1A and XBP-1 were repressed by p53 in a miR-34a-dependent manner, whereas p53-deficient cells showed induction of IRE1A and XBP-1(S). Furthermore, miR-34a expression was directly suppressed by XBP-1(S). In p53-deficient CRC cells, hypoxia-induced EMT, migration, invasion, metastases formation, and resistance to 5-FU were dependent on IRE1A/XBP-1(S) activation. Hypoxia-induced autophagy was identified as an XBP-1(S)-dependent mediator of 5-FU resistance and was reversed by ectopic miR-34a expression. The HIF1A/IRE1A/XBP-1(S)/p53/miR-34a feedback loop described here represents a central regulator of the response to hypoxia and ER stress that maintains cellular homeostasis. In tumors, the inactivation of p53 and miR-34a may result in IRE1A/XPB-1(S)-mediated EMT and autophagy, which ultimately promotes metastasis and chemoresistance.

Funder

Deutsche Forschungsgemeinschaft/DFG

Publisher

MDPI AG

Subject

Cancer Research,Oncology

Reference42 articles.

1. Role of hypoxia in the hallmarks of human cancer;Ruan;J. Cell. Biochem.,2009

2. Hypoxia-driven gene expression is an independent prognostic factor in stage II and III colon cancer patients;Dekervel;Clin. Cancer Res.,2014

3. The impact of O2 availability on human cancer;Bertout;Nat. Rev. Cancer,2008

4. HIF-1alpha in colorectal carcinoma: Review of the literature;Ioannou;J. BUON,2015

5. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition;Higgins;J. Clin. Investig.,2007

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3