A MALAT1/HIF-2α feedback loop contributes to arsenite carcinogenesis
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Fei Luo1,2,*, Baofei Sun3,*, Huiqiao Li4,*, Yuan Xu1,2,5, Yi Liu1,2, Xinlu Liu1,2, Lu Lu 1,2, Jun Li3, Qingling Wang3, Shaofeng Wei3, Le Shi1,2, Xiaolin Lu1,2, Qizhan Liu1,2, Aihua Zhang3
1Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People’s Republic of China
2The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People’s Republic of China
3The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guiyang Medical University, Guiyang 550025, Guizhou, People’s Republic of China
4Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People’s Republic of China
5Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
*These authors contributed equally to this work
Qizhan Liu, e-mail: [email protected]
Aihua Zhang, e-mail: [email protected]
Keywords: lncRNAs, HIFs, arsenite, carcinogenesis
Received: July 16, 2015 Accepted: December 05, 2015 Published: December 31, 2015
Arsenic is well established as a human carcinogen, but the molecular mechanisms leading to arsenic-induced carcinogenesis are complex and elusive. It is also not known if lncRNAs are involved in arsenic-induced liver carcinogenesis. We have found that MALAT1, a non-coding RNA, is over-expressed in the sera of people exposed to arsenite and in hepatocellular carcinomas (HCCs), and MALAT1 has a close relation with the clinicopathological characteristics of HCC. In addition, hypoxia-inducible factor (HIF)-2α is up-regulated in HCCs, and MALAT1 and HIF-2α have a positive correlation in HCC tissues. During the malignant transformation of human hepatic epithelial (L-02) cells induced by a low concentration (2.0 μM) of arsenite, MALAT1 and HIF-2α are increased. In addition, arsenite-induced MALAT1 causes disassociation of the von Hippel-Lindau (VHL) protein from HIF-2α, therefore, alleviating VHL-mediated HIF-2α ubiquitination, which causes HIF-2α accumulation. In turn, HIF-2α transcriptionally regulates MALAT1, thus forming a positive feedback loop to ensure expression of arsenite-induced MALAT1 and HIF-2α, which are involved in malignant transformation. Moreover, MALAT1 and HIF-2α promote the invasive and metastatic capacities of arsenite-induced transformed L-02 cells and in HCC-LM3 cells. The capacities of MALAT1 and HIF-2α to promote tumor growth are validated in mouse xenograft models. In mice, arsenite induces an inflammatory response, and MALAT1 and HIF-2α are over-expressed. Together, these findings suggest that the MALAT1/HIF-2α feedback loop is involved in regulation of arsenite-induced malignant transformation. Our results not only confirm a novel mechanism involving reciprocal regulation between MALAT1 and HIF-2α, but also expand the understanding of the carcinogenic potential of arsenite.
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