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Oncotarget. 2016 Feb 2;7(5):5769-87. doi: 10.18632/oncotarget.6806.

A MALAT1/HIF-2α feedback loop contributes to arsenite carcinogenesis.

Luo F1,2, Sun B3, Li H4, Xu Y1,2,5, Liu Y1,2, Liu X1,2, Lu L1,2, Li J3, Wang Q3, Wei S3, Shi L1,2, Lu X1,2, Liu Q1,2, Zhang A3.

Author information

1
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
2
The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
3
The 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.
4
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
5
Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

Abstract

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.

KEYWORDS:

HIFs; arsenite; carcinogenesis; lncRNAs

PMID:
26735578
PMCID:
PMC4868720
DOI:
10.18632/oncotarget.6806
[Indexed for MEDLINE]
Free PMC Article

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