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

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)-2? is up-regulated in HCCs, and MALAT1 and HIF-2? 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 ?M) of arsenite, MALAT1 and HIF-2? are increased. In addition, arsenite-induced MALAT1 causes disassociation of the von Hippel-Lindau (VHL) protein from HIF-2?, therefore, alleviating VHL-mediated HIF-2? ubiquitination, which causes HIF-2? accumulation. In turn, HIF-2? transcriptionally regulates MALAT1, thus forming a positive feedback loop to ensure expression of arsenite-induced MALAT1 and HIF-2?, which are involved in malignant transformation. Moreover, MALAT1 and HIF-2? promote the invasive and metastatic capacities of arsenite-induced transformed L-02 cells and in HCC-LM3 cells. The capacities of MALAT1 and HIF-2? to promote tumor growth are validated in mouse xenograft models. In mice, arsenite induces an inflammatory response, and MALAT1 and HIF-2? are over-expressed. Together, these findings suggest that the MALAT1/HIF-2? 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-2?, but also expand the understanding of the carcinogenic potential of arsenite.

SUBMITTER: Luo F

PROVIDER: S-EPMC4868720 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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

Luo Fei F Sun Baofei B Li Huiqiao H Xu Yuan Y Liu Yi Y Liu Xinlu X Lu Lu L Li Jun J Wang Qingling Q Wei Shaofeng S Shi Le L Lu Xiaolin X Liu Qizhan Q Zhang Aihua A

Oncotarget 20160201 5

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 facto ...[more]

PMID: 26735578

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

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

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