A MALAT1/HIF-2α feedback loop contributes to arsenite carcinogenesis.
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.
Mesh Terms:
Animals, Apoptosis, Arsenites, Basic Helix-Loop-Helix Transcription Factors, Blotting, Western, Carcinoma, Hepatocellular, Carcinoma, Renal Cell, Cell Proliferation, Cell Transformation, Neoplastic, Cells, Cultured, Chromatin Immunoprecipitation, Epithelial Cells, Feedback, Physiological, Female, Humans, Immunoenzyme Techniques, Immunoprecipitation, Kidney Neoplasms, Liver Neoplasms, Male, Mice, Middle Aged, Neoplasm Staging, Prognosis, RNA, Long Noncoding, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Survival Rate, Xenograft Model Antitumor Assays
Animals, Apoptosis, Arsenites, Basic Helix-Loop-Helix Transcription Factors, Blotting, Western, Carcinoma, Hepatocellular, Carcinoma, Renal Cell, Cell Proliferation, Cell Transformation, Neoplastic, Cells, Cultured, Chromatin Immunoprecipitation, Epithelial Cells, Feedback, Physiological, Female, Humans, Immunoenzyme Techniques, Immunoprecipitation, Kidney Neoplasms, Liver Neoplasms, Male, Mice, Middle Aged, Neoplasm Staging, Prognosis, RNA, Long Noncoding, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Survival Rate, Xenograft Model Antitumor Assays
Oncotarget
Date: Feb. 02, 2016
PubMed ID: 26735578
View in: Pubmed Google Scholar
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