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

Luo, Fei; Sun, Baofei; Li, Huiqiao; Xu, Yuan; Liu, Yi; Liu, Xinlu; Lu, Lu; Li, Jun; Wang, Qingling; Wei, Shaofeng; Shi, Le; Lü, Xiaolin; Liu, Qizhan; Zhang, Aihua

doi:10.18632/oncotarget.6806

Cited by 71 publications

(61 citation statements)

References 55 publications

(69 reference statements)

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“…In our previous work, we found that HOTAIR was involved in malignant transformation induced in cells by cigarette smoke extract [44]. In addition, we have found that MALAT is involved in arseniteinduced malignant transformation of liver cells [21]. However, the role of MALAT1 on energy metabolism was still unclear.…”

Section: Discussionmentioning

confidence: 98%

“…Cell proliferation was evaluated with WST-8 (a tetrazolium salt that is cleaved to formazan) using cell counting kit-8 (Dojindo Molecular Technologies, Inc.), as described previously [21]. Briefly, cells were seeded into 96-well tissue culture plates at 4000 cells per well.…”

Section: Determination Of Cell Proliferationmentioning

confidence: 99%

“…To assess some common lncRNAs related to energy metabolism [25][26][27][28], and noting that MALAT1 is involved in arsenite-induced malignant transformation of liver cells [21], we determined the levels of these lncRNAs in L-02 cells exposed to 2 μM arsenite for 24 h. The levels of H19, HOTAIR, and MALAT1 were higher in cells exposed to arsenite than in normal cells; of the three lncRNAs, the differential expression of MALAT1 was highest (Fig. 3A).…”

Section: In L-02 Cells Arsenite Increases Levels Of Lncrnas and Hifsmentioning

confidence: 99%

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The lncRNA MALAT1, acting through HIF-1α stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells

Luo

Liu

Ling

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Accelerated glycolysis, a common process in tumor cells called the Warburg effect, is associated with various biological phenomena. However, the role of glycolysis induced by arsenite, a well-established human carcinogen, is unknown. Long non-coding RNAs (lncRNAs) act as regulators in various cancers, but how lncRNAs regulate glucose metabolism remains largely unexplored. We have found that, in human hepatic epithelial (L-02) cells, arsenite increases lactate production; glucose consumption; and expression of glycolysis-related genes, including HK-2, Eno-1, and Glut-4. In L-02 cells exposed to arsenite, the lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and hypoxia inducible factors (HIFs)-α, the transcriptional regulators of cellular response to hypoxia, are over-expressed. In addition, HIF-1α, not HIF-2α, is involved in arsenite-induced glycolysis, and MALAT1 enhances arsenite-induced glycolysis. Although MALAT1 regulates HIF-α and promotes arsenite-induced glycolysis, MALAT1 promotes glycolysis through HIF-1α, not HIF-2α. Moreover, arsenite-increased MALAT1 enhances the disassociation of Von Hippel-Lindau (VHL) tumor suppressor from HIF-1α, alleviating VHL-mediated ubiquitination of HIF-1α, which causes accumulation of HIF-1α. In sum, these findings indicate that MALAT1, acting through HIF-1α stabilization, is a mediator that enhances glycolysis induced by arsenite. These results provide a link between the induction of lncRNAs and the glycolysis in cells exposed to arsenite, and thus establish a previously unknown mechanism for arsenite-induced hepatotoxicity.

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Section: Discussionmentioning

confidence: 98%

Section: Determination Of Cell Proliferationmentioning

confidence: 99%

Section: In L-02 Cells Arsenite Increases Levels Of Lncrnas and Hifsmentioning

confidence: 99%

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The lncRNA MALAT1, acting through HIF-1α stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells

Luo

Liu

Ling

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…High expression levels of Malat1 within tumors have been associated with poor prognosis and severity of various types of cancer, including bladder (17), lung (18), gallbladder (19) and liver cancers (20). In addition, circulating Malat1 levels have also been recently shown to predict development of hepatocellular carcinoma (21,22), suggesting its possible use as a reliable biomarker. Moreover, Malat1 may be directly implicated in the development of cancer through its effect on cellular proliferation and its facilitating role in cell invasion and metastasis, two important hallmarks of cancer (18,23,24).…”

Section: Introductionmentioning

confidence: 99%

Absence of Malat1 does not prevent DEN-induced hepatocarcinoma in mice

et al. 2017

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Long non-coding RNAs (lncRNA) are key regulators of gene expression both at the transcriptional and post-transcriptional levels. The lncRNA metastasis associated lung adenocarcinoma transcript 1 (Malat1) is overexpressed in many types of cancer, including hepatocarcinoma, and induces cell proliferation in several cell lines in vitro. However, the direct causal effects of Malat1 on hepatocyte proliferation and liver carcinogenesis in vivo are not fully understood. To better determine the contribution of Malat1 to hepatocarcinoma oncogenesis, this study was aimed at testing the hypothesis that its absence confers resistance to the development of liver tumors. Male Malat1-/- mice and their wild-type (WT) littermates were studied one year after treatment with the genotoxic agent diethylnitrosamine (DEN), a potent inducer of liver cancer. As expected, in WT mice, Malat1 expression was significantly higher in hepatic tumors than in healthy liver regions. Altered hepatic mRNA levels of Ki67, HDAC3, NFκB and p27 were observed in DEN-treated Malat1-/- mice. Despite this, these mice were characterized by similar liver weight, prevalence of tumors, and histological features compared to those of their WT littermates. In parallel, plasma lipids and glucose homeostasis did not significantly differ between DEN-treated groups. These findings support a role for Malat1 as a marker of liver carcinogenesis, but also suggest that its role in the regulation of hepatocyte hyperproliferation in mice is either minimal or masked by redundant and/or overwhelming mechanisms.

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“…[25] In addition, MALAT1 level positively correlates with the expression of HIF-2α, but not with that of HIF-1α in tumor cells. [26]…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-210 Plays a Critical Role in the Angiogenic Effect of Isoprenaline on Human Umbilical Vein Endothelial Cells via Regulation of Noncoding RNAs

Yan

Wang

Zhao

et al. 2016

Chinese Medical Journal

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Background:β-adrenoceptors play a crucial regulatory role in blood vessel endothelial cells. Isoprenaline (ISO, a β-adrenergic agonist) has been reported to promote angiogenesis through upregulation of vascular endothelial growth factor (VEGF) expression; however, the underlying mechanism remains to be investigated. It is widely accepted that certain noncoding RNAs, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), can regulate endothelial cell behavior, including their involvement in angiogenesis. Therefore, we aimed to investigate whether noncoding RNAs participate in ISO-mediated angiogenesis using human umbilical vein endothelial cells (HUVECs).Methods:We evaluated VEGF-A messenger RNA (mRNA) and protein levels in ISO-treated HUVECs by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. To establish whether noncoding RNAs are associated with ISO-mediated angiogenesis, we measured expression of the miRNAs miR-210, miR-21, and miR-1, as well as that of the lncRNAs growth arrest-specific transcript 5 (GAS5), maternally expressed 3 (MEG3), and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in HUVECs exposed to ISO. Furthermore, to ascertain its importance in ISO-mediated angiogenesis, we constructed the HUVECs with overexpressing miR-210 and detected the subsequent expression of VEGF-A and noncoding RNAs. All statistical analyses were performed using SPSS 16.0 software. Intergroup comparisons were carried out by one-way analysis of variance.Results:VEGF-A mRNA levels were elevated in the ISO group (1.57 ± 0.09) compared to those in the control group (P < 0.01). Moreover, concentrations of VEGF-A in culture supernatants significantly differed between the control (113.00 ± 19.21 pg/ml) and ISO groups (287.00 ± 20.27 pg/ml; P < 0.01). Expression of miR-1, miR-21, and miR-210 was higher (3.89 ± 0.44, 2.87 ± 087, and 3.33 ± 1.31, respectively) in ISO-treated cells than that in controls (P < 0.01), whereas that of GAS5 and MEG3 (0.22 ± 0.10 and 0.58 ± 0.16, respectively) was lower as a result of ISO administration (P < 0.05). There was no significant difference in the expression of MALAT1 between the groups. Interestingly, miR-210 overexpression heightened the levels of VEGF-A and miR-21 (5.87 ± 1.24 and 2.74 ± 1.15, respectively; P < 0.01) and reduced those of GAS5 and MEG3 (0.19 ± 0.01 and 0.09 ± 0.05, respectively; P < 0.01).Conclusions:ISO-mediated angiogenesis was associated with altered expression of miR-210, miR-21, and the lncRNAs GAS5 and MEG3. The effects of miR-210 on the expression of VEGF-A and noncoding RNAs were similar to those of ISO, indicating that it might play an important role in ISO-mediated angiogenesis.

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

Cited by 71 publications

References 55 publications

The lncRNA MALAT1, acting through HIF-1α stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells

The lncRNA MALAT1, acting through HIF-1α stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells

Absence of Malat1 does not prevent DEN-induced hepatocarcinoma in mice

MicroRNA-210 Plays a Critical Role in the Angiogenic Effect of Isoprenaline on Human Umbilical Vein Endothelial Cells via Regulation of Noncoding RNAs

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