PMID- 30334557
OWN - NLM
STAT- MEDLINE
DCOM- 20190805
LR  - 20190805
IS  - 1756-591X (Electronic)
IS  - 1756-5901 (Linking)
VI  - 10
IP  - 11
DP  - 2018 Nov 14
TI  - miRNA-182-5p, via HIF2alpha, contributes to arsenic carcinogenesis: evidence from 
      human renal epithelial cells.
PG  - 1607-1617
LID - 10.1039/c8mt00251g [doi]
AB  - Chronic exposure to high levels of arsenic has been associated with high risks 
      for many cancers, including renal cell carcinoma (RCC). However the underlying 
      mechanisms are not clear. In the present study, chronic arsenite exposure (2 muM 
      or 5 muM, 30 weeks) induced malignant transformation of HK-2 human renal 
      epithelial cells as indicated by elevated colony formation (6.2- and 5.4-fold 
      increase, respectively), secreted MMP-9 activity (10.1- and 11.3-fold increase, 
      respectively) and proliferation rate (1.2- and 1.3-fold increase in 72 h, 
      respectively). Lipid accumulation, typical of clear cell RCC, was observed in 
      arsenic-transformed (As-TM) cells. Overexpression of hypoxia-inducible factor 2alpha 
      (HIF2alpha) and suppression of carnitine palmitoyltransferase 1A (CPT1A) were found 
      at the level of mRNA (1.5- and 0.49-fold of control, respectively) and protein 
      (4.0- and 0.28-fold of control, respectively) after exposure to 2 muM arsenite for 
      20 weeks. Silencing of HIF2alpha significantly attenuated arsenite-induced malignant 
      phenotypes and lipid accumulation. Inactivation of Von Hippel-Lindau (VHL) and 
      impaired protein degradation of HIF2alpha were not found in As-TM cells. Expression 
      of miR-182-5p and miR-802 in As-TM cells was 42.4% and 54.0% of control, 
      respectively (p < 0.05). The levels of mRNA and protein of HIF2alpha were increased 
      2.4 folds and 1.6 folds of negative control in response to the miR-182-5p 
      inhibitor, respectively, but decreased to 58.1% and 50.1% of negative control in 
      response to miR-182-5p mimics, respectively. No significant alteration was 
      observed in HIF2alpha expression when miR-802 was silenced. Our data provide further 
      evidence for the carcinogenic role of arsenic in the kidney. Moreover, the 
      miR-182-5p/HIF2alpha pathway is indicated to be involved in malignant transformation 
      of human renal epithelial cells under arsenite exposure.
FAU - Fang, Xin
AU  - Fang X
AD  - School of Public Health, China Medical University, No. 77 Puhe Road, Shenbei New 
      District, Shenyang, Liaoning, P. R. China110122. yyxu@cmu.edu.cn 
      laurel1214@hotmail.com.
FAU - Sun, Ru
AU  - Sun R
FAU - Hu, Yuxin
AU  - Hu Y
FAU - Wang, Huihui
AU  - Wang H
FAU - Guo, Yi
AU  - Guo Y
FAU - Yang, Bei
AU  - Yang B
FAU - Pi, Jingbo
AU  - Pi J
FAU - Xu, Yuanyuan
AU  - Xu Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Metallomics
JT  - Metallomics : integrated biometal science
JID - 101478346
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (MicroRNAs)
RN  - 0 (Mirn182 microRNA, human)
RN  - 1B37H0967P (endothelial PAS domain-containing protein 1)
RN  - N712M78A8G (Arsenic)
MH  - Arsenic/*toxicity
MH  - Basic Helix-Loop-Helix Transcription Factors/genetics/*metabolism
MH  - Carcinogenesis/chemically induced/metabolism/*pathology
MH  - Cells, Cultured
MH  - Gene Expression Regulation, Neoplastic/*drug effects
MH  - Humans
MH  - Kidney Neoplasms/etiology/metabolism/*pathology
MH  - Kidney Tubules, Proximal/drug effects/*pathology
MH  - MicroRNAs/*genetics
EDAT- 2018/10/20 06:00
MHDA- 2019/08/06 06:00
CRDT- 2018/10/19 06:00
PHST- 2018/10/20 06:00 [pubmed]
PHST- 2019/08/06 06:00 [medline]
PHST- 2018/10/19 06:00 [entrez]
AID - 10.1039/c8mt00251g [doi]
PST - ppublish
SO  - Metallomics. 2018 Nov 14;10(11):1607-1617. doi: 10.1039/c8mt00251g.