Synergism of HPV and MNNG repress miR-218 promoting Het-1A cell malignant transformation by targeting GAB2

Ying Zhang; Yuhong Zheng; Enchun Pan; Chao Zhao; Hu Zhang; Ran Liu; Shizhi Wang; Yuepu Pu; Lihong Yin

doi:10.1016/j.tox.2020.152635

Synergism of HPV and MNNG repress miR-218 promoting Het-1A cell malignant transformation by targeting GAB2

Toxicology. 2021 Jan 15:447:152635. doi: 10.1016/j.tox.2020.152635. Epub 2020 Nov 12.

Authors

Ying Zhang¹, Yuhong Zheng², Enchun Pan³, Chao Zhao⁴, Hu Zhang⁵, Ran Liu⁶, Shizhi Wang⁷, Yuepu Pu⁸, Lihong Yin⁹

Affiliations

¹ Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China. Electronic address: 230198329@seu.edu.cn.
² Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China. Electronic address: 220162988@seu.edu.cn.
³ Huai'an Center for Disease Control and Prevention, Huai'an, 223001, Jiangsu, China. Electronic address: hypec@163.com.
⁴ Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China. Electronic address: 230179272@seu.edu.cn.
⁵ Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China. Electronic address: 230189707@seu.edu.cn.
⁶ Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China. Electronic address: ranliu@seu.edu.cn.
⁷ Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China. Electronic address: shizhiwang2009@seu.edu.cn.
⁸ Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China. Electronic address: yppu@seu.edu.cn.
⁹ Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China. Electronic address: lhyin@seu.edu.cn.

PMID: 33189795
DOI: 10.1016/j.tox.2020.152635

Abstract

Dysregulation of microRNAs (miRNAs) is induced during tumorigenesis. Our previous research suggested that HPV and MNNG led to malignant transformation of esophageal epithelial cells. To investigate the regulation and function of miR-218(miR-218-5p) during the malignant transformation of esophageal epithelial cells, we found miR-218 was inhibited synergistically by HPV and MNNG, suppressing cell proliferation, migration and invasion by up-regulating 3' untranslated region (3'UTR) GAB2 in Het-1A-HPV-MNNG cells (malignant Het-1A cells induced by HPV and MNNG). A negative correlation was found between miR-218 and GAB2 mRNA expression in esophageal cancer patients and control people. GAB2 was up-regulated in Het-1A-HPV-MNNG cells. Further, down-expression of GAB2 reversed HPV&MNNG-mediated activation of migration and invasion and repressed SHP2/ERK and Akt/mTOR pathway signaling. In conclusion, miR-218 partially accounts for the prevention effect during malignant transformation of normal esophageal epithelial cells, which targets GAB2, which supplies the potential treatment in cancer therapy.

Keywords: Esophageal cancer; HPV; Nitrosamine; Synergistic carcinogenesis; miR-218.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism*
Cell Line
Humans
Methylnitronitrosoguanidine / administration & dosage*
Methylnitronitrosoguanidine / metabolism*
MicroRNAs / antagonists & inhibitors*
MicroRNAs / metabolism*
Papillomaviridae / metabolism*
Papillomavirus Infections / metabolism
Respiratory Mucosa / drug effects
Respiratory Mucosa / metabolism
Respiratory Mucosa / virology

Substances

Adaptor Proteins, Signal Transducing
GAB2 protein, human
MIRN218 microRNA, human
MicroRNAs
Methylnitronitrosoguanidine