MiRNA-194 activates the Wnt/β-catenin signaling pathway in gastric cancer by targeting the negative Wnt regulator, SUFU.

Abstract

Emerging evidence has shown that miRNA-194 is aberrantly upregulated in gastric cancer (GC); however, the biological mechanisms underlying its involvement are largely unknown. Wnt/β-catenin signaling has been implicated in gastric tumorigenesis; we therefore hypothesized that miRNA-194 promotes gastric carcinogenesis by activating Wnt/β-catenin signaling. MiRNA-194 was found to be overexpressed in GC cell lines and 43 paired GC tissues. Overexpression of miRNA-194 promoted cell proliferation and migration, while inhibition of miRNA-194 blocked these processes. Inhibition of miRNA-194 decreased tumor volumes in nude mice. Furthermore, miRNA-194 inhibitors promoted cytoplasmic localization of β-catenin, leading to repression of Wnt signaling. We also discovered that SUFU, a known negative regulator of Hedgehog and Wnt signaling, was a target of miRNA-194. Anti-SUFU siRNAs rescued the inhibitory effects of miRNA-194 antagonists on cell proliferation and migration and on colony formation. We also found that SUFU expression was downregulated in GC tissues and cell lines and negatively correlated with miRNA-194 expression in primary GC tissues. Moreover, SUFU expression was negatively correlated with tumor stage, supporting its potential as a diagnostic or prognostic marker in GC. Taken together, these findings suggest that miRNA-194 is oncogenic and promotes GC cell proliferation and migration by activating Wnt signaling, at least in part, via suppression of SUFU.

• Authors: Yin Peng, Xiaojing Zhang, Qiang Ma, Ruibin Yan, Ying Qin, Yanqiu Zhao, Yulan Cheng, Mengting Yang, Qixiang Wang, Xianling Feng, Yong Huang, Weiling Huang, Zhenfu Zhao, Liang Wang, Yanjie Wei, Zhendan He, Xinmin Fan, Song Li, Zhe Jin, Stephen J Meltzer
• Journal: Cancer letters (Cancer Lett) Vol. 385 Pg. 117-127 (01 28 2017) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 27810403 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• MIRN194 microRNA, human
• MicroRNAs
• Repressor Proteins
• SUFU protein, human

Topics

• Animals
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Down-Regulation
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (genetics, metabolism)
• Neoplasm Invasiveness
• Neoplasm Staging
• Oncogenes
• RNA Interference
• Repressor Proteins (genetics, metabolism)
• Stomach Neoplasms (genetics, metabolism, pathology)
• Time Factors
• Transfection
• Wnt Signaling Pathway