MiRNA-194 activates the Wnt/β-catenin signaling pathway in gastric cancer by targeting the negative Wnt regulator, SUFU.
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.
Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China; Department of Pathology, Wuhan University School of Basic Medical Sciences, Hubei, People's Republic of China.
Yin
Y
Peng
Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China; Shenzhen Key Laboratory of Translational Medicine of Tumor, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.
Xiaojing
X
Zhang
Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.
Qiang
Q
Ma
Laboratory of Chemical Genomics, Shenzhen Graduate School of Peking University, Shenzhen, Guangdong, People's Republic of China.
Ruibin
R
Yan
Department of Gastrointestinal Surgery, Shenzhen Second People's Hospital, Shenzhen, Guangdong, People's Republic of China.
Ying
Y
Qin
Laboratory of Chemical Genomics, Shenzhen Graduate School of Peking University, Shenzhen, Guangdong, People's Republic of China.
Yanqiu
Y
Zhao
Department of Medicine/GI Division and Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Yulan
Y
Cheng
Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.
Mengting
M
Yang
Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.
Qixiang
Q
Wang
Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.
Xianling
X
Feng
Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.
Yong
Y
Huang
Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.
Weiling
W
Huang
Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.
Zhenfu
Z
Zhao
Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China; Shenzhen Key Laboratory of Translational Medicine of Tumor, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.
Liang
L
Wang
Center for High Performance Computing, Shenzhen Institutes of Advanced Technology, Shenzhen, Guangdong, People's Republic of China.
Yanjie
Y
Wei
Shenzhen Key Laboratory of Micromolecule Innovatal Drugs, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.
Zhendan
Z
He
Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China.
Xinmin
X
Fan
Laboratory of Chemical Genomics, Shenzhen Graduate School of Peking University, Shenzhen, Guangdong, People's Republic of China.
Song
S
Li
Department of Pathology, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China; Shenzhen Key Laboratory of Micromolecule Innovatal Drugs, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China; Shenzhen Key Laboratory of Translational Medicine of Tumor, Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China. Electronic address: zhejin@szu.edu.cn.
Zhe
Z
Jin
Department of Medicine/GI Division and Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Stephen J
SJ
Meltzer
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009857:Oncogenes; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D060449:Wnt Signaling Pathway
C554846:MIRN194 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; C490764:SUFU protein, human
Gastric cancer; SUFU; Wnt/β-catenin signaling pathway; miRNA-194