MicroRNA-144 inhibits the metastasis of gastric cancer by targeting MET expression.
Gastric cancer (GC) remains one of the most common types of malignant cancer, and the molecular mechanism underlying its metastasis is still largely unclear. MicroRNAs have emerged as important regulators of metastasis because of their ability to act on multiple signaling pathways. In our study, we found that miR-144 is significantly downregulated in both highly metastatic GC cell lines and tissues. Results from both gain-of-function and loss-of-function experiments demonstrate that increased miR-144 expression significantly reduced GC cell migration, whereas decreased miR-144 expression dramatically enhanced GC cell migration. The met proto-oncogene (MET), which is often amplified in human cancers and functions as an important regulator of cell growth and tumor invasion, was identified as a direct target of miR-144. Moreover, silencing of MET using small interfering RNA (siRNA) recapitulated the anti-metastatic function of miR-144, whereas restoring MET expression attenuated the function of miR-144 in GC cells. Furthermore, we found that miR-144, by targeting MET, suppresses phosphorylation of Akt. Finally, we observed an inverse correlation between the expression of miR-144 and MET mRNA in GC metastatic tissues. In summary, miR-144 suppresses GC progression by directly downregulating MET expression, which subsequently prevents activation of the pro-oncogenic Akt pathway. Reintroduction of miR-144 expression in GC cells presents an attractive therapeutic approach to block the metastasis of gastric cancer.
Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, PR China. liujun21cn@126.com.
Jun
J
Liu
Shanghai University of Traditional Chinese Medicine, School of Basic Medicine, institution of Neijing, Shanghai, 201203, China. xuehui1979@126.com.
Hui
H
Xue
Department of Oral and Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, PR China. zjjshuobo@163.com.
Jianjun
J
Zhang
Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, PR China. suo.tao@zs-hospital.sh.cn.
Tao
T
Suo
Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, PR China. qqdemi728@126.com.
Yijin
Y
Xiang
Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, PR China. zhang.wen1@zs-hospital.sh.cn.
Wen
W
Zhang
Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, PR China. majun86930@sina.com.cn.
Jun
J
Ma
Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, PR China. dingfangcai@163.com.
Dingfang
D
Cai
Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, PR China. guxixi@sina.com.
Xixi
X
Gu
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D016000:Cluster Analysis; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D034622:RNA Interference; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D059467:Transcriptome
C000715470:MAS1 protein, human; C554293:MIRN144 microRNA, human; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met