title: Activation of PAX3-MET pathways due to miR-206 loss promotes gastric cancer metastasis.
abstract: MicroRNAs (miRNAs) are thought to have an important role in tumor metastasis by regulating diverse cellular pathways. Here, we describe the function and regulation network of miR-206 in gastric cancer (GC) metastasis. MiR-206 expression was downregulated in GC cells especially in high metastatic potential cells and was also significantly decreased in metastatic lesions compared with their corresponding primary tumor samples. Both gain- and loss-of-function studies confirmed that miR-206 significantly suppressed GC cell invasion and metastasis both in vitro and in vivo. Mechanistically, paired box gene 3 (PAX3) was identified as a functional target of miR-206 in GC cells. MiR-206 inhibited GC metastasis by negatively regulating expression of PAX3. In addition, PAX3 expression was markedly higher in GC tissues than in adjacent non-cancerous tissues. GC patients with positive PAX3 expression had shorter overall survival times. Transwell assays and in vivo metastasis assays demonstrated that overexpression of PAX3 significantly promoted the invasiveness and pulmonary metastasis of GC cells. On the other hand, downregulation of PAX3 markedly reduced cell metastatic potential. Mechanistic investigations indicated that prometastasis function of PAX3 was mediated by upregulating downstream target MET. Moreover, we found that levels of PAX3 and MET were positively correlated in matched human GC specimens, and their coexpression was associated with poor prognoses. In conclusion, our results reveal that miR-206-PAX3-MET signaling is critical to GC metastasis. Targeting the pathway described here may open new therapeutic prospects to restrict the metastatic potential of GC.
authors: State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 17 Changle Western Road, Xi'an, Shaanxi Province 710032, People's Republic of China, Medical Clinic of The Chinese People's Liberation Army General Political Department, 21 North Andeli Road, Beijing 100120, People's Republic of China.
authors: Lin
authors: L
authors: Zhang
authors: State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 17 Changle Western Road, Xi'an, Shaanxi Province 710032, People's Republic of China.
authors: Limin
authors: L
authors: Xia
authors: Department of Radiation Oncology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 17 Changle Western Road, Xi'an, Shaanxi Province 710032, People's Republic of China and.
authors: Lina
authors: L
authors: Zhao
authors: State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 17 Changle Western Road, Xi'an, Shaanxi Province 710032, People's Republic of China.
authors: Zhangqian
authors: Z
authors: Chen
authors: State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 17 Changle Western Road, Xi'an, Shaanxi Province 710032, People's Republic of China.
authors: Xin
authors: X
authors: Shang
authors: Engineering Research Center of Molecular and Neuro Imaging of Ministry of Education, School of Life Science and Technology, Xidian University, 2 South Taibai Road, Xi'an, Shaanxi Province 710071, People's Republic of China.
authors: Jing
authors: J
authors: Xin
authors: Engineering Research Center of Molecular and Neuro Imaging of Ministry of Education, School of Life Science and Technology, Xidian University, 2 South Taibai Road, Xi'an, Shaanxi Province 710071, People's Republic of China.
authors: Muhan
authors: M
authors: Liu
authors: State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 17 Changle Western Road, Xi'an, Shaanxi Province 710032, People's Republic of China.
authors: Xuegang
authors: X
authors: Guo
authors: State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 17 Changle Western Road, Xi'an, Shaanxi Province 710032, People's Republic of China.
authors: Kaichun
authors: K
authors: Wu
authors: State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 17 Changle Western Road, Xi'an, Shaanxi Province 710032, People's Republic of China, daimingfan@fmmu.edu.cn panyanglin1@gmail.com.
authors: Yanglin
authors: Y
authors: Pan
authors: State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 17 Changle Western Road, Xi'an, Shaanxi Province 710032, People's Republic of China, daimingfan@fmmu.edu.cn.
authors: Daiming
authors: D
authors: Fan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*
chemical_list: C546087:MIRN206 microRNA, human; D035683:MicroRNAs; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met