title: SRF expedites metastasis and modulates the epithelial to mesenchymal transition by regulating miR-199a-5p expression in human gastric cancer.
abstract: Dysregulation of transcription factors (TFs) is associated with tumor progression, but little is known about TF expression patterns in the context of gastric cancer (GC) metastasis. Using array-based profile analysis, we found that 22 TFs showed differential activities between GC cell lines with low- and high-metastatic potential. Of this group of TFs, serum response factor (SRF) was significantly upregulated in metastatic GC cells. SRF expression was frequently elevated in a panel of metastatic GC cells and tissues, and high-level expression of SRF was significantly associated with a more aggressive phenotype and poor prognosis in patients with GC. In GC cell lines, overexpression of SRF potently promoted cell migration and invasion in vitro as well as the formation of intrahepatic and pulmonary metastases in vivo, whereas loss of SRF inhibited GC cell invasion and metastasis. We also performed a microRNA microarray to screen for transcriptional targets of SRF and found that SRF transactivates miR-199a-5p and miR-199a-3p by directly binding to their promoters. We further determined that overexpression of miR-199a-5p, but not miR-199a-3p, increased GC cell invasion and metastasis. In contrast, inhibition of miR-199a-5p impaired the metastatic potential of GC cells in vitro and in vivo, and E-cadherin was identified as a direct and functional target of miR-199a-5p in GC cells. Specifically, our results showed that SRF promotes GC metastasis and the epithelial to mesenchymal transition (EMT) though miR-199a-5p-mediated downregulation of E-cadherin. The present study thus provides insight into the specific biological behavior of SRF in GC metastasis. As increased activity of the SRF/miR-199a-5p/E-cadherin pathway appears to promote GC cell EMT and metastasis, these regulators may therefore be developed as therapeutic targets or biomarkers for GC progression.
authors: State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital of Digestive Diseases, the Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: X
authors: X
authors: Zhao
authors: 1] State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital of Digestive Diseases, the Fourth Military Medical University, Xi'an, Shaanxi, China [2] Department of Nephrology, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: L
authors: L
authors: He
authors: State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital of Digestive Diseases, the Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: T
authors: T
authors: Li
authors: State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital of Digestive Diseases, the Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: Y
authors: Y
authors: Lu
authors: 1] State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital of Digestive Diseases, the Fourth Military Medical University, Xi'an, Shaanxi, China [2] Department of Gastroenterology, the People's Hospital of Ningxia Hui Nationality Autonomous Region, Yinchuan, Ningxia Hui Autonomous Region, China.
authors: Y
authors: Y
authors: Miao
authors: State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital of Digestive Diseases, the Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: S
authors: S
authors: Liang
authors: State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital of Digestive Diseases, the Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: H
authors: H
authors: Guo
authors: State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital of Digestive Diseases, the Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: M
authors: M
authors: Bai
authors: State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital of Digestive Diseases, the Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: H
authors: H
authors: Xie
authors: State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital of Digestive Diseases, the Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: G
authors: G
authors: Luo
authors: State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital of Digestive Diseases, the Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: L
authors: L
authors: Zhou
authors: State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital of Digestive Diseases, the Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: G
authors: G
authors: Shen
authors: State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital of Digestive Diseases, the Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: C
authors: C
authors: Guo
authors: Department of Gastroenterology, the People's Hospital of Ningxia Hui Nationality Autonomous Region, Yinchuan, Ningxia Hui Autonomous Region, China.
authors: F
authors: F
authors: Bai
authors: Department of Nephrology, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: S
authors: S
authors: Sun
authors: State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital of Digestive Diseases, the Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: K
authors: K
authors: Wu
authors: State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital of Digestive Diseases, the Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: Y
authors: Y
authors: Nie
authors: State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital of Digestive Diseases, the Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: D
authors: D
authors: Fan
mesh_terms: D015703:Antigens, CD; D001483:Base Sequence; D001665:Binding Sites; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D026362:Serum Response Factor / Q000502:physiology*; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D059467:Transcriptome; D060449:Wnt Signaling Pathway
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D035683:MicroRNAs; C476858:SRF protein, human; D026362:Serum Response Factor; C531408:mirn199 microRNA, human