RNA Binding Motif Protein 3 Promotes Cell Metastasis and Epithelial–Mesenchymal Transition Through STAT3 Signaling Pathway in Hepatocellular Carcinoma

Lu Zhang,1,* Yi Zhang,1,* Dongliang Shen,1 Ying Chen,1 Jianguo Feng,2 Xing Wang,1 Lunkun Ma,1 Yi Liao,3,4 Liling Tang1 1Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, People’s Republi...
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Lu Zhang,1,* Yi Zhang,1,* Dongliang Shen,1 Ying Chen,1 Jianguo Feng,2 Xing Wang,1 Lunkun Ma,1 Yi Liao,3,4 Liling Tang1 1Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, People’s Republic of China; 2Southwest Medical University, Department Anesthesiology, Affiliated Hospital, Luzhou, 646000, People’s Republic of China; 3The Central Laboratory, Shenzhen Second People’s Hospital/First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, 518035, People’s Republic of China; 4Department of Thoracic Surgery, Southwest Hospital, Army Medical University, Chongqing, 400038, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liling Tang; Yi Liao, Tel +86 139 9605 1730 ; +86 139 9656 6993, Fax +86-23-65111901 ; +86-23-68763333, Email tanglilingcqu.edu.cn; science0528@163.comPurpose: RNA binding motif protein 3 (RBM3) has been reported to be dysregulated in various cancers and associated with tumor aggressiveness. Epithelial–mesenchymal transition (EMT) is an important biological process by which tumor cells acquire metastatic abilities. This study aimed to explore the regulatory and molecular mechanisms of RBM3 in EMT process.Methods: Western blotting, IHC, and qRT-PCR were performed to evaluate the expression of target genes. Transwell assay was used to investigate the migration and invasion. RNA immunoprecipitation and luciferase reporter assay were performed to explore the correlation of RBM3 with STAT3 or microRNA-383. Animal HCC models were used to explore the role of RBM3 in metastasis in vivo.Results: RBM3 was highly expressed in HCC tissues compared to healthy tissues, and its level was negatively correlated with the prognosis of HCC patients. RBM3 overexpression accelerated migration and invasion, promoted EMT process, and activated STAT3 signaling. EMT induced by RBM3 was not only attenuated by inhibiting pSTAT3 via S3I-201 but also abolished by suppressing STAT3 expression via siRNAs. Mechanistically, RBM3 increased STAT3 expression by stabilizing STAT3 mRNA via binding to its mRNA. As an upstream target of RBM3, microRNA-383 inhibited RBM3 expression by binding to its 3ʹUTR and resulted in the inhibition of the EMT process. Inhibition of RBM3 in HCC animal models prolonged survival and ameliorated malignant phenotypes in mice.Conclusion: Our findings support that RBM3 promotes HCC metastasis by activating STAT3 signaling.Keywords: RBM3, metastasis, EMT, STAT3, microRNA-383 Ausführliche Beschreibung