Tetraspanin 1 promotes epithelial-to-mesenchymal transition and metastasis of cholangiocarcinoma via PI3K/AKT signaling

• Published in: Journal of experimental & clinical cancer research 2018-12, Vol.37 (1), p.300-300, Article 300
• Main Authors: Wang, Yan, Liang, Yingjian, Yang, Guangchao, Lan, Yaliang, Han, Jihua, Wang, Jiabei, Yin, Dalong, Song, Ruipeng, Zheng, Tongsen, Zhang, Shugeng, Pan, Shangha, Liu, Xirui, Zhu, Mingxi, Liu, Yao, Cui, Yifeng, Meng, Fanzheng, Zhang, Bo, Liang, Shuhang, Guo, Hongrui, Liu, Yufeng, Hassan, Md Khaled, Liu, Lianxin
• Format: Article
• Language: English
• Subjects: Animals; Bile Duct Neoplasms - genetics; Bile Duct Neoplasms - metabolism; Bile Duct Neoplasms - pathology; Biomarkers; Cancer; Cell adhesion & migration; Cell Line, Tumor; Cholangiocarcinoma; Cholangiocarcinoma - genetics; Cholangiocarcinoma - metabolism; Cholangiocarcinoma - pathology; Epithelial-Mesenchymal Transition; Epithelial-to-mesenchymal transition; Feedback; Gene expression; Heterografts; Humans; Integrin α6β1; Kinases; Leukemia; Male; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNA-194-5p; MicroRNAs; MicroRNAs - metabolism; Middle Aged; Motility; Neoplasm Metastasis; Phosphatase; Phosphatidylinositol 3-Kinases - metabolism; Proteins; Proto-Oncogene Proteins c-akt - metabolism; PTEN Phosphohydrolase - metabolism; Signal Transduction; Snail Family Transcription Factors - metabolism; Studies; Tetraspanin 1; Tetraspanins - metabolism; Transfection
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-018-0969-y

Numerous studies have demonstrated that tetraspanin 1 (TSPAN1), a transmembrane protein, functions as an oncoprotein in many cancer types. However, its role and underlying molecular mechanism in cholangiocarcinoma (CCA) progression remain unclear. In the present study, the expression of TSPAN1 in human CCA and adjacent nontumor tissues was examined using real-time PCR, western blot and immunohistochemistry. The effect of TSPAN1 on proliferation and metastasis was evaluated by functional assays both in vitro and in vivo. A luciferase reporter assay was performed to investigate the interaction between microRNA-194-5p (miR-194-5p) and TSPAN1 3'-untranslated region. Co-immunoprecipitation (co-IP) was used to confirm the interaction between TSPAN1 protein and integrin α6β1 and western blot was used to explore TSPAN1 mechanism. We found that TSPAN1 was frequently upregulated in CCA and high levels of TSPAN1 correlated with TNM stage, especially metastasis in CCA. TSPAN1 overexpression promoted CCA growth, metastasis, and induced epithelial-to-mesenchymal transition (EMT), while its silencing had the opposite effect both in vitro and in vivo. To explore the differential expression of TSPAN1, we screened miR-194-5p as the upstream regulator of TSPAN1. A combination of high-level TSPAN1 and low-level miR-194-5p predicted poor prognosis in patients with CCA. Furthermore, in accordance with the functional characteristics of the TSPAN superfamily, we proved that TSPAN1 interacted with integrin α6β1 to amplify the phosphoinositide-3-kinase (PI3K)/AKT/glycogen synthase kinase (GSK)-3β/Snail family transcriptional repressor (Snail)/phosphatase and tensin homolog (PTEN) feedback loop. The results indicate that TSPAN1 could be a potential therapeutic target for CCA.