Journal
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
Volume 37, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s13046-018-0969-y
Keywords
Cholangiocarcinoma; Tetraspanin 1; Epithelial-to-mesenchymal transition; MicroRNA-194-5p; Integrin alpha 6 beta 1
Categories
Funding
- National Key Program for Science and Technology Research and Development [2016YFC0106503, 2016YFC0106500, 2016YFC0905902]
- Program for Innovative Research Team (in Science and Technology) in Higher Educational Institutions of Heilongjiang Province [2009td06]
- Changjiang Scholars and Innovative Research Team in University [IRT1122]
- National Natural Scientific Foundation of China [81602058, 81301807, 81772588, 81773194]
- Heilongjiang Province Nature Science Foundation [LC2013C31, H2018034]
- Innovative Research Program for Graduate of Harbin Medical University [YJSCX2016-18HYD]
- Wu Liande Science Foundation for Young Scholars of Harbin Medical University [WLD-QN1403]
- Heilongjiang Postdoctoral Fund [LBH-Z16100]
- First Affiliated Hospital of Harbin Medical University Doctoral Research Innovation Fund [2018B003]
- Heilongjiang Province Youth Innovating Talents Training Plan Fund for Regular Undergraduate Colleges [UNPYSCT-2017066]
- China Postdoctoral Science Foundation [2016 M590292, 2018 M631948, 2018 M630368]
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Background: 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. Methods: 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 alpha 6 beta 1 and western blot was used to explore TSPAN1 mechanism. Results: 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 alpha 6 beta 1 to amplify the phosphoinositide-3-kinase (PI3K)/AKT/glycogen synthase kinase (GSK)-3 beta/Snail family transcriptional repressor (Snail)/phosphatase and tensin homolog (PTEN) feedback loop. Conclusion: The results indicate that TSPAN1 could be a potential therapeutic target for CCA.
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