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

  • J Exp Clin Cancer Res. 2018 Dec 4;37(1):300. doi: 10.1186/s13046-018-0969-y.
Yan Wang  1 ,  Yingjian Liang  1 ,  Guangchao Yang  1 ,  Yaliang Lan  1 ,  Jihua Han  1 ,  Jiabei Wang  1 ,  Dalong Yin  1 ,  Ruipeng Song  1 ,  Tongsen Zheng  2 ,  Shugeng Zhang  1 ,  Shangha Pan  1 ,  Xirui Liu  1 ,  Mingxi Zhu  1 ,  Yao Liu  1 ,  Yifeng Cui  1 ,  Fanzheng Meng  1 ,  Bo Zhang  1 ,  Shuhang Liang  1 ,  Hongrui Guo  1 ,  Yufeng Liu  1 ,  Md Khaled Hassan  1 ,  Lianxin Liu  3  4
Affiliations
  • 1. Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, Heilongjiang, China.
  • 2. Department of Gastrointestinal Medical Oncology, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
  • 3. Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, Heilongjiang, China. [email protected].
  • 4. Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China. [email protected].
PMID: 30514341 DOI: 10.1186/s13046-018-0969-y
Abstract

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 α6β1 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 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.

Conclusion: The results indicate that TSPAN1 could be a potential therapeutic target for CCA.

Keywords
Cholangiocarcinoma; Epithelial-to-mesenchymal transition; Integrin α6β1; MicroRNA-194-5p; Tetraspanin 1.
Products