Dataset Information

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

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 ?6?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 ?6?1 to amplify the phosphoinositide-3-kinase (PI3K)/AKT/glycogen synthase kinase (GSK)-3?/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.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6280496 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Wang Yan Y Liang Yingjian Y Yang Guangchao G Lan Yaliang Y Han Jihua J Wang Jiabei J Yin Dalong D Song Ruipeng R Zheng Tongsen T Zhang Shugeng S Pan Shangha S Liu Xirui X Zhu Mingxi M Liu Yao Y Cui Yifeng Y Meng Fanzheng F Zhang Bo B Liang Shuhang S Guo Hongrui H Liu Yufeng Y Hassan Md Khaled MK Liu Lianxin L

Journal of experimental & clinical cancer research : CR 20181204 1

<h4>Background</h4>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.<h4>Methods</h4>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 wa ...[more]

PMID: 30514341

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Project description:BackgroundThe epithelial-mesenchymal transition (EMT) is crucial for metastasis and positively regulated by calcium-related signaling. The melastatin-related transient receptor potential 7 (TRPM7) regulates a non-selective cation channel and promotes cancer metastasis. However, the mechanisms underlying the action of TRPM7 in ovarian cancer are unclear.MethodsThe expression of TRPM7 and EMT markers (Vimentin, N-cadherin, Twist and E-cadherin) in ovarian cancer samples was detected. TRPM7was knockdown by shRNA in Ovarian cancer cell lines to examine calcium [Ca2+]i, EMT markers and PI3K/AKT markers. Various cellular assays, such as invasion and migration, were performed in vitro, and further confirmed in vivo.ResultsTRPM7 expression is negatively correlated with E-cadherin, but positively with N-cadherin, Vimentin and Twist expression in ovarian cancer samples. TRPM7 depletion inhibited the migration and invasion in SKOV3 and OVCAR3 cells. In addition, TRPM7 silencing decreased the lung metastasis of SKOV3 tumors and prolonged the survival of tumor-bearing mice. Similar to that of TRPM7 silencing, treatment with MK886, a potent 5-lipoxygenase inhibitor to reduce TRPM7 expression, and/or BAPTA-AM, an intracellular calcium chelator, significantly mitigated the Epidermal growth factor (EGF) or Insulin-like growth factors (IGF)-stimulated migration, invasion, and the EMT in ovarian cancer cells by decreasing the levels of intracellular calcium [Ca2+]i. Furthermore, treatment with LY2904002, a PI3K inhibitor, also inhibited the migration, invasion, and treatment with both LY2904002 and BAPTA-AM further enhanced their inhibition in ovarian cancer cells. Moreover, treatment with BAPTA-AM mitigated the IGF-stimulated migration, invasion, particularly in TRPM7-silenced ovarian cancer cells. Finally, TRPM7 silencing attenuated the PI3K/AKT activation, which was enhanced by BAPTA-AM, MK886 or LY2904002 treatment in ovarian cancer cells.ConclusionsTRPM7 silencing inhibited the EMT and metastasis of ovarian cancer by attenuating the calcium-related PI3k/AKT activation. Our findings suggest that TRPM7 may be a therapeutic target for intervention of ovarian cancer.

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

Similar Datasets

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