Abstract
BackgroundNumerous 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.MethodsIn 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.ResultsWe 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.ConclusionThe results indicate that TSPAN1 could be a potential therapeutic target for CCA.
Highlights
Numerous studies have demonstrated that tetraspanin 1 (TSPAN1), a transmembrane protein, functions as an oncoprotein in many cancer types
Tetraspanin 1 (TSPAN1) is frequently upregulated in human CCA QRT-PCR results showed that TSPAN1 mRNA was increased in human CCA tissues (n = 60) compared with that in the liver (n = 40, p < 0.0001) and bile duct samples (n = 10, p = 0.0005, Fig. 1a)
IHC analysis was used to determine that TSPAN1 expression showed strong staining in CCA tissues with a total positive proportion of 70% (42/60), which was higher than the 13.3% (4/30) observed in the liver and 20% (6/30) in normal bile duct samples (Fig. 1c)
Summary
Numerous studies have demonstrated that tetraspanin 1 (TSPAN1), a transmembrane protein, functions as an oncoprotein in many cancer types. TSPAN1 was reported to accelerate many kinds of cancer progression, especially digestive malignancies such as hepatocellular carcinoma (HCC), pancreatic, gastric, colorectal, and esophageal cancers [3,4,5,6,7], and some other non-digestive cancers such as osteosarcoma and cervical cancer [8, 9]. In these studies, TSPAN1 was treated as an oncogene promoting cancer process. Subrungruanga et al [10] conducted a whole-transcript expression array study using microarray profiling of 15 pairs of intrahepatic CCA tumors and corresponding normal liver tissue samples, and TSPAN1 was one of the 42 upregulated genes in intrahepatic CCA
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