Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

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

Authors: Yan Wang, Yingjian Liang, Guangchao Yang, Yaliang Lan, Jihua Han, Jiabei Wang, Dalong Yin, Ruipeng Song, Tongsen Zheng, Shugeng Zhang, Shangha Pan, Xirui Liu, Mingxi Zhu, Yao Liu, Yifeng Cui, Fanzheng Meng, Bo Zhang, Shuhang Liang, Hongrui Guo, Yufeng Liu, Md Khaled Hassan, Lianxin Liu

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
2.
Detchokul S, Williams ED, Parker MW, Frauman AG. Tetraspanins as regulators of the tumour microenvironment: implications for metastasis and therapeutic strategies. Br J Pharmacol. 2014;171:5462–90.CrossRefPubMedPubMedCentral
3.
Wang GL, Chen L, Wei YZ, Zhou JM, Wu YY, Zhang YX, et al. The effect of NET-1 on the proliferation, migration and endocytosis of the SMMC-7721 HCC cell line. Oncol Rep. 2012;27:1944–52.PubMed
4.
Hou FQ, Lei XF, Yao JL, Wang YJ, Zhang W. Tetraspanin 1 is involved in survival, proliferation and carcinogenesis of pancreatic cancer. Oncol Rep. 2015;34:3068–76.CrossRefPubMed
5.
Lu Z, Luo T, Nie M, Pang T, Zhang X, Shen X, et al. TSPAN1 functions as an oncogene in gastric cancer and is downregulated by miR-573. FEBS Lett. 2015;589:1988–94.CrossRefPubMed
6.
Zhang J, Fei B, Wang Q, Song M, Yin Y, Zhang B, et al. MicroRNA-638 inhibits cell proliferation, invasion and regulates cell cycle by targeting tetraspanin 1 in human colorectal carcinoma. Oncotarget. 2014;5:12083–96.PubMedPubMedCentral
7.
Gu T, Chen W, Chen L, Wang G, Li T, Zhu Y, et al. Expression and function of tetraspanin 1 in esophageal carcinoma. Oncol Lett. 2017;14:6815–22.PubMedPubMedCentral
8.
Duan J, Liu J, Liu Y, Huang B, Rao L. miR-491–3p suppresses the growth and invasion of osteosarcoma cells by targeting TSPAN1. Mol Med Rep. 2017;16:5568–74.CrossRefPubMed
9.
Hölters S, Anacker J, Jansen L, Beer-Grondke K, Dürst M, Rubio I. Tetraspanin 1 promotes invasiveness of cervical cancer cells. Int J Oncol. 2013;43:503–12.CrossRefPubMed
10.
Subrungruanga I, Thawornkunob C, Chawalitchewinkoon-Petmitrc P, Pairojkul C, Wongkham S, Petmitrb S, et al. Gene expression profiling of intrahepatic cholangiocarcinoma. Asian Pac J Cancer Prev. 2013;14:557–63.CrossRefPubMed
11.
Chen Y, Gao DY, Huang L. In vivo delivery of miRNAs for cancer therapy: challenges and strategies. Adv Drug Deliv Rev. 2015;81:128–41.CrossRefPubMed
12.
Kong Q, Zhang S, Liang C, Zhang Y, Kong Q, Chen S, et al. LncRNA XIST functions as a molecular sponge of miR-194-5p to regulate MAPK1 expression in hepatocellular carcinoma cell. J Cell Biochem. 2018;119:4458–68.CrossRefPubMed
13.
Wang SH, Wu XC, Zhang MD, Weng MZ, Zhou D, Quan ZW. Long noncoding RNA H19 contributes to gallbladder cancer cell proliferation by modulated miR-194-5p targeting AKT2. Tumour Biol. 2016;37:9721–30.CrossRefPubMed
14.
15.
Su R, Cao S, Ma J, Liu Y, Liu X, Zheng J, et al. Knockdown of SOX2OT inhibits the malignant biological behaviors of glioblastoma stem cells via up-regulating the expression of miR-194-5p and miR-122. Mol Cancer. 2017;16:171.
16.
Dell’Aversana C, Giorgio C, D’Amato L, Lania G, Matarese F, Saeed S, et al. miR-194-5p/BCLAF1 deregulation in AML tumorigenesis. Leukemia. 2017;31:2315–25.CrossRefPubMedPubMedCentral
17.
Qian Y, Yao W, Yang T, Yang Y, Liu Y, Shen Q, et al. aPKC-ι/P-Sp1/snail signaling induces epithelial-mesenchymal transition and immunosuppression in cholangiocarcinoma. Hepatology. 2017;66:1165–82.CrossRefPubMed
18.
Yang LX, Gao Q, Shi JY, Wang ZC, Zhang Y, Gao PT, et al. Mitogen-activated protein kinase kinase kinase 4 deficiency in intrahepatic cholangiocarcinoma leads to invasive growth and epithelial-mesenchymal transition. Hepatology. 2015;62:1804–16.CrossRefPubMed
19.
20.
Gahmberg CG, Fagerholm SC, Nurmi SM, Chavakis T, Marchesan S, Grönholm M. Regulation of integrin activity and signalling. Biochim Biophys Acta. 2009;1790:431–44.CrossRefPubMedPubMedCentral
21.
Wang J, Xie C, Pan S, Liang Y, Han J, Lan Y, et al. N-myc downstream-regulated gene 2 inhibits human cholangiocarcinoma progression and is regulated by leukemia inhibitory factor/MicroRNA-181c negative feedback pathway. Hepatology. 2016;64:1606–22.CrossRefPubMed
22.
Utispan K, Sonongbua J, Thuwajit P, Chau-In S, Pairojkul C, Wongkham S, et al. Periostin activates integrin α5β1 through a PI3K/AKT-dependent pathway in invasion of cholangiocarcinoma. Int J Oncol. 2012;41:1110–8.CrossRefPubMed
23.
Ding YB, Deng B, Huang YS, Xiao WM, Wu J, Zhang YQ, et al. A high level of integrin α6 expression in human intrahepatic cholangiocarcinoma cells is associated with a migratory and invasive phenotype. Dig Dis Sci. 2013;58:1627–35.CrossRefPubMed
24.
Patsenker E, Wilkens L, Banz V, Osterreicher CH, Weimann R, Eisele S, et al. The alphavbeta6 integrin is a highly specific immunohistochemical marker for cholangiocarcinoma. J Hepatol. 2010;52:362–9.CrossRefPubMed
25.
Seguin L, Desgrosellier JS, Weis SM, Cheresh DA. Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol. 2015;25:234–40.CrossRefPubMedPubMedCentral
26.
Ke AW, Shi GM, Zhou J, Huang XY, Shi YH, Ding ZB, et al. CD151 amplifies signaling by integrin α6β1 to PI3K and induces the epithelial-mesenchymal transition in HCC cells. Gastroenterology. 2011;140:1629–41.CrossRefPubMed
27.
Nishiuchi R, Takagi J, Hayashi M, Ido H, Yagi Y, Sanzen N, et al. Ligand-binding specificities of laminin-binding integrins: a comprehensive survey of laminin-integrin interactions using recombinant alpha3beta1, alpha6beta1, alpha7beta1 and alpha6beta4 integrins. Matrix Biol. 2006;25:189–97.CrossRefPubMed
28.
Julien S, Puig I, Caretti E, Bonaventure J, Nelles L, van Roy F, et al. Activation of NF-kappaB by Akt upregulates snail expression and induces epithelium mesenchyme transition. Oncogene. 2007;26:7445–56.CrossRefPubMed
29.
Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, et al. Dual regulation of snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol. 2004;6:931–40.CrossRefPubMed
30.
Escrivà M, Peiró S, Herranz N, Villagrasa P, Dave N, Montserrat-Sentís B, et al. Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis. Mol Cell Biol. 2008;28:1528–40.CrossRefPubMedPubMedCentral
31.
Todd SC, Doctor VS, Levy S. Sequences and expression of six new members of the tetraspanin/TM4SF family. Biochim Biophys Acta. 1998;1399:101–4.CrossRefPubMed
32.
33.
Nitta T, Mitsuhashi T, Hatanaka Y, Miyamoto M, Oba K, Tsuchikawa T, et al. Prognostic significance of epithelial-mesenchymal transition-related markers in extrahepatic cholangiocarcinoma: comprehensive immunohistochemical study using a tissue microarray. Br J Cancer. 2014;111:1363–72.CrossRefPubMedPubMedCentral
34.
35.
Berditchevski F. Complexes of tetraspanins with integrins: more than meets the eye. J Cell Sci. 2001;114:4143–51.PubMed
36.
Herlevsen M, Schmidt DS, Miyazaki K, Zöller M. The association of the tetraspanin D6.1A with the alpha6beta4 integrin supports cell motility and liver metastasis formation. J Cell Sci. 2003;116:4373–90.CrossRefPubMed
Metadata
Title
Tetraspanin 1 promotes epithelial-to-mesenchymal transition and metastasis of cholangiocarcinoma via PI3K/AKT signaling
Authors
Yan Wang
Yingjian Liang
Guangchao Yang
Yaliang Lan
Jihua Han
Jiabei Wang
Dalong Yin
Ruipeng Song
Tongsen Zheng
Shugeng Zhang
Shangha Pan
Xirui Liu
Mingxi Zhu
Yao Liu
Yifeng Cui
Fanzheng Meng
Bo Zhang
Shuhang Liang
Hongrui Guo
Yufeng Liu
Md Khaled Hassan
Lianxin Liu
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0969-y

Other articles of this Issue 1/2018

Journal of Experimental & Clinical Cancer Research 1/2018 Go to the issue

Research

Integrated genomic analyses in PDX model reveal a cyclin-dependent kinase inhibitor Palbociclib as a novel candidate drug for nasopharyngeal carcinoma

Review

Pancreatic cancer associated with obesity and diabetes: an alternative approach for its targeting

Research

The effects of ultrasound exposure on P-glycoprotein-mediated multidrug resistance in vitro and in vivo

Research

Acidic microenvironment plays a key role in human melanoma progression through a sustained exosome mediated transfer of clinically relevant metastatic molecules

Research

Hippo component YAP promotes focal adhesion and tumour aggressiveness via transcriptionally activating THBS1/FAK signalling in breast cancer

Research

Epigenetic reprogramming of epithelial mesenchymal transition in triple negative breast cancer cells with DNA methyltransferase and histone deacetylase inhibitors
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits