Integrin β6 acts as an unfavorable prognostic indicator and promotes cellular malignant behaviors via ERK-ETS1 pathway in pancreatic ductal adenocarcinoma (PDAC)
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Pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadly cancers and is expected to become the second leading cause of cancer death by 2030. Despite extensive efforts to improve surgical treatment, limited progress has been made. Increasing evidence indicates that integrin β6 plays a crucial role in carcinoma invasion and metastasis. However, the expression and role of β6 in PDAC remain largely unknown. In the present study, we investigated the expression of β6 in PDAC and its potential value as a prognostic factor and therapeutic target. β6 upregulation was identified as an independent unfavorable prognostic indicator. Integrin β6 markedly promoted the proliferation and invasion of pancreatic carcinoma cells and induced ETS1 phosphorylation in an ERK-dependent manner, leading to the upregulation of matrix metalloprotease-9, which is essential for β6-mediated invasiveness of pancreatic carcinoma cells. Accordingly, small interfering RNA-mediated silencing of integrin β6 markedly suppressed xenograft tumor growth in vivo. Taken together, our results suggest that integrin β6 plays important roles in the progression of pancreatic carcinoma and contributes to reduced survival times, and may serve as a novel therapeutic target for the treatment of PDAC.
KeywordsIntegrin β6 PDAC Prognostic indicator Invasiveness ETS1
This study is supported by National Natural Science Foundation of China (no. 81272653) and by Natural Science Foundation of Shandong Province (no. ZR2015HM071). The authors thank Biogen Idec for the special antibodies and Professor Hui Wang for the assistance in statistical analysis.
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Conflicts of interest
- 3.Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913–21. doi: 10.1158/0008-5472.CAN-14-0155.CrossRefPubMedGoogle Scholar
- 19.Bates RC, Bellovin DI, Brown C, Maynard E, Wu B, Kawakatsu H, et al. Transcriptional activation of integrin beta6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma. J Clin Invest. 2005;115(2):339–47. doi: 10.1172/JCI23183.CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Defilles C, Lissitzky JC, Montero MP, Andre F, Prevot C, Delamarre E, et al. alphavbeta5/beta6 integrin suppression leads to a stimulation of alpha2beta1 dependent cell migration resistant to PI3K/Akt inhibition. Exp Cell Res. 2009;315(11):1840–9. doi: 10.1016/j.yexcr.2009.03.014.CrossRefPubMedGoogle Scholar
- 30.Sipos B, Hahn D, Carceller A, Piulats J, Hedderich J, Kalthoff H, et al. Immunohistochemical screening for beta6-integrin subunit expression in adenocarcinomas using a novel monoclonal antibody reveals strong up-regulation in pancreatic ductal adenocarcinomas in vivo and in vitro. Histopathology. 2004;45(3):226–36. doi: 10.1111/j.1365-2559.2004.01919.x.CrossRefPubMedGoogle Scholar