J Cancer 2018; 9(23):4449-4462. doi:10.7150/jca.25926

Research Paper

Tenascin-C Modulates Cell Cycle Progression to Enhance Tumour Cell Proliferation through AKT/FOXO1 Signalling in Pancreatic Cancer

Jun Cai1, Wenli Lu2, Shaoxia Du1, Zhongkui Guo1, Hui Wang1, Wei Wei3, Xiaohong Shen1✉

1. School of medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China.
2. Department of Health Statistics, School of Public Health, Tianjin Medical University, Tianjin 300000, China.
3. Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Huanhu West Road, Tianjin 300060, China.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a disease with an extremely poor prognosis that is characterized by a rich extracellular matrix (ECM). Tenascin-C (TNC) is a component of the ECM and plays a role in tumour progression. In this study, we reported that TNC is overexpressed in PDAC tissues and is correlated with tumour stage and cyclin D1 expression. Cyclin D1 is key regulator of the cell cycle G1/S transition. Further experiments revealed that TNC promotes G1/S transition through AKT signalling. TNC/AKT increases the expression of cyclin D1 by enhancing the transcriptional activity of β-catenin, whereas the translocation of FOXO1 from the nucleus results in the downregulation of p27Kip1. Cyclin D1 and p27Kip1 regulate the activity of cyclin D1-CDK4 complexes and retinoblastoma (Rb), and then they stimulate the progression of G1/S transition and tumour cell proliferation. In conclusion, TNC exerts its activating effect on the proliferation of pancreatic cancer cells in vitro and in vivo through its functional target AKT/FOXO1/β-catenin. The molecular mechanisms that drive PDAC progression will be useful for the development of molecular markers and the evaluation of patient prognosis.

Keywords: TNC, FOXO1, cell cycle, pancreatic cancer, proliferation

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How to cite this article:
Cai J, Lu W, Du S, Guo Z, Wang H, Wei W, Shen X. Tenascin-C Modulates Cell Cycle Progression to Enhance Tumour Cell Proliferation through AKT/FOXO1 Signalling in Pancreatic Cancer. J Cancer 2018; 9(23):4449-4462. doi:10.7150/jca.25926. Available from http://www.jcancer.org/v09p4449.htm