Connective Tissue Growth Factor Activates Pluripotency Genes and Mesenchymal-Epithelial Transition in Head and Neck Cancer Cells
Resource
Cancer Res., 73(13), 4147-4157
Journal
Cancer Res.
Journal Volume
73
Journal Issue
13
Pages
4147-4157
Date Issued
2013
Date
2013
Author(s)
Chang, Cheng-Chi
Hsu, Wen-Hao
Wang, Chen-Chien
Chou, Chun-Hung
Kuo, Mark Yen-Ping
Lin, Been-Ren
Chen, Szu-Ta
Tai, Shyh-Kuan
Kuo, Min-Liang
Yang, Muh-Hwa
Abstract
The epithelial-mesenchymal transition (EMT) is a key mechanism in both embryonic development and cancer metastasis. The EMT introduces stem-like properties to cancer cells. However, during somatic cell reprogramming, mesenchymal-epithelial transition (MET), the reverse process of EMT, is a crucial step toward pluripotency. Connective tissue growth factor (CTGF) is a multifunctional secreted protein that acts as either an oncoprotein or a tumor suppressor among different cancers. Here, we show that in head and neck squamous cell carcinoma (HNSCC), CTGF promotes the MET and reduces invasiveness. Moreover, we found that CTGF enhances the stem-like properties of HNSCC cells and increases the expression of multiple pluripotency genes. Mechanistic studies showed that CTGF induces c-Jun expression through alpha v beta 3 integrin and that c-Jun directly activates the transcription of the pluripotency genes NANOG, SOX2, and POU5F1. Knockdown of CTGF in TW2.6 cells was shown to reduce tumor formation and attenuate E-cadherin expression in xenotransplanted tumors. In HNSCC patient samples, CTGF expression was positively correlated with the levels of CDH1, NANOG, SOX2, and POU5F1. Coexpression of CTGF and the pluripotency genes was found to be associated with a worse prognosis. These findings are valuable in elucidating the interplay between epithelial plasticity and stem-like properties during cancer progression and provide useful information for developing a novel classification system and therapeutic strategies for HNSCC. (C) 2013 AACR.
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