Connective Tissue Growth Factor Activates Pluripotency Genes and Mesenchymal–Epithelial Transition in Head and Neck Cancer Cells

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 13; pp. 4147 - 4157
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.07.2013
• Subjects: Animals; Antineoplastic agents; Binding Sites; Biological and medical sciences; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - mortality; Carcinoma, Squamous Cell - pathology; Cell Movement; Connective Tissue Growth Factor - physiology; Disease-Free Survival; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - mortality; Head and Neck Neoplasms - pathology; HEK293 Cells; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Kaplan-Meier Estimate; Medical sciences; Mice; Mice, Nude; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nanog Homeobox Protein; Neoplasm Invasiveness; Neoplasm Transplantation; Neoplastic Stem Cells - metabolism; Octamer Transcription Factor-3 - genetics; Octamer Transcription Factor-3 - metabolism; Oligonucleotide Array Sequence Analysis; Otorhinolaryngology (head neck, general aspects and miscellaneous); Otorhinolaryngology. Stomatology; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-jun - metabolism; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; Spheroids, Cellular - metabolism; Transcriptional Activation; Transcriptome; Tumors; Gene; ENT disease; Head and neck cancer; Connective tissue growth factor; Genetics; Malignant tumor; Epithelial mesenchymal transition; Cell transformation; Cell; In vitro; Pluripotency; Cancer
• DOI: 10.1158/0008-5472.CAN-12-4085
• ISSN: 0008-5472; 1538-7445

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 αvβ3 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. Cancer Res; 73(13); 4147–57. ©2013 AACR.