title: Connective tissue growth factor activates pluripotency genes and mesenchymal-epithelial transition in head and neck cancer cells.
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 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.
authors.affiliation: Graduate Institute of Oral Biology, Graduate Institute of Clinical Dentistry, School of Dentistry, Taipei, Taiwan.
authors.forename: Cheng-Chi
authors.initials: CC
authors.lastname: Chang
authors.forename: Wen-Hao
authors.initials: WH
authors.lastname: Hsu
authors.forename: Chen-Chien
authors.initials: CC
authors.lastname: Wang
authors.forename: Chun-Hung
authors.initials: CH
authors.lastname: Chou
authors.forename: Mark Yen-Ping
authors.initials: MY
authors.lastname: Kuo
authors.forename: Been-Ren
authors.initials: BR
authors.lastname: Lin
authors.forename: Szu-Ta
authors.initials: ST
authors.lastname: Chen
authors.forename: Shyh-Kuan
authors.initials: SK
authors.lastname: Tai
authors.forename: Min-Liang
authors.initials: ML
authors.lastname: Kuo
authors.forename: Muh-Hwa
authors.initials: MH
authors.lastname: Yang
mesh_terms: D000818:Animals; D001665:Binding Sites; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002465:Cell Movement; D055513:Connective Tissue Growth Factor / Q000502:physiology*; D018572:Disease-Free Survival; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008819:Mice, Nude; D000071317:Nanog Homeobox Protein; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D018874:Spheroids, Cellular / Q000378:metabolism; D015533:Transcriptional Activation; D059467:Transcriptome
chemical_list: D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D016755:Proto-Oncogene Proteins c-jun; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D055513:Connective Tissue Growth Factor