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Cytoskeletal alteration modulates cancer cell invasion through RhoA-YAP signaling in stromal fibroblasts

 Do Kyeong Kim  ;  Eun Kyoung Kim  ;  Da-Woon Jung  ;  Jin Kim 
 PLOS ONE, Vol.14(3) : e0214553, 2019-03 
Journal Title
Issue Date
Adaptor Proteins, Signal Transducing / metabolism* ; Cancer-Associated Fibroblasts / pathology* ; Carcinoma, Squamous Cell / pathology ; Cell Line, Tumor ; Coculture Techniques ; Cytoskeleton / metabolism* ; Cytoskeleton / pathology ; Gene Expression Regulation, Neoplastic ; Humans ; Mouth Neoplasms / pathology ; Neoplasm Invasiveness ; Signal Transduction* ; Transcription Factors / metabolism* ; YAP-Signaling Proteins ; rhoA GTP-Binding Protein / metabolism*
Cancer-associated fibroblasts(CAFs) participate in carcinogenesis through interaction with cancer cells. This study aimed to investigate the mechanism of cytoskeletal alteration of CAFs and its role in invasion of oral squamous cell carcinoma(OSCC),Immortalized normal fibroblasts(hTERT-hNOFs) co-cultured with OSCC cells showed myofibroblastic and senescent phenotypes like CAFs. Thus, this study substituted hTERT-hNOFs for CAFs. Next, the cytoskeletal alteration and its molecular mechanism were investigated in hTERT-hNOFs co-cultured with OSCC. As results, we found that RhoA regulated cytoskeletal organization in fibroblasts surrounding OSCC cells. Furthermore, as a downstream transcriptional factor of RhoA, YAP was mainly localized in the nucleus of hTERT-hNOFs co-cultured with OSCC. Consequently, we examined whether nuclear YAP localization of fibroblasts could influence cancer progression. YAPS127A fibroblasts manifesting nuclear localization of YAP induced cytoskeletal alteration and increased gel contractility and matrix stiffness, and thereby enhances the invasiveness of OSCC cells. In conclusion, the modification of tumor microenvironment, such as cytoskeletal change and matrix remodeling via RhoA-YAP in CAFs, modulates OSCC invasion. These understandings will provide the development of novel approaches for CAFs-based cancer therapy.
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2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jin(김진)
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