Hyaluronic acid enhances cell migration and invasion via the YAP1/TAZ-RHAMM axis in malignant pleural mesothelioma

// Wataru Shigeeda 1, 3 , Masahiko Shibazaki 1 , Shinji Yasuhira 1 , Tomoyuki Masuda 2 , Tatsuo Tanita 3 , Yuka Kaneko 1 , Tatsuhiro Sato 4 , Yoshitaka Sekido 4 and Chihaya Maesawa 1 1 Department of Tumor Biology, Institute of Biomedical Science, Iwate Medical University, Iwate, Japan 2 Department of Pathology, School of Medicine, Iwate Medical University, Iwate, Japan 3 Department of Thoracic Surgery, School of Medicine, Iwate Medical University, Iwate, Japan 4 Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan Correspondence to: Masahiko Shibazaki, email: mashiba@iwate-med.ac.jp Keywords: invasion, migration, mesothelioma, RHAMM, YAP1/TAZ Received: April 07, 2017      Accepted: July 29, 2017      Published: September 08, 2017 ABSTRACT Most malignant mesotheliomas (MPMs) frequently show activated forms of Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ), which transcriptionally regulates the receptor for hyaluronic acid-mediated motility (RHAMM). As RHAMM is involved in cell migration and invasion in various tumors, we speculated that hyaluronic acid (HA) in pleural fluid might affect the progression of mesothelioma by stimulating cell migration and invasion through RHAMM. The level of RHAMM expression was decreased by YAP1/TAZ knockdown, and conversely increased by forced expression of the active form of YAP1, suggesting that RHAMM was regulated by YAP1/TAZ in MPM cells. Cell migration and invasion were also decreased by YAP1/TAZ or RHAMM knockdown. Notably, HA treatment increased cell motility and invasion, and this was abolished by RHAMM knockdown, suggesting that HA may augment local progression of MPM cells via RHAMM. Furthermore, treatment with fluvastatin, which regulates RHAMM transcription by modulating YAP1/TAZ activity, decreased the motility and invasion of MPM cells. Collectively, these data suggest that HA is an “unfavorable” factor because it promotes malignancy in mesothelioma and that the YAP1/TAZ-RHAMM axis may have potential value as a therapeutic target for inhibition of disease progression in MPM.