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.
Highlights
Malignant mesothelioma is an aggressive neoplasm arising from the pleura, pericardium, and peritoneum
Based on the genetic background of Lats2 status described above, we selected three cell lines, ACC-MESO-4, NCI-H28, and Y-MESO-27 (Lats2-deletion), for further study to investigate the involvement of the Yesassociated protein 1 (YAP1)/transcriptional co-activator with PDZ-binding motif (TAZ)-receptor for hyaluronic acid-mediated motility (RHAMM) axis, as direct regulation of YAP1 by LATS2 might be conserved in these cell lines
We found that the YAP1/TAZ-RHAMM axis is involved in the regulation of migration and invasion in malignant pleural mesothelioma (MPM) cell lines, and that hyaluronic acid (HA), which is massively present in pleural effusion in MPM patients, may contribute to the progression of mesothelioma
Summary
Malignant mesothelioma is an aggressive neoplasm arising from the pleura, pericardium, and peritoneum. It is induced by long-term exposure to asbestos, a naturally occurring silicate mineral, and its incidence and associated mortality rate are increasing in most countries [1, 2]. Among the several types of mesothelioma, malignant pleural mesothelioma (MPM) accounts for approximately 80% of all cases, and poor sensitivity to drug therapy is a frequent clinical problem in affected patients [5]. Despite intensive treatment with surgery, radiation therapy or chemotherapy such as cisplatin and pemetrexed, widely disseminated MPM in the pleural space often spreads to the intra-thoracic lymph nodes, and the clinical outcome is invariably poor [3, 6]. A search for molecular www.impactjournals.com/oncotarget targets to inhibit cell migration and invasion would seem justified
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