Podoplanin promotes progression of malignant pleural mesothelioma by regulating motility and focus formation

Shinji Takeuchi, Koji Fukuda, Tadaaki Yamada, Sachiko Arai, Satoshi Takagi, Genichiro Ishii, Atsushi Ochiai, Shotaro Iwakiri, Kazumi Itoi, Hisanori Uehara, Hiroshi Nishihara, Naoya Fujita, Seiji Yano

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Malignant pleural mesothelioma (MPM) is characterized by dissemination and aggressive growth in the thoracic cavity. Podoplanin (PDPN) is an established diagnostic marker for MPM, but the function of PDPN in MPM is not fully understood. The purpose of this study was to determine the pathogenetic function of PDPN in MPM. Forty-seven of 52 tumors (90%) from Japanese patients with MPM and 3/6 (50%) MPM cell lines tested positive for PDPN. Knocking down PDPN in PDPN-high expressing MPM cells resulted in decreased cell motility. In contrast, overexpression of PDPN in PDPN-low expressing MPM cells enhanced cell motility. PDPN stimulated motility was mediated by activation of the RhoA/ROCK pathway. Moreover, knocking down PDPN with short hairpin (sh) RNA in PDPN-high expressing MPM cells resulted in decreased development of a thoracic tumor in mice with severe combined immune deficiency (SCID). In sharp contrast, transfection of PDPN in PDPN-low expressing MPM cells resulted in an increase in the number of Ki-67-positive proliferating tumor cells and it promoted progression of a thoracic tumor in SCID mice. Interestingly, PDPN promoted focus formation in vitro, and a low level of E-cadherin expression and YAP1 activation was observed in PDPN-high MPM tumors. These findings indicate that PDPN is a diagnostic marker as well as a pathogenetic regulator that promotes MPM progression by increasing cell motility and inducing focus formation. Therefore, PDPN might be a pathogenetic determinant of MPM dissemination and aggressive growth and may thus be an ideal therapeutic target.

Original languageEnglish
Pages (from-to)696-703
Number of pages8
JournalCancer science
Volume108
Issue number4
DOIs
Publication statusPublished - 2017 Apr

Keywords

  • YAP1
  • focus formation
  • mesothelioma
  • motility
  • podoplanin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Takeuchi, S., Fukuda, K., Yamada, T., Arai, S., Takagi, S., Ishii, G., Ochiai, A., Iwakiri, S., Itoi, K., Uehara, H., Nishihara, H., Fujita, N., & Yano, S. (2017). Podoplanin promotes progression of malignant pleural mesothelioma by regulating motility and focus formation. Cancer science, 108(4), 696-703. https://doi.org/10.1111/cas.13190