Podoplanin promotes progression of malignant pleural mesothelioma by regulating motility and focus formation.
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.
Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Shinji
S
Takeuchi
Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Koji
K
Fukuda
Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Tadaaki
T
Yamada
Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Sachiko
S
Arai
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Satoshi
S
Takagi
Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Genichiro
G
Ishii
Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Atsushi
A
Ochiai
Department of Respiratory Surgery, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Japan.
Shotaro
S
Iwakiri
Department of Respiratory Surgery, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Japan.
Kazumi
K
Itoi
Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Hisanori
H
Uehara
Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Hiroshi
H
Nishihara
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Naoya
N
Fujita
Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Seiji
S
Yano
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008654:Mesothelioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016513:Mice, SCID; D010750:Phosphoproteins / Q000378:metabolism; D010997:Pleural Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D015398:Signal Transduction; D014157:Transcription Factors; D014183:Transplantation, Heterologous; D000091102:YAP-Signaling Proteins; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D000098853:Podoplanin
D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D019394:Ki-67 Antigen; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D020741:rho GTP-Binding Proteins; D054460:rho-Associated Kinases; C117468:PDPN protein, human; D000098853:Podoplanin; C088374:YAP1 protein, human
YAP1; focus formation; mesothelioma; motility; podoplanin