Podoplanin promotes progression of malignant pleural mesothelioma by regulating
motility and focus formation
#MMPMID28182302
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
Cancer Sci
2017[Apr]; 108
(4
): 696-703
PMID28182302
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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.
|Adaptor Proteins, Signal Transducing/metabolism
[MESH]
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