Downregulation of RalGTPase-activating protein promotes invasion of prostatic epithelial cells and progression from intraepithelial neoplasia to cancer during prostate carcinogenesis

Masayuki Uegaki, Yuki Kita, Ryutaro Shirakawa, Yuki Teramoto, Yuki Kamiyama, Ryoichi Saito, Takeshi Yoshikawa, Hiromasa Sakamoto, Takayuki Goto, Shusuke Akamatsu, Toshinari Yamasaki, Takahiro Inoue, Akira Suzuki, Hisanori Horiuchi, Osamu Ogawa, Takashi Kobayashi

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Abstract

RalGTPase-activating protein (RalGAP) is an important negative regulator of small GTPases RalA/B that mediates various oncogenic signaling pathways in various cancers. Although the Ral pathway has been implicated in prostate cancer (PCa) development and progression, the significance of RalGAP in PCa has been largely unknown. We examined RalGAPα2 expression using immunohistochemistry on two independent tissue microarray sets. Both datasets demonstrated that the expression of RalGAPα2 was significantly downregulated in PCa tissues compared to adjacent benign prostatic epithelia. Silencing of RalGAPα2 by short hairpin RNA enhanced migration and invasion abilities of benign and malignant prostate epithelial cell lines without affecting cell proliferation. Exogenous expression of wild-type RalGAP, but not the GTPase-activating protein activity-deficient mutant of RalGAP, suppressed migration and invasion of multiple PCa cell lines and was phenocopied by pharmacological inhibition of RalA/B. Loss of Ralgapa2 promoted local microscopic invasion of prostatic intraepithelial neoplasia without affecting tumor growth in a Pten-deficient mouse model for prostate tumorigenesis. Our findings demonstrate the functional significance of RalGAP downregulation to promote invasion ability, which is a property necessary for prostate carcinogenesis. Thus, loss of RalGAP function has a distinct role in promoting progression from prostatic intraepithelial neoplasia to invasive adenocarcinoma.

Original languageEnglish
Pages (from-to)1535-1544
Number of pages10
JournalCarcinogenesis
Volume40
Issue number12
DOIs
Publication statusPublished - 2019 Dec 1

ASJC Scopus subject areas

  • Cancer Research

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    Uegaki, M., Kita, Y., Shirakawa, R., Teramoto, Y., Kamiyama, Y., Saito, R., Yoshikawa, T., Sakamoto, H., Goto, T., Akamatsu, S., Yamasaki, T., Inoue, T., Suzuki, A., Horiuchi, H., Ogawa, O., & Kobayashi, T. (2019). Downregulation of RalGTPase-activating protein promotes invasion of prostatic epithelial cells and progression from intraepithelial neoplasia to cancer during prostate carcinogenesis. Carcinogenesis, 40(12), 1535-1544. https://doi.org/10.1093/carcin/bgz082