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Title	en Role of Dimerized C16orf74 in Aggressive Pancreatic Cancer : A Novel Therapeutic Target
Creator	en Kushibiki, Toshihiro en Nakamura, Toru NRID 1000070645796 en Tsuda, Masumi NRID 1000030431307 en Tsuchikawa, Takahiro NRID 1000050507572 en Hontani, Koji en Inoko, Kazuho en Takahashi, Mizuna en Asano, Toshimichi NRID 1000010756688 en Okamura, Keisuke NRID 1000090724401 en Murakami, Soichi NRID 1000080706573 en Kurashima, Yo NRID 1000040374350 en Ebihara, Yuma NRID 1000050632981 en Noji, Takehiro NRID 1000010739296 en Nakanishi, Yoshitsugu NRID 1000040447058 en Tanaka, Kimitaka NRID 1000010758642 en Maishi, Nako NRID 1000000632423 en Sasaki, Katsunori NRID 1000060336394 en Park, Woong-Ryeon en Shichinohe, Toshiaki NRID 1000070374353 en Hida, Kyoko NRID 1000040399952 en Tanaka, Shinya NRID 1000070261287 en Hirano, Satoshi NRID 1000050322813
Accessrights	metadata only access
Subject	NDC 490
Description	Abstract en Over the past 30 years, the therapeutic outcome for pancreatic ductal adenocarcinoma (PDAC) has remained stagnant due to the lack of effective treatments. We performed a genome-wide analysis to identify novel therapeutic targets for PDAC. Our analysis showed that Homo sapiens chromosome 16 open reading frame 74 (C16orf74) was upregulated in most patients with PDAC and associated with poor prognosis. Previously, we demonstrated that C16orf74 interacts with the catalytic subunit alpha of protein phosphatase 3 and plays an important role in PDAC invasion. However, the pathophysiologic function of C16orf74 is still unclear. In this study, through the analysis of C16orf74 interaction, we demonstrate a new strategy to inhibit the growth and invasion of PDAC. C16orf74 exists in the homodimer form under the cell membrane and binds integrin alpha V beta 3 and is also involved in invasion by activating Rho family (Rac1) and MMP2. Considering that this dimeric form was found to be involved in the function of C16orf74, we designed an 11R-DB (dimer block) cell-permeable dominant-negative peptide that inhibits the dimer form of C16orf74. 11R-DB suppressed invasion and proliferation of PDAC cell lines by inhibiting phosphorylation of Akt and mTOR and also by inactivation of MMP2. 11R-DB also showed antitumor effects in an orthotopic xenograft model and peritoneal metastasis model. Thus, this study demonstrates that dimerized C16orf74, present in the cell membrane, is involved in pancreatic cancer invasion and proliferation. In addition, the C16orf74 dimer block cell-permeable peptide (11-RDB) has a potent therapeutic effect on PDAC in vitro and in vivo.
Publisher	en American Association for Cancer Research (AACR)
Date	Issued2020-01
Language	eng
Resource Type	journal article
Version Type	NA
Identifier	HDL http://hdl.handle.net/2115/80090
Relation	isIdenticalTo DOI https://doi.org/10.1158/1535-7163.MCT-19-0491
Journal	PISSN 1535-7163 en Molecular cancer therapeutics Volume Number19 Issue Number1 Page Start187 Page End198
Oaidate	2023-07-26