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 αVβ3 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 (11R-DB) has a potent therapeutic effect on PDAC in vitro and in vivo.

中文翻译：

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二聚化 C16orf74 在侵袭性胰腺癌中的作用：一种新的治疗靶点

在过去的 30 年中，由于缺乏有效的治疗方法，胰腺导管腺癌 (PDAC) 的治疗结果一直停滞不前。我们进行了全基因组分析，以确定 PDAC 的新治疗靶点。我们的分析表明，智人 16 号染色体开放阅读框 74（C16orf74）在大多数 PDAC 患者中上调并与不良预后相关。以前，我们证明 C16orf74 与蛋白磷酸酶 3 的催化亚基 alpha 相互作用，并在 PDAC 入侵中发挥重要作用。然而，C16orf74 的病理生理功能仍不清楚。在这项研究中，通过对 C16orf74 相互作用的分析，我们展示了一种抑制 PDAC 生长和侵袭的新策略。C16orf74 以同型二聚体形式存在于细胞膜下并结合整联蛋白 αVβ3，还通过激活 Rho 家族 (Rac1) 和 MMP2 参与入侵。考虑到发现这种二聚体形式与 C16orf74 的功能有关，我们设计了一种 11R-DB（二聚体阻断）细胞渗透性显性负肽，可抑制 C16orf74 的二聚体形式。11R-DB 通过抑制 Akt 和 mTOR 的磷酸化以及 MMP2 的失活来抑制 PDAC 细胞系的侵袭和增殖。11R-DB 在原位异种移植模型和腹膜转移模型中也显示出抗肿瘤作用。因此，该研究表明存在于细胞膜中的二聚化 C16orf74 参与胰腺癌的侵袭和增殖。此外，