Abstract
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.
Highlights
The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing by about 1% per year, and an estimated 56,770 new cases and 45,750 deaths occurred in the United States in 2019, even today, with progress in therapy, the 5-year combined survival rate of all stages is only 9%
From the morphologic observation of C16orf74-stable cell lines, we acknowledged findings that strongly indicated the activation of the Rho family such as lamellipodium and stress fiber [16, 17]
C16orf74 can localize in the cell membrane only when present in a dimeric form and shows direct binding to integrin aVb3
Summary
The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing by about 1% per year, and an estimated 56,770 new cases and 45,750 deaths occurred in the United States in 2019, even today, with progress in therapy, the 5-year combined survival rate of all stages is only 9% GA: American Cancer Society 2019; http://www.cancer.org/ research/cancerfactsstatistics/cancer-facts-and-figures-2019). FOLFIRINOX (a combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin) and gemcitabine with nab-paclitaxel therapy have been developed and show higher antitumor effect than gemcitabine for patients with metastatic PDAC. It has been reported that various adverse effects appear in the chemotherapy [1,2,3]. Gemcitabine with erlotinib was developed as a molecular
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
