Abstract
Clinical outcome of pancreatic ductal adenocarcinoma (PDAC) has not been improved in the last three decades due to the lack of effective molecular-targeted drugs. To identify a novel therapeutic target for PDAC, we have performed genome-wide anamysis and found that Homo sapiens chromosome 16 open reading frame 74 (C16orf74) was up-regulated in the vast majority of PDAC. Overexpression of C16orf74protein detected by immunohistochemical analysis was an independent prognostic factor for patients with PDAC. The knockdown of endogenous C16orf74 expression in the PDAC cell lines KLM-1 and PK-59 by vector-based small hairpin-RNA (shRNA) drastically attenuated the growth of those cells, whereas ectopic C16orf74 overexpression in HEK293T and NIH3T3 cells promoted cell growth and invasion, respectively. More importantly, the endogenous threonine 44 (T44)-phosphorylated form of C16orf74 interacted with the protein phosphatase 3 catalytic subunit alpha (PPP3CA) via the PDIIIT sequence in the PPP3CA-binding motif within the middle portion of C16orf74 in PDAC cells. The overexpression of mutants of C16orf74 lacking the PDIIIT sequence or T44 phosphorylation resulted in the suppression of invasive activity compared with wild-type C16orf74, indicating that their interaction should be indispensable for PDAC cell invasion. These results suggest that C16orf74 plays an important role for PDAC invasion and proliferation, and is a promising target for a specific treatment for patients with PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) reveals worse prognosis than any other types of malignant tumor
We verified by semi-quantitative RT-PCR that C16orf74 was up-regulated in 10 of 12 pancreatic cancer specimens compared with normal pancreatic ducts, and was up-regulated in capan-1, capan-2 pancreatic cancer cell lines compared with normal pancreatic ducts, it was observed a weak band in normal duct cells. (Figure 1A)
Because the EST sequence of the C16orf74 gene in the National Center for Biotechnology Information (NCBI) database (Accession: BE875115; 586bp) is smaller than the approximately 1-kb transcript shown in Figure 1B, we screened the full-length cDNA clone from a cDNA library prepared from pancreatic cancer cell lines and isolated three different isoforms (Figure 1C)
Summary
Pancreatic ductal adenocarcinoma (PDAC) reveals worse prognosis than any other types of malignant tumor. Systemic chemotherapy is the standard treatment for patients with metastatic PDAC; the median overall survival is only 11.1 months with FOLFIRINOX (a combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin), 8.5 months with gemcitabine plus nab-paclitaxel, and 6.24 months with gemcitabine plus erlotinib (an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor) [2,3,4]. In combination chemotherapy, such as FOLFIRINOX, side effects including hematological www.impactjournals.com/oncotarget toxicity, febrile neutropenia, sensory neuropathy, and gastrointestinal toxicity are higher than for single-agent gemcitabine; guidelines recommend that FOLFIRINOX be used in patients ≤75 years of age, with a good performance status of 0 or 1 and a level of bilirubin ≤1.5 ULN [5]
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