Abstract
Pancreatic differentiation 2 (PD2), an important subunit of the human PAF complex, was identified after differential screening analysis of 19q13 amplicon, and its overexpression induces oncogenic transformation of NIH3T3 cells, hence raising the possibility of a role for PD2 in tumorigenesis and metastasis. To test this hypothesis, we analyzed here the functional role and clinical significance of PD2 in pancreatic ductal adenocarcinoma (PDAC) and its pathogenesis. Using immunohistochemical analysis, we found that PD2 is detected in the acini but not in the ducts in the normal pancreas. In human PDAC specimens, PD2 was instead primarily detected in the ducts (12/48 patients 25%; p-value < 0.0001), thereby showing that PDAC correlates with increased ductal expression of PD2. Consistently, PD2 expression was increased in telomerase-immortalized human pancreatic ductal cells (HPNE cells) modified to express the HPV16 E6 and E7 proteins, whose respective functions are to block p53 and RB. In addition, ectopic expression of PD2 in PDAC cells (Capan-1 and SW1990) led to increased clonogenicity and migration in vitro, and tumor growth and metastasis in vivo. Interestingly, PD2 overexpression also resulted in enrichment of cancer stem cells (CSCs) and upregulation of oncogenes such as c-Myc and cell cycle progression marker, cyclin D1. Taken together, our results support that PD2 is overexpressed in the ducts of PDAC tissues, and results in tumorigenesis and metastasis via upregulation of oncogenes such as c-Myc and cyclin hence D1 implicating PD2 upregulation in pancreatic oncogenesis with targeted therapeutic potential.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in USA and projected to be the second leading cause of cancer deaths by 2020 [1]
Immunohistochemistry (IHC) analyses revealed that the expression of Pancreatic differentiation 2 (PD2) was significantly higher in PDAC ducts when compared to the normal duct (Figure 1A, 1B)
The PD2 immunostaining was analyzed in a total of 89 spots which were comprised of 48 PDAC, 32 metastasis to different organs (20 liver spots, 8 diaphragm spots, and 4 small bowel spots), and 9 normal tissue sections
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in USA and projected to be the second leading cause of cancer deaths by 2020 [1]. According to the American cancer society, PDAC incidence to mortality ratio is nearly one [2]. The poor survival rate of PDAC patients is due to late diagnosis, early metastasis [3] and resistance to current therapies. 70 percent of PDAC deaths are due to metastasis to distant organs and recent research has been focused towards the identification of molecular targets to prevent metastasis and disease recurrence. Emerging reports have shown that cancer stem cells www.impactjournals.com/oncotarget (CSCs) contribute to the epithelial to mesenchymal transition (EMT) phenotype, metastasis [4] and disease recurrence. The high mortality rate of PDAC patients makes it imperative to study the key oncogenic molecules essential for the maintenance of CSC population that causes PDAC progression and metastasis
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