Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a disease of aging. The TP53 gene product regulates cell growth, aging, and cancer. To determine the important targets of TP53 in PDAC, we examined the expression of 440 proteins on a reverse phase protein array (RPPA) in PDAC-derived MIA-PaCa-2 cells which either had WT-TP53 or lacked WT-TP53. MIA-PaCa-2 cells have a TP53 mutation as well as mutant KRAS and represent a good in vitro model to study PDAC. RPPA analysis demonstrated expression of tumor promoting proteins in cells that lacked WT-TP53; and this feature could be reversed significantly when the cells were transfected with vector encoding WT-TP53 or treated with berberine or a modified berberine (BBR). Expression of miR-34a-associated signaling was elevated in cells expressing WT-TP53 compared to cells expressing mTP53. Results from in vivo studies using human PDAC specimens confirmed the in vitro results as the expression of miR-34a and associated signaling was significantly decreased in PDAC specimens compared to non-cancerous tissues. This study determined SERPINE1 as a miR-34a target with relevance to the biology of PDAC. Thus, we have identified a key target (SERPINE1) of the TP53/miR-34a axis that may serve as a potential biomarker for early detection of pancreatic cancer.
Highlights
The risk of developing cancer of the pancreas increases with age; it was estimated that only 13% of all patients with pancreatic cancer are diagnosed before the age of 60 [1]
To determine the important targets of TP53 in Pancreatic ductal adenocarcinoma (PDAC), we examined the expression of 440 proteins on a reverse phase protein array (RPPA) in PDAC-derived MIA-PaCa-2 cells which either had WT-TP53 or lacked WT-TP53
KRAS mutations occur in about 90% of PDAC while TP53 mutations occur in approximately 75% of pancreatic cancers [9]
Summary
The risk of developing cancer of the pancreas increases with age; it was estimated that only 13% of all patients with pancreatic cancer are diagnosed before the age of 60 [1]. KRAS (activation) mutations occur in about 90% of PDAC while TP53 (inactivation) mutations occur in approximately 75% of pancreatic cancers [9]. In this study we focused on miR-34a over other miRNAs because of the following reasons: (i) Expression of miR-34a is significantly down-regulated or absent in a variety of cancers including hepatocellular and renal cell carcinomas, colon, breast, lung, prostate, ovarian, and pancreatic cancers [16,17,18,19,20,21,22]; (ii) The two major oncogenes that are mutated in PDAC are KRAS and TP53 [23]; (iii) TP53 directly transactivates miR-34a www.aging-us.com expression [24] while mutated KRAS indirectly lowers expression of miR-34a via the transcription factor, ZEB1 [25, 26]. Inactivation of TP53 and increases in mutated KRAS expression result in a sharp decline in miR-34a expression during tumorigenesis
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