Abstract
The importance of Pituitary homeobox 2 (Pitx2) in malignancy remains enigmatic, and Pitx2 has not been previously implicated in pancreatic ductal adenocarcinoma (PDAC). In this study, we performed gene expression profiling of human PDAC tissues and identified Pitx2 as a promising candidate. Pitx2 expression was decreased from 2.6- to 19-fold in human PDAC tissues from microarray units. Immunochemistry staining showed that Pitx2 expression was moderate to intense in normal pancreatic and pancreatic intraepithelial neoplastic lesions, whereas low in human PDAC tissues. The Pitx2 levels correlated with overall patient survival post-operatively in PDAC. Induction of Pitx2 expression partly inhibited the malignant phenotype of PDAC cells. Interestingly, low Pitx2 expression was correlated with Smad4 mutant inactivation, but not with Pitx2 DNA-methylation. Furthermore, Smad4 protein bound to Pitx2 promoter and stimulated Pitx2 expression in PDAC. In addition, Pitx2 protein bound to the promoter of the protein phosphatase 2A regulatory subunit B55α (PPP2R2A) and upregulated PPP2R2A expression, which may activate dephosphorylation of Akt in PDAC. These findings provide new mechanistic insights into Pitx2 as a tumor suppressor in the downstream of Smad4. And Pitx2 protein promotes PPP2R2A expression which may inhibit Akt pathway. Therefore, we propose that the Smad4-Pitx2-PPP2R2A axis, a new signaling pathway, suppresses the pancreatic carcinogenesis.
Highlights
Microarray has been used to further understand the molecular pathogenesis of carcinogenesis and explore differentially expressed genes which may be potential therapeutic targets [1, 2]
Microarray analysis was performed to identify potential markers correlated with the known suppressors Smad4, p16, Tp53 and BRCA2, which are most frequently inactivated in pancreatic ductal adenocarcinoma (PDAC)
We aimed to identify potential markers correlated with the known suppressors Smad4, p16, Tp53 or BRCA2 with the most frequently inactivated mutation in PDAC, among the sixty-four differentially expressed genes
Summary
Microarray has been used to further understand the molecular pathogenesis of carcinogenesis and explore differentially expressed genes which may be potential therapeutic targets [1, 2]. Hirose et al reported that Pitx levels were inversely correlated with in vitro colon cancer cell growth and invasion [10] According to these observations, Pitx may suppress carcinogenesis. Several studies showed that Pitx may promote tumor progression, and www.impactjournals.com/oncotarget it was considered to be a potential oncogene in thyroid cancer [11, 12], prostate cancer [13] and ovarian cancer [14, 15]. These studies indicate the diverse and complex functions of Pitx in carcinogenesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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
