Wang Qi, Li Juanjuan, Wu Wei, Shen Ruizhe, Jiang He, Qian Yuting, Tang Yanping, Bai Tingting, Wu Sheng, Wei Lumin, Zang Yi, Zhang Ji, Wang Lifu
Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
State Key Laboratory of Medical Genomics and Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Oncotarget. 2016 Mar 8;7(10):11208-22. doi: 10.18632/oncotarget.7158.
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.
垂体同源框2（Pitx2）在恶性肿瘤中的重要性仍然不明，且此前Pitx2未被认为与胰腺导管腺癌（PDAC）有关。在本研究中，我们对人类PDAC组织进行了基因表达谱分析，并确定Pitx2是一个有前景的候选基因。在微阵列单位的人类PDAC组织中，Pitx2表达降低了2.6至19倍。免疫化学染色显示，Pitx2在正常胰腺和胰腺上皮内瘤变病变中表达为中度至强阳性，而在人类PDAC组织中表达较低。Pitx2水平与PDAC患者术后的总体生存率相关。Pitx2表达的诱导部分抑制了PDAC细胞的恶性表型。有趣的是，低Pitx2表达与Smad4突变失活相关，但与Pitx2 DNA甲基化无关。此外，Smad4蛋白与Pitx2启动子结合并刺激PDAC中Pitx2的表达。另外，Pitx2蛋白与蛋白磷酸酶2A调节亚基B55α（PPP2R2A）的启动子结合并上调PPP2R2A的表达，这可能激活PDAC中Akt的去磷酸化。这些发现为Pitx2作为Smad4下游的肿瘤抑制因子提供了新的机制见解。并且Pitx2蛋白促进PPP2R2A的表达，这可能抑制Akt途径。因此，我们提出Smad4-Pitx2-PPP2R2A轴作为一条新的信号通路，可抑制胰腺癌的发生。
