The biological features of PanIN initiated from oncogenic Kras mutation in genetically engineered mouse models
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- 作者：Ruizhe Shen ; Qi Wang ; Shidan Cheng ; Tingting Liu ; He Jiang ; Jiaxing Zhu ; Yunlin Wu ; Lifu Wang
- 关键词：PanIN ; pancreatic intraepithelial neoplasia ; PDAC ; pancreatic ductal adenocarcinoma ; PPP2R2A ; protein phosphatase 2 ; regulatory subunit B ; alpha
- 刊名：Cancer Letters
- 出版年：2013
- 出版时间：1 October, 2013
- 年：2013
- 卷：339
- 期：1
- 页码：135-143
- 全文大小：2899 K
文摘
Pancreatic intraepithelial neoplasia (PanIN) is the most common premalignant lesion of the pancreas. Further understanding of the biological behavior and molecular genetic alterations in the stepwise progression of PanINs is necessary toward the development of pancreatic ductal adenocarcinoma (PDAC) interventions. In this study, we analyzed the morphological characteristics, molecular alterations, and biological behavior of pancreatic wild-type and neoplasia tissues, including analysis of PanIN cell line SH-PAN (isolated from Pdx-1-Cre; LSL-KrasG12D/+ mouse) and PDAC cell line DT-PCa (isolated from Pdx1-Cre; LSL-KrasG12D/+; LSL-Tp53R172H/+ mouse). Results show that KrasG12D induces ductal lesion PanINs. Increased expression of EGFR, Her-2/Neu, p-MAPK and ¦Â-Catenin was observed in low-grade PanINs. Tp53 was not expressed in wild-type and low-grade PanINs, however, increased expression was observed in high-grade PanINs. Furthermore, SH-PAN cells did not exhibit any colony formation and showed significantly lower migration and invasion ability compared with DT-PCa cells. Notably, we first found PPP2R2A (protein phosphatase 2, regulatory subunit B, alpha) expression was significantly higher in SH-PAN cells than DT-PCa cells, and was high in 96 of 172 peritumoral normal human pancreatic tissues and 20 of 36 human low- or middle-grade PanIN tissues, whereas, was weak or negligible in 12 of 20 human high-grade PanIN tissues and 124 of 172 human PDAC tissues post-operation. The expression of PPP2R2A appears to be correlated with clinical survival. Taken together, KrasG12D - driven PanIN showed the tumorigenic ability, however, did not undergo a malignant transformation, and decreased expression of PPP2R2A in PDACs may provided a new target for pancreatic carcinoma intervention.