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Cancer Sci. 2019 May 31. doi: 10.1111/cas.14085. [Epub ahead of print]

Targeting PIN1 exerts potent antitumor activity in pancreatic ductal carcinoma via inhibiting tumor metastasis.

Author information

1
Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350122, China.
2
Department of Pathology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China.
3
Division of Translational Therapeutics, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
4
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.

Abstract

Human prolyl isomerase PIN1, best known for its association with carcinogenesis, has recently been indicated in the disease of pancreatic ductal adenocarcinoma(PDAC). However, the functions of PIN1 and the feasibility of targeting PIN1 in PDAC remain exclusive. For this purpose, we examined the expression of PIN1 in cancer, related paracarcinoma and metastatic cancer tissues by immunohistochemistry and analyzed the associations with the pathogenesis of PDAC in 173 patients. The functional roles of PIN1 in PDAC were explored in vitro and in vivo using both genetic and chemical PIN1inhibition.We showed PIN1 was upregulation in pancreatic cancer and metastatic tissues. PIN1 highly expression is significantly association with poor clinicopathological features and shorter overall survival and disease free survival. Further stratified analysis showed PIN1 phenotypes refined prognostication in PDAC. Inhibition of PIN1 expression with RNA interference or with ATRA decreased not only the growth but also migration and invasion of PDAC cells through regulating the key molecules of multiple cancer driving pathways simultaneously resulting in cell cycle arrest and mesenchymal-epithelial transition(MET) in vitro. Furthermore, genetic and chemical PIN1 ablation showed dramatically inhibition of the tumorigenesis and metastatic spreading and then reduced the tumor burden in vivo. We provided further evidences for the use of PIN1 as a promising therapeutic target in PDAC. Genetic and chemical PIN1 ablation exerted potent antitumor effects through blocking multiple cancer driving pathways in PDAC. Better developments or more potent and specific PIN1 targeted inhibitors could be exploited to treat this aggressive cancer. This article is protected by copyright. All rights reserved.

KEYWORDS:

ATRA ; PIN1; metastatic spreading; pancreatic ductal adenocarcinoma; tumorigenesis

PMID:
31148345
DOI:
10.1111/cas.14085
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