Prolonged survival in pancreatic cancer patients with increased regucalcin gene expression: Overexpression of regucalcin suppresses the proliferation in human pancreatic cancer MIA PaCa-2 cells in vitro

Yamaguchi,Masayoshi; Osuka,Satoru; Weitzmann,M.  Neale; El-Rayes,Bassel  F.; Shoji,Mamoru; Murata,Tomiyasu

doi:10.3892/ijo.2016.3409

Prolonged survival in pancreatic cancer patients with increased regucalcin gene expression: Overexpression of regucalcin suppresses the proliferation in human pancreatic cancer MIA PaCa-2 cells in vitro

Authors:
- Masayoshi Yamaguchi
- Satoru Osuka
- M. Neale Weitzmann
- Bassel F. El-Rayes
- Mamoru Shoji
- Tomiyasu Murata
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Affiliations: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA, Department of Neurosurgery, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA, Division of Endocrinology and Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, 1329 WMRB, Atlanta, GA 30322, USA, Laboratory of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, Yagotoyama 150, Tempaku, Nagoya 468-8503, Japan
Published online on: February 25, 2016 https://doi.org/10.3892/ijo.2016.3409
Pages: 1955-1964

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Abstract

Approximately 90% of all pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). PDAC is a highly aggressive malignancy and is one of the deadliest. This poor clinical outcome is due to the prominent resistance of pancreatic cancer to drug and radiation therapies. Regucalcin plays a pivotal role as a suppressor protein in signal transduction in various types of cells including tumor tissues. We demonstrated that the prolonged survival is induced in PDAC patients with increased regucalcin gene expression using a dataset of PDAC obtained from GEO database (GSE17891) together with the clinical annotation data file. Moreover, overexpression of regucalcin with full length was demonstrated to suppress the proliferation, cell death and migration in human pancreatic cancer MIA PaCa-2 (K-ras mutated) cells that possess resistance to drug and radiation therapies. Suppressive effects of regucalcin on cell proliferation and death were not seen in the cells overexpressed with regucalcin cDNA alternatively spliced variants (deleted exon 4 or deleted exon 4 and 5). Regucalcin was suggested to induce G1 and G2/M phase cell cycle arrest in MIA PaCa-2 cells. Suppressive effects of regucalcin on cell proliferation were independent of cell death. Overexpression of regucalcin was found to suppress signaling pathways including Akt, MAP kinase and SAPK/JNK, to increase the protein levels of p53, a tumor suppresser, and to decrease K-ras, c-fos and c-jun, a oncogene, by suppressing signaling pathways that are related to signaling of K-ras. Regucalcin may play a potential role as a suppressor protein in human pancreatic cancer.

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