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World J Gastroenterol. Aug 21, 2014; 20(31): 10813-10824
Published online Aug 21, 2014. doi: 10.3748/wjg.v20.i31.10813
Targeting tight junctions during epithelial to mesenchymal transition in human pancreatic cancer
Daisuke Kyuno, Hiroshi Yamaguchi, Tatsuya Ito, Tsuyoshi Kono, Yasutoshi Kimura, Masafumi Imamura, Takumi Konno, Koichi Hirata, Norimasa Sawada, Takashi Kojima
Daisuke Kyuno, Hiroshi Yamaguchi, Tatsuya Ito, Tsuyoshi Kono, Yasutoshi Kimura, Masafumi Imamura, Koichi Hirata, Department of Surgery, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
Tsuyoshi Kono, Takumi Konno, Takashi Kojima, Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
Norimasa Sawada, Department of Pathology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
Author contributions: Kyuno D and Kojima T contributed equally to this work; Yamaguchi H, Ito T, Kono T, Kimura Y, Imamura M, Konno T, Hirata K and Sawada N designed the research; Kyuno D and Kojima T wrote the paper.
Supported by Ministry of Education, Culture, Sports Science, and Technology, and the Ministry of Health, Labour and Welfare of Japan
Correspondence to: Takashi Kojima, PhD, Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, South 1, West 17, Sapporo 060-8556, Japan. ktakashi@sapmed.ac.jp
Telephone: +81-11-6112111 Fax: +81-11-6112299
Received: October 25, 2013
Revised: January 11, 2014
Accepted: April 30, 2014
Published online: August 21, 2014
Abstract

Pancreatic cancer continues to be a leading cause of cancer-related death worldwide and there is an urgent need to develop novel diagnostic and therapeutic strategies to reduce the mortality of patients with this disease. In pancreatic cancer, some tight junction proteins, including claudins, are abnormally regulated and therefore are promising molecular targets for diagnosis, prognosis and therapy. Claudin-4 and -18 are overexpressed in human pancreatic cancer and its precursor lesions. Claudin-4 is a high affinity receptor of Clostridium perfringens enterotoxin (CPE). The cytotoxic effects of CPE and monoclonal antibodies against claudin-4 are useful as novel therapeutic tools for pancreatic cancer. Claudin-18 could be a putative marker and therapeutic target with prognostic implications for patients with pancreatic cancer. Claudin-1, -7, tricellulin and marvelD3 are involved in epithelial to mesenchymal transition (EMT) of pancreatic cancer cells and thus might be useful as biomarkers during disease. Protein kinase C is closely related to EMT of pancreatic cancer and regulates tight junctions of normal human pancreatic duct epithelial cells and the cancer cells. This review focuses on the regulation of tight junctions via protein kinase C during EMT in human pancreatic cancer for the purpose of developing new diagnostic and therapeutic modalities for pancreatic cancer.

Keywords: Tight junctions, Claudins, Tricellulin, MarvelD3, Normal human pancreatic duct epithelial cells, Pancreatic cancer, Protein kinase C, Epithelial to mesenchymal transition

Core tip: There is an urgent need to develop novel diagnostic and therapeutic strategies to reduce the mortality of pancreatic cancer patients. In pancreatic cancer, some tight junction proteins, including claudins, are abnormally regulated and thus are promising molecular targets for Clostridium perfringens enterotoxin and monoclonal antibodies. Protein kinase C is closely related to epithelial to mesenchymal transition (EMT) of this cancer and regulates tight junctions of normal human pancreatic duct epithelial (HPDE) cells and pancreatic cancer cells. This review focuses on the regulation of tight junctions via protein kinase C during EMT in human pancreatic cancer compared to normal HPDE cells.