Pancreatology e br Contents lists available at ScienceDirect br Pancreatology

Pancreatology 19 (2019) 88e96
Contents lists available at ScienceDirect
Pancreatology
Claudin 7 as a possible novel molecular target for the treatment of pancreatic cancer
Norimitsu Okui a, Yuko Kamata b, Yukiko Sagawa b, Akiko Kuhara b, Kazumi Hayashi c, Tadashi Uwagawa a, Sadamu Homma b, *, Katsuhiko Yanaga a a Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
b Division of Oncology, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan
c Division of Clinical Oncology and Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
Article history:
Received in revised form
Available online 2 November 2018
Keywords:
Cell proliferation
Claudin 7
Gene expression
Pancreatic cancer
Cell cycle
Background/objectives: Pancreatic cancer consists of various subpopulations of cells, some of which have aggressive proliferative properties. The molecules responsible for the aggressive proliferation of pancreatic cancer may become molecular targets for the therapies against pancreatic cancer. Methods: From a human pancreatic cancer cell line, MIA PaCa-2, MIA PaCa-2-A INCB018424 with an epithelial morphology and MIA PaCa-2-R cells with a non-epithelial morphology were clonogenically isolated by the limiting dilution method. Gene expression of these subpopulations was analyzed by DNA microarray. Gene knockdown was performed using siRNA.
Results: Although the MIA PaCa-2-A and MIA PaCa-2-R cells displayed the same DNA short tandem repeat (STR) pattern identical to that of the parental MIA PaCa-2 cells, the MIA PaCa-2-A cells were more proliferative than the MIA PaCa-2-R cells both in culture and in tumor xenografts generated in immu-nodeficient mice. Furthermore, the MIA PaCa-2-A cells were more resistant to gemcitabine than the MIA PaCa-2-R cells. DNA microarray analysis revealed a high expression of claudin (CLDN) 7 in the MIA PaCa-2-A cells, as opposed to a low expression in the MIA PaCa-2-R cells. The knockdown of CLDN7 in the MIA PaCa-2-A cells induced a marked inhibition of proliferation. The MIA PaCa-2-A cells in which CLDN7 was knocked down exhibited a decreased expression of phosphorylated extracellular signal-regulated kinase (p-Erk)1/2 and G1 cell cycle arrest.
Conclusions: CLDN7 may be expressed in the rapidly proliferating and dominant cell population in hu-man pancreatic cancer tissues and may be a novel molecular target for the treatment of pancreatic cancer.
© 2018 IAP and EPC. Published by Elsevier B.V. All rights reserved.
Introduction
Pancreatic cancer is a common cause of cancer-related mortality worldwide [1,2]. This disease is so aggressive that the tumors of the majority of patients are unresectable at the time of diagnosis. Although 10% of patients can be treated with surgical resection, >80% relapse within 2 years [3]. The median survival is < 1 year for patients with locally advanced disease and 3e6 months for patients with metastases [4]. Chemotherapy is used to prolong the survival
* Corresponding author. Division of Oncology, Research Center for Medical Sci-ences, The Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan. E-mail address: [email protected] (S. Homma).
of patients with unresectable pancreatic cancer [5,6]. Gemcitabine has been the standard treatment regimen and is widely used in pancreatic cancer therapy [7]. The newer regimens, FOLFIRINOX (combination of oxaliplatin, irinotecan, fluorouracil and leucovorin) and gemcitabine/nab-paclitaxel have led to improved survival compared to treatment with gemcitabine alone and are now becoming standard treatments in developed countries [8,9]. How-ever, as these therapies have considerably limited effects on advanced pancreatic cancer, the establishment of effective thera-pies against pancreatic cancer is urgently required.