Intestinal phenotype is maintained by Atoh1 in the cancer region of intraductal papillary mucinous neoplasm.

Abstract

Intraductal papillary mucinous neoplasm (IPMN) is a precancerous lesion of pancreatic cancer. Although there are 4 types of IPMN, among which intestinal-type IPMN is likely to progress into invasive cancer known as colloid carcinoma, no information regarding the involvement of the intestinal phenotype in the carcinogenesis of IPMN exists. The present study was conducted to explore how the intestinal differentiation system is maintained during the tumor progression of intestinal-type IPMN using surgical resection specimens. Results showed that Atoh1, a critical transcriptional factor for intestinal differentiation toward the secretory lineages of intestinal epithelial cells, was expressed in an invasive-grade IPMN. To determine the function of Atoh1 in pancreatic cancer, we generated a pancreatic ductal adenocarcinoma (PDAC) cell line overexpressing Atoh1. In a xenograft model, we successfully induced an IPMN phenotype in PDAC cells via Atoh1 induction. Finally, for the first time, we discovered that GPA33 is expressed in intestinal-type IPMN, thereby suggesting a novel target for cancer therapy. In conclusion, the intestinal differentiation system might be maintained during tumor progression of intestinal-type IPMN. Further analysis of the function of Atoh1 in IPMN might be useful for understanding the molecular mechanism underlying the malignant potential during the tumor progression of IPMN.

• Authors: Nobuhiro Katsukura, Sho Watanabe, Tomoaki Shirasaki, Shuji Hibiya, Yoshihito Kano, Keiichi Akahoshi, Minoru Tanabe, Susumu Kirimura, Takumi Akashi, Masanobu Kitagawa, Ryuichi Okamoto, Mamoru Watanabe, Kiichiro Tsuchiya
• Journal: Cancer science (Cancer Sci) Vol. 112 Issue 2 Pg. 932-944 (Feb 2021) ISSN: 1349-7006 [Electronic] England
• PMID: 33275808 (Publication Type: Journal Article)
• Copyright: © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• ATOH1 protein, human
• Basic Helix-Loop-Helix Transcription Factors
• GPA33 protein, human
• Membrane Glycoproteins

Topics

• Aged
• Aged, 80 and over
• Animals
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Cell Differentiation (physiology)
• Cell Line, Tumor
• Female
• Heterografts
• Humans
• Intestines (pathology)
• Male
• Membrane Glycoproteins (metabolism)
• Mice
• Middle Aged
• Pancreatic Intraductal Neoplasms (metabolism, pathology)
• Phenotype