IL-33 overexpression in gallbladder cancers associated with pancreatobiliary maljunction.

Abstract

AIMS:

To investigate whether genetic or inflammatory pro-oncogenic factors are relevant to the increased risk of gallbladder cancers in patients with pancreaticobiliary maljunction (PBM).

METHODS AND RESULTS:

Mutations in KRAS exon 2 were examined by a highly sensitive, droplet digital PCR platform using surgically resected specimens of PBM-associated (n = 31) and non-associated gallbladder cancers (n = 49). The tissue expression of IL-6 and IL-33, which are suspected to promote biliary carcinogenesis, was analysed by quantitative real-time PCR and in-situ hybridisation. The incidence of KRAS mutations was similarly low in PBM-associated (five of 32 cases; 16%) and non-associated cancers (four of 49 cases; 8%) (P = 0.272). The tissue expression of IL-33 mRNA, but not IL-6 mRNA, was significantly higher in PBM-associated gallbladder cancers than in gallbladder cancers without PBM (P = 0.004). A similar degree of IL-33 overexpression was also observed in the background non-cancerous mucosa in cases of PBM-associated gallbladder cancers, and was significantly greater than that in PBM cases with cholecystitis alone (P < 0.001). The results of in-situ hybridisation indicated that the source of IL-33 production in PBM-associated carcinomas was the endothelium, cancer cells and non-neoplastic biliary epithelium. In a combined PBM-associated and non-associated cohort, IL-33 overexpression in gallbladder cancers correlated with less aggressive features (e.g. a lower pT stage and longer overall survival), similar to recently reported findings on large-duct cholangiocarcinomas.

CONCLUSIONS:

KRAS mutations do not appear to be associated with a high risk of malignancy in PBM, while IL-33 overexpression may provide a pro-oncogenic microenvironment in the gallbladder mucosa of patients with PBM.

• Authors: Yuichiro Tomioka, You-Na Sung, Ryuichiro Sawada, Seung-Mo Hong, Masayuki Akita, Tomoo Itoh, Tetsuo Ajiki, Takumi Fukumoto, Yoh Zen
• Journal: Histopathology (Histopathology) Vol. 75 Issue 3 Pg. 365-375 (Sep 2019) ISSN: 1365-2559 [Electronic] England
• PMID: 30882917 (Publication Type: Journal Article)
• Copyright: © 2019 John Wiley & Sons Ltd.

Chemical References

• IL33 protein, human
• Interleukin-33
• KRAS protein, human
• Proto-Oncogene Proteins p21(ras)

Topics

• Aged
• Common Bile Duct (abnormalities)
• Female
• Gallbladder Neoplasms (genetics, metabolism, pathology)
• Humans
• Interleukin-33 (biosynthesis)
• Male
• Middle Aged
• Mutation
• Pancreatic Ducts (abnormalities)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Up-Regulation