XB130 deficiency enhances carcinogen-induced skin tumorigenesis.

Abstract

XB130 is an adaptor protein that functions as a mediator of multiple tyrosine kinases important for regulating cell proliferation, survival, migration and invasion. Formerly predicted as an oncogene, alterations of its expression are documented in various human cancers. However, the exact role of XB130 in tumorigenesis is unknown. To address its function in skin tumorigenesis, a two-stage dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA) study was performed on XB130 knockout (KO), heterozygous (HZ) and wild-type (WT) littermate mice. DMBA/TPA-treated XB130 KO and HZ males developed a significantly higher number of epidermal tumors that were notably larger in size than did WT mice. Interestingly, DMBA/TPA-treated female mice did not show any difference in tumor multiplicity regardless of the genotypes. The skin tumor lesions of XB130 KO males were more progressed with an increased frequency of keratoacanthoma. Deficiency of XB130 dramatically increased epidermal tumor cell proliferation. The responses to DMBA and TPA stimuli were also individually investigated to elucidate the mechanistic role of XB130 at different stages of tumorigenesis. DMBA-treated male XB130 KO mice showed compensatory p53-mediated stress response. TPA-treated XB130 KO males demonstrated more skin ulceration with more severe edema, enhanced cell proliferation, accumulation of infiltrating neutrophils and increased production of pro-inflammatory cytokine genes compared with WT mice. Enhanced activities of nuclear factor-kappa B pathway, increased protein expression of metalloproteinase-9 and ERK1/2 phosphorylation were found in these KO mice. These findings demonstrate that XB130 acts as a tumor suppressor in carcinogen-induced skin tumorigenesis that may be mediated through inhibiting inflammation.

• Authors: Hae-Ra Cho, Yingchun Wang, Xiaohui Bai, Yun-Yan Xiang, Christina Lu, Alexander Post, Ayman Al Habeeb, Mingyao Liu
• Journal: Carcinogenesis (Carcinogenesis) Vol. 40 Issue 11 Pg. 1363-1375 (11 25 2019) ISSN: 1460-2180 [Electronic] England
• PMID: 30820526 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Adaptor Proteins, Signal Transducing
• Carcinogens
• Microfilament Proteins
• XB130 protein, mouse
• 9,10-Dimethyl-1,2-benzanthracene
• Tetradecanoylphorbol Acetate

Topics

• 9,10-Dimethyl-1,2-benzanthracene (toxicity)
• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Animals
• Carcinogenesis
• Carcinogens (toxicity)
• Cell Proliferation
• Female
• Genes, Tumor Suppressor
• Inflammation
• Male
• Mice
• Mice, Knockout
• Microfilament Proteins (genetics, metabolism)
• Skin Neoplasms (etiology, genetics, metabolism, physiopathology)
• Tetradecanoylphorbol Acetate (toxicity)