XB130 deficiency enhances carcinogen-induced skin tumorigenesis
| Autor: | Ayman Al Habeeb, Hae-Ra Cho, Yun-Yan Xiang, Alexander Post, Xiao-Hui Bai, Christina Lu, Mingyao Liu, Yingchun Wang |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Cancer Research Skin Neoplasms Carcinogenesis 9 10-Dimethyl-1 2-benzanthracene DMBA Inflammation Biology medicine.disease_cause Mice 03 medical and health sciences 0302 clinical medicine medicine Animals Genes Tumor Suppressor Adaptor Proteins Signal Transducing Cell Proliferation XB130 Mice Knockout integumentary system Oncogene Cell growth Microfilament Proteins General Medicine 030104 developmental biology 030220 oncology & carcinogenesis Carcinogens Cancer research Tetradecanoylphorbol Acetate Phosphorylation Female medicine.symptom Tyrosine kinase |
| Zdroj: | Carcinogenesis. 40:1363-1375 |
| ISSN: | 1460-2180 0143-3334 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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