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.

XB130, regulated by miR‐203, miR‐219, and miR‐4782‐3p, mediates the proliferation and metastasis of non‐small‐cell lung cancer cells

“…Bai et al 3 explained that highly expressed XB130 is necessary for maintaining the normal physiological function of stomach and thyroid cells, and cancer cells with lowly expressed XB130 may manipulate the XB130‐mediated signal pathways that regulate cell proliferation, migration, and invasion to help tumor growth and invasion in gastric and thyroid cancers. Interestingly, XB130 has been shown to behave as a tumor suppressor in skin tumorigenesis induced by carcinogens recently and XB130 knockdown significantly promoted epidermal tumor cell proliferation 12 . Therefore, XB130 has attracted increasing interest from researchers due to its controversial effects on cancers.…”

“…Therefore, XB130 has been predicted to be an oncogene and a potential diagnostic marker and therapeutic target for cancers 3,4 . But after that, in 2019, XB130 has been reported to be a tumor suppressor in skin tumorigenesis induced by carcinogen through inhibiting inflammation, 12 which was in contrast with previous conclusions and indicated that XB130 may play different roles in different tumors.…”

“…Interestingly, XB130 has been shown to behave as a tumor suppressor in skin tumorigenesis induced by carcinogens recently and XB130 knockdown significantly promoted epidermal tumor cell proliferation. 12 Therefore, XB130 has attracted increasing interest from researchers due to its controversial effects on cancers.…”

The Expression and Significance of XB130 in Skin Basal Cell Carcinoma

“…The study indicated tumor-suppressive functions of XB130. DMBA/TPA-treated XB130 KO male mice developed a higher number of skin tumors including dysplasia, verrucous dysplasia and keratoacanthoma [28]. Deficiency of XB130 dramatically increased epidermal tumor cell proliferation and enhanced the inflammatory response with accumulation of infiltrating neutrophils and inflammatory cytokines.…”

Members of the miR‑30 family inhibit the epithelial‑to‑mesenchymal transition of non‑small‑cell lung cancer cells by suppressing XB130 expression levels

“…XB130, a multifunctional adaptor protein, is an oncogene that mediates cell proliferation, migration and invasion in osteosarcoma, hepatocellular and esophageal squamous cell carcinoma and pancreatic ductal adenocarcinoma, as well as prostrate, breast and gastric cancer (15)(16)(17)(18)(19)(20)(21)(22). However, Cho et al (23) recently suggested that XB130 acts as a tumor suppressor in skin tumorigenesis by inhibiting inflammation, which indicates that XB130 may serve different roles in different types of tumor. Our previous study (24) demonstrated that, similar to miR-30 family members, XB130 silencing can inhibit cell migration, invasion and EMT in NSCLC.…”