Induction of chemokine receptor CXCR4 expression by transforming growth factor-¦Â1 in human basal cell carcinoma cells

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• 作者：Chia-Yu Chu ; Yi-Shuan Sheen ; Shih-Ting Cha ; Yeh-Fang Hu ; Ching-Ting Tan ; Hsien-Ching Chiu ; Cheng-Chi Chang ; Min-Wei Chen ; Min-Liang Kuo ; Shiou-Hwa Jee
• 关键词：Basal cell carcinoma ; Chemokine ; Invasion ; Transforming growth factor
• 刊名：Journal of Dermatological Science
• 出版年：2013
• 出版时间：November, 2013
• 年：2013
• 卷：72
• 期：2
• 页码：123-133
• 全文大小：2599 K

文摘

Background

Higher CXCR4 expression enhances basal cell carcinoma (BCC) invasion and angiogenesis. The underlying mechanism of increased CXCR4 expression in invasive BCC is still not well understood.

Objective

To investigate the mechanisms involved in the regulation of CXCR4 expression in invasive BCC.

Methods

We used qRT-PCR, RT-PCR, Western blot, and flow cytometric analyses to examine different CXCR4 levels among the clinical samples, co-cultured BCC cells and BCC cells treated with recombinant transforming growth factor-¦Â1 (TGF-¦Â1) and connective tissue growth factor (CTGF). Immunohistochemical studies were used to demonstrate the correlation between TGF-¦Â1 and CXCR4 expressions. The signal transduction pathway and transcriptional regulation were confirmed by treatments with chemical inhibitors, neutralizing antibodies, or short interfering RNAs, as well as luciferase reporter activity.

Results

Invasive BCC has higher TGF-¦Â1 and CTGF levels compared to non-invasive BCC. Non-contact dermal fibroblasts co-culture with human BCC cells also increases the expression of CXCR4 in BCC cells. Treatment with recombinant human TGF-¦Â1, but not CTGF, enhanced the CXCR4 levels in time- and dose-dependent manners. The protein level and surface expression of CXCR4 in human BCC cells was increased by TGF-¦Â1 treatment. TGF-¦Â1 was intensely expressed in the surrounding fibroblasts of invasive BCC and was positively correlated with the CXCR4 expression of BCC cells. The transcriptional regulation of CXCR4 by TGF-¦Â1 is mediated by its binding to the TGF-¦Â receptor II and phosphorylation of the extracellular signal-related kinase 1/2 (ERK1/2)-ETS-1 pathway.

Conclusion

TGF-¦Â1 induces upregulation of CXCR4 in human BCC cells by phosphorylation of ERK1/2-ETS-1 pathway.