Abstract
Homeobox D10 (HoxD10) plays important roles in the differentiation of embryonic cells and progression of breast cancer. Our previous report revealed that insulin-like growth factor binding protein-3 (IGFBP3) was regulated by HoxD10 in gastric cancer cells; however, the functional roles and underlying mechanisms of IGFBP3 in gastric cancer remain unclear. Here, we found that the expression of IGFBP3 were upregulated after ectopic expression of HoxD10 in gastric cancer cells. Chromatin immunoprecipitation assay showed that HoxD10 bound to three potential regions of IGFBP3 promoter. Exogenous HoxD10 significantly enhanced the activity of luciferase reporter containing these binding regions in gastric cancer cells. Further data showed that all of these binding sites had Hox binding element “TTAT”. Immunohistochemical staining results revealed that IGFBP3 expression was significantly downregulated in 86 gastric adenocarcinomas tissues relative to their adjacent non-cancerous tissues (p<0.001). Moreover, IGFBP3 expression was significantly lower in gastric tumor with lymph node metastasis compared with that without lymph node metastasis (p=0.045). Patients with high expression level of IGFBP3 showed favorable 5 year overall survival (p=0.011). Knockdown of IGFBP3 accelerated gastric cancer cell migration and invasion and induced the expression of invasive factors including MMP14, uPA and uPAR. Thus, our data suggest that HoxD10-targeted gene IGFBP3 may suppress gastric cancer cell invasion and favors the survival of gastric cancer patients.
Highlights
Gastric cancer is the fourth most frequent cancer and currently is the second leading cause of cancer-related death worldwide [1]
We identified that the chromatin precipitated by homeobox D10 (HoxD10) specific antibody was amplified using A2, A3 and A4 primers, which encompass HBS3, HBS4 and HBS5 respectively, while no amplification was observed with A1 primers encompassing HBSs were localized at -2191~ -2182bp (HBS1) and 2 (Figure 2B)
Our studies provided first evidence to show that HoxD10 directly binds the insulin-like growth factor binding protein-3 (IGFBP3) promoter to activate the expression of IGFBP3 in gastric cancer cells
Summary
Gastric cancer is the fourth most frequent cancer and currently is the second leading cause of cancer-related death worldwide [1]. Half of the gastric caner patients have already advanced to the late stage with lymphatic or distant metastasis at diagnosis and lose the opportunity for surgery [2]. These patients have a poor outcome and the five-year survival rate for those with distant metastasis is less than 5% [3]. We have systematically screened the potential targets of HoxD10 by cDNA microarray and identified multiple genes, including insulin-like growth factor binding protein-3 (IGFBP3) that might be responsible for the tumor suppressing effect of HoxD10 in gastric cancer [4]
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