Abstract
BackgroundHomeobox B9 (HOXB9), a transcriptional factor, regulates developmental processes and tumor progression and has recently been recognized as one of important transcriptional factors related to angiogenesis. This study aimed to investigate the role of HOXB9 in tumorigenesis and angiogenesis.MethodsWe examined the expression of HOXB9 in colorectal cancer using qPCR and in situ hybridization. We also examined the effect of HOXB9 overexpression in colorectal cancer using a proliferation assay, ELISA, a multiplex assay, and xenograft models. The clinical significance of HOXB9 was statistically evaluated in resected specimens.ResultsHOXB9 was expressed in colorectal cancer specimens. HOXB9 induced angiogenesis and tumor proliferation in vitro, which resulted in high tumorigenicity in vivo and poor overall survival. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, remarkably suppressed tumor proliferation by inhibiting angiogenesis in HOXB9-overexpressing xenografts, and it improved overall survival and provided prolonged progression-free survival in HOXB9-overexpressing patients. A comprehensive multiplex assay of the supernatant of cancer cells co-cultured with human vascular endothelial cells and fibroblasts indicated significantly higher interleukin-6 (IL6) levels than those in the supernatant of monocultured cells. HOXB9 overexpression in clinical specimens was significantly correlated with increased IL6 expression. An IL6-neutralizing antibody inhibited VEGF secretion and tumor proliferation in the co-culture system.ConclusionsHOXB9 promotes the secretion of angiogenic factors, including VEGF, to induce tumor proliferation through microenvironmental production of cytokines including IL6 signaling. Moreover, silencing of VEGF or IL6 terminates cytokine release in tumor microenvironment. Thus, HOXB9 and IL6 may be potential biomarkers for bevacizumab treatment.
Highlights
Homeobox B9 (HOXB9), a transcriptional factor, regulates developmental processes and tumor progression and has recently been recognized as one of important transcriptional factors related to angiogenesis
Role of HOXB9 in angiogenesis, transforming growth factor (TGF)-beta axis and tumorigenesis We introduced the HOXB9 construct into the HT29 and HCT116 cancer cell lines (HT29-T and HCT116-T, respectively), both of which showed low HOXB9 mRNA expression relative to that in the other human colorectal cancer cell lines (Additional file 1: Figure S1c), in order to evaluate the functional consequence of HOXB9 overexpression in colorectal cancer
Angiogenic factors, including amphiregulin (AREG), epiregulin (ERG), basic fibroblast growth factor, interleukin-8 (IL8), and vascular endothelial growth factor (VEGF) were significantly upregulated by HOXB9 (Figure 1g)
Summary
Homeobox B9 (HOXB9), a transcriptional factor, regulates developmental processes and tumor progression and has recently been recognized as one of important transcriptional factors related to angiogenesis. Homeobox (HOX) genes are key regulators of embryonic development and are evolutionarily conserved [1]. Homeobox B9 (HOXB9) is expressed in several adult human tissues, including the endometrium [2], mammary glands [3], and blood precursor cells [4]. Angiogenesis plays critical roles in tumor growth [7,8] and cancer metastasis [9] because the generation of new vessels to meet the metabolic demands of under-perfused regions promotes tumor growth. Angiogenesis has become a target for cancer therapy through inhibition of vascular endothelial growth factor (VEGF) signaling by various drugs, including bevacizumab, sorafenib, and sunitinib
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