Bevacizumab terminates homeobox B9-induced tumor proliferation by silencing microenvironmental communication

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.

Increased expression of HOXB9 in hepatocellular carcinoma predicts poor overall survival but a beneficial response to sorafenib

“…Although, HOXB9 expression in HCC did not affect disease-free survival after surgery (data not shown), increased HOXB9 expression in HCC was significantly associated with a poor prognosis in OS (5-year OS rate; 63.5 vs. 58.5%; p=0.0324) (Fig. 1C), as previously reported for breast and colorectal cancer (9,10). Moreover, HOXB9 mRNA expression was significantly higher in patients exhibiting vascular invasion (both portal and hepatic vein) compared to those who were negative for vascular invasion (Fig.…”

“…2C). These results are consistent with previously reported results in breast cancer (2,10). Moreover, a decrease in HOXB9 expression in the two HCC cell lines also mitigated the Raf/MEK/ERK pathway (Fig.…”

Immunoexpression of hoxb7 and hoxb9 in salivary gland tumours

“…Homeobox‐containing ( HOX ) genes are evolutionarily conserved family of genes that play important roles during embryogenesis . HOX genes are classified into two main groups as class I and class II genes .…”

“…HOX genes are classified into two main groups as class I and class II genes . In mammals, class I HOX genes contain 39 members with a shared, highly conserved 61‐amino acid homeodomain motif that is organized in four paralogous clusters (A, B, C and D) arranged in chromosomes 7, 17, 12 and 2, respectively . Each cluster contains 9–11 genes arranged in 13 groups based on homeobox sequence and the position within the cluster.…”

“…Each cluster contains 9–11 genes arranged in 13 groups based on homeobox sequence and the position within the cluster. In addition to the well‐known role played by HOX genes in normal development process, an increasing number of studies have recently demonstrated that these genes seem to be dysregulated in a variety of human cancers .…”