Deregulated HOXB7 Expression Predicts Poor Prognosis of Patients with Esophageal Squamous Cell Carcinoma and Regulates Cancer Cell Proliferation In Vitro and In Vivo

Abstract

BackgroundWe observed abnormal HOXB7 expression in esophageal squamous cell carcinoma (ESCC) previously. This study was to evaluate the prognostic significance of HOXB7 and reveal the potential mechanism.MethodsImmunohistochemistry was used to confirm the abnormal expression of HOXB7 in ESCC. The prognostic significance of HOXB7 expression was analyzed in two independent cohorts. RNAi was used to establish two stable HOXB7-knockdown cell strains. CCK8 assay, cell growth curve assay, colony formation assay, flow cycle analysis and tumorigenicity assay in nude mice were employed to investigate the effect of HOXB7 on proliferation in vitro and in vivo.ResultsImmunohistochemistry confirmed the abnormal expression of HOXB7 in ESCC compared with paracancerous mucosa (18/23 vs. 9/23, p=0.039). HOXB7 expression was positively correlated with the T stage, lymph node metastasis and TNM stage. The median survival of patients with high HOXB7 expression was significantly shorter than that with low expression (45 months vs. 137 months, p = 0.007 for cohort 1; 19 months vs. 34 months, p = 0.001 for cohort 2). Multivariate survival analysis showed that HOXB7 expression was another independent prognostic factor (HR [95% CI] = 0.573 [0.341–0.963], p = 0.036 for cohort 1; HR [95%CI] = 0.543 [0.350–0.844], p = 0.024 for cohort 2). Experiments in vitro and in vivo showed that after knockdown of HOXB7, the proliferation rate dropped, growth rate descended, colony-formation ability reduced, G1-phase arrest occurred and the tumorigenicity reduced remarkably.ConclusionsHOXB7 could promote cancer cell proliferation and might be an independent prognostic factor for patients with ESCC.

Targeting HOX/PBX dimer formation as a potential therapeutic option in esophageal squamous cell carcinoma

“…Herein, we established cell strains with stable knockdown of single HOXB7 / HOXC6/HOXC8 genes using RNAi to observe their oncogenic properties. Results of HOXB7 knockdown in ESCC cells have been reported in our previous study, which showed that cell proliferation rate dropped, cell growth rate decreased, colony‐formation ability reduced and tumorigenicity reduced remarkably. In the present study, we observed oncogenic function redundancy between HOXB7 and HOXC6/HOXC8.…”

“…Our previous studies reported that 11 of 39 HOX genes were overexpressed in esophageal cancer tissues, in which HOXB7, HOXC6 and HOXC8 are positioned closely together and might consequently show functional redundancy. It has been shown that ESCC patients with high expression of HOXB7/HOXC6/HOXC8 had poorer prognosis than those with low expression . However, no evidence has established their oncogenic function in ESCC.…”

“…In our previous study, we found that 11 of 39 HOX genes were overexpressed in ESCC tissues compared with paired noncancerous mucosa, including HOXB7, HOXC6 and HOXC8. Moreover, we showed that these HOX genes promoted oncogenic properties in ESCC cells and presented negative survival significance in ESCC patients . Specifically, knockdown of HOXB7, HOXC6 or HOXC8 resulted in antiproliferation and proapoptosis phenotype in ESCC cell lines, and induced cell cycle arrest in G1 phase, and inhibited tumor growth in a mice xenograft model.…”

“…Moreover, we showed that these HOX genes promoted oncogenic properties in ESCC cells and presented negative survival significance in ESCC patients. 14,15 Specifically, knockdown of HOXB7, HOXC6 or HOXC8 resulted in antiproliferation and proapoptosis phenotype in ESCC cell lines, and induced cell cycle arrest in G1 phase, and inhibited tumor growth in a mice xenograft model. HOX genes have distinct functions in a specific context during early development, and this functional complexity is also seen in tumorigenesis, with some HOX genes functioning as oncogenes and others as tumor suppressors.…”

Increased HOXC6 expression predicts chemotherapy sensitivity in patients with esophageal squamous cell carcinoma

“…Alterations in the expression patterns of HOX gene family members cause dysregulation of HOX protein function, further leading to unbalanced cell proliferation and differentiation; this is hypothesized to contribute to tumorigenesis. In the last two decades, studies have identified that the expression patterns of HOX genes are abnormal in a variety of tumors, including esophageal cancer (7)(8)(9)(10)(11). Our previous studies (8,10) demonstrated that HOXC6 serves a key function in esophageal squamous cell carcinoma (ESCC) and is abnormally expressed in ESCC tissues.…”