Moy.01HOXB9: an emerging novel prognostic marker and potential target for gene-therapy in colorectal liver metastases

Abstract

Abstract Aims Homeobox (HOX) proteins are emerging as promising biomarkers and targets for gene-therapy in cancer; however, their role in colorectal liver metastases (CRLM) is unknown. This study aims to investigate the role of HOXB9 as prognostic marker and potential therapeutic target in CRLM. Methods Two patient-cohorts were included: a) Patients with colorectal cancer (CRC) from the National Cancer Institute, Tissue Cancer Genome Atlas (TCGA) database (n = 614) and b) Institutional patient cohort who underwent liver resection for CRLM (n = 110) between 2007-2014. Primary outcome was 10-year overall survival (OS). COX regression and Kaplan-Meier survival analyses were performed including HOXB9 expression, demographics, clinicopathological and treatment-related variables. HOXB9 gene expression was modulated to assess its impact on CRC cell growth in vitro. Therefore, we conducted experimental studies using plasmid-vector and siRNA-interference to overexpress and knockdown HOXB9 respectively. Results Univariable TCGA analysis showed that HOXB9 did not predispose to poor OS (HR = 1, 95%CI:0.92-1.1, p = 0.620). On the contrary, univariable analysis in the CRLM patient cohort showed that high HOXB9 levels, right sided CRC, CRLM number≥4, CRLM diameter≥5cm, and intrahepatic recurrence were associated with significantly increased risk for worse OS. On multivariable models, only high HOXB9 expression (HR = 3.82, 95%CI:1.59-9.2, p = 0.003) and intrahepatic recurrence (HR = 4.28, 95%CI:1.88-9.72, p = 0.001) retained significance as independent prognostic factors after liver resection. Experimental studies showed that HOXB9 overexpression increased cell proliferation (p < 0.001) whereas HOXB9 inhibition markedly supressed CRC cell growth (p < 0.001) in vitro. Conclusions HOXB9 demonstrates oncogenic properties and may serve as novel prognostic marker and potential target for gene-directed therapy in CRC/CRLM.