A Systematic Review on HOX Genes as Potential Biomarkers in Colorectal Cancer: An Emerging Role of HOXB9

Abstract

Emerging evidence shows that Homeobox (HOX) genes are important in carcinogenesis, and their dysregulation has been linked with metastatic potential and poor prognosis. This review (PROSPERO-CRD42020190953) aims to systematically investigate the role of HOX genes as biomarkers in CRC and the impact of their modulation on tumour growth and progression. The MEDLINE, EMBASE, Web of Science and Cochrane databases were searched for eligible studies exploring two research questions: (a) the clinicopathological and prognostic significance of HOX dysregulation in patients with CRC and (b) the functional role of HOX genes in CRC progression. Twenty-five studies enrolling 3003 CRC patients, showed that aberrant expression of HOX proteins was significantly related to tumour depth, nodal invasion, distant metastases, advanced stage and poor prognosis. A post-hoc meta-analysis on HOXB9 showed that its overexpression was significantly associated with the presence of distant metastases (pooled OR 4.14, 95% CI 1.64–10.43, I2 = 0%, p = 0.003). Twenty-two preclinical studies showed that HOX proteins are crucially related to tumour growth and metastatic potential by affecting cell proliferation and altering the expression of epithelial-mesenchymal transition modulators. In conclusion, HOX proteins may play vital roles in CRC progression and are associated with overall survival. HOXB9 may be a critical transcription factor in CRC.

HOXB9 Overexpression Promotes Colorectal Cancer Progression and Is Associated with Worse Survival in Liver Resection Patients for Colorectal Liver Metastases

“…Indeed, studies by Hoshino et al and Huang et al have reported a positive association between high HOXB9 protein levels and lymph node invasion, presence of distant metastases, and poor differentiation in patients with CRC [11,12]. Additionally, in our systematic review, we found by conducting a post hoc meta-analysis that high HOXB9 expression levels were associated with a significantly increased risk for metastases (OR 4.14, 95% CI: 1.64-10.43, p = 0.003) [10]. In our CRLM patient group, although we did not find a significant association with the adverse CRLM characteristics, we noticed that high HOXB9 levels were positively correlated with the presence of metastatic disease in the regional lymph nodes at the time of the primary cancer resection, indicating that HOXB9 may promote CRC progression and affect survival.…”

“…Likewise, the experimental observations also differed between studies with regard to the role of HOXB9 in CRC progression. Our study, Huang et al [11] and Hoshino et al [12] reported a potential tumour promoting role of HOXB9 whereas Zhan et al [13] observed a potential tumour suppressive function of HOXB9 in CRC [10]. Variability in the selection of downstream functional assays could be one reason for the contradictory findings.…”

“…However, it is interesting that studies report contradictory findings in terms of its clinicopathological significance as well as its mechanistic role in CRC progression. Studies including our own, report opposing findings regarding the association of HOXB9 in OS [10][11][12][13]. This could be attributed to the different methodological approaches implemented by the studies with regard to the categorization of high and low HOXB9 expression patient groups.…”

“…This could be attributed to the different methodological approaches implemented by the studies with regard to the categorization of high and low HOXB9 expression patient groups. For instance, despite the fact that studies used IHC as an evaluation method of HOXB9 protein expression, the categorization based on staining intensity varied between studies [10][11][12][13]. Additionally, in our study, we accounted for both the intensity as well as the percentage of stained cells to ensure a more robust classification method of HOXB9 protein expression.…”

“…Additionally, high HOXB9 protein levels have also been reported by many studies to be associated with a poor prognosis in patients with lung, breast, hepatocellular, and pancreatic carcinoma [8]. In CRC, few studies have reported contradictory findings regarding the HOXB9 prognostic role and function in CRC progression [10]. However, no studies have examined colorectal liver metastases (CRLM) [11][12][13].…”