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

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.

HOX Protein Activity Regulation by Cellular Localization

While the functions of HOX genes have been and remain extensively studied in distinct model organisms from flies to mice, the molecular biology of HOX proteins remains poorly documented. In particular, the mechanisms involved in regulating the activity of HOX proteins have been poorly investigated. Nonetheless, based on data available from other well-characterized transcription factors, it can be assumed that HOX protein activity must be finely tuned in a cell-type-specific manner and in response to defined environmental cues. Indeed, records in protein–protein interaction databases or entries in post-translational modification registries clearly support that HOX proteins are the targets of multiple layers of regulation at the protein level. In this context, we review here what has been reported and what can be inferred about how the activities of HOX proteins are regulated by their intracellular distribution.

Hox genes in the coordination of embryonic development. Model of hourglass in the description of vertebrate ontogenesis

The paper analyzes the role of HOX genes in the processes of embryonic development of vertebrates. Based on the analysis, it is concluded that HOX genes are the most important regulators of embryonic development. The HOX genes predominantly realize their influence through specific HOX proteins that have the ability to regulate the expression of target genes. The order of expression of the HOX genes, as a rule, obeys the rule of temporal and spatial colinearity. This mechanism determines the temporal and spatial course of tissue morphogenesis during embryonic development and tissue regeneration in organisms that have reached the stage of maturity. The process of embryo morphogenesis, determined by highly conserved HOX genes, explains the appearance of the phylotypic period - the stage of embryonic development of vertebrates, at which embryos of different classes of vertebrates have distinct morphological similarities.

The Role of HOX Genes as Potential Biomarkers in Colorectal Cancer: A Systematic Review

Background: Colorectal cancer (CRC) is worldwide the third leading cause of cancer-related death, and despite therapeutic advances, survival remains low. Emerging evidence shows that Homeobox (HOX) genes are important in carcinogenesis, and their dysregulation has been linked with metastatic potential and poor prognosis. This systematic review aims to present the current evidence on the role of HOX genes as biomarkers in CRC and the impact of their modulation in tumour growth and progression. Methods: MEDLINE, EMBASE, Web of Science and Cochrane databases were searched by following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Eligible studies investigated two research questions: a) the clinicopathological and prognostic significance of HOX gene dysregulation in patients with CRC and b) the functional role of HOX genes in CRC progression. This study was registered in the international prospective register of systematic reviews (PROSPERO), CRD42020190953. Results: Twenty-five studies enrolling 3003 patients with stage I-IV CRC, showed that 26 out of 39 HOX genes were dysregulated in cancerous versus normal colon. Aberrant expression of HOX proteins was significantly related to tumour depth, nodal invasion, distant metastases, advanced stage and poor prognosis. 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. Conclusions: In conclusion, our findings suggest that HOX proteins play vital roles in CRC progression and significantly affect survival. Further research, though, is required to elucidate their potential role as biomarkers in CRC.

Hox Proteins in the Regulation of Muscle Development

Hox genes encode evolutionary conserved transcription factors that specify the anterior–posterior axis in all bilaterians. Being well known for their role in patterning ectoderm-derivatives, such as CNS and spinal cord, Hox protein function is also crucial in mesodermal patterning. While well described in the case of the vertebrate skeleton, much less is known about Hox functions in the development of different muscle types. In contrast to vertebrates however, studies in the fruit fly, Drosophila melanogaster, have provided precious insights into the requirement of Hox at multiple stages of the myogenic process. Here, we provide a comprehensive overview of Hox protein function in Drosophila and vertebrate muscle development, with a focus on the molecular mechanisms underlying target gene regulation in this process. Emphasizing a tight ectoderm/mesoderm cross talk for proper locomotion, we discuss shared principles between CNS and muscle lineage specification and the emerging role of Hox in neuromuscular circuit establishment.

The Role of HOX Genes as Potential Biomarkers in Colorectal Cancer: A Systematic Review

Background: Colorectal cancer (CRC) is worldwide the third leading cause of cancer-related death, and despite therapeutic advances, survival remains low. Emerging evidence shows that Homeobox (HOX) genes are important in carcinogenesis, and their dysregulation has been linked with metastatic potential and poor prognosis. This systematic review aims to present the current evidence on the role of HOX genes as biomarkers in CRC and the impact of their modulation in tumour growth and progression. Methods: MEDLINE, EMBASE, Web of Science and Cochrane databases were searched by following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Eligible studies investigated two research questions: a) the clinicopathological and prognostic significance of HOX gene dysregulation in patients with CRC and b) the functional role of HOX genes in CRC progression. This study was registered in the international prospective register of systematic reviews (PROSPERO), CRD42020190953. Results: Twenty-five studies enrolling 3003 patients with stage I-IV CRC, showed that 26 out of 39 HOX genes were dysregulated in cancerous versus normal colon. Aberrant expression of HOX proteins was significantly related to tumour depth, nodal invasion, distant metastases, advanced stage and poor prognosis. 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. Conclusions: In conclusion, our findings suggest that HOX proteins play vital roles in CRC progression and significantly affect survival. Further research, though, is required to elucidate their potential role as biomarkers in CRC.

The Role of HOX Genes as Potential Biomarkers in Colorectal Cancer: A Systematic Review

Background: Colorectal cancer (CRC) is worldwide the third leading cause of cancer-related death, and despite therapeutic advances, survival remains low. Emerging evidence shows that Homeobox (HOX) genes are important in carcinogenesis, and their dysregulation has been linked with metastatic potential and poor prognosis. This systematic review aims to present the current evidence on the role of HOX genes as biomarkers in CRC and the impact of their modulation in tumour growth and progression. Methods: MEDLINE, EMBASE, Web of Science and Cochrane databases were searched by following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Eligible studies investigated two research questions: a) the clinicopathological and prognostic significance of HOX gene dysregulation in patients with CRC and b) the functional role of HOX genes in CRC progression. This study was registered in the international prospective register of systematic reviews (PROSPERO), CRD42020190953. Results: Twenty-five studies enrolling 3003 patients with stage I-IV CRC, showed that 26 out of 39 HOX genes were dysregulated in cancerous versus normal colon. Aberrant expression of HOX proteins was significantly related to tumour depth, nodal invasion, distant metastases, advanced stage and poor prognosis. 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. Conclusions: In conclusion, our findings suggest that HOX proteins play vital roles in CRC progression and significantly affect survival. Further research, though, is required to elucidate their potential role as biomarkers in CRC.

HOXA1 Is an Antagonist of ERα in Breast Cancer

Breast cancer is a heterogeneous disease and the leading cause of female cancer mortality worldwide. About 70% of breast cancers express ERα. HOX proteins are master regulators of embryo development which have emerged as being important players in oncogenesis. HOXA1 is one of them. Here, we present bioinformatic analyses of genome-wide mRNA expression profiles available in large public datasets of human breast cancer samples. We reveal an extremely strong opposite correlation between HOXA1 versus ER expression and that of 2,486 genes, thereby supporting a functional antagonism between HOXA1 and ERα. We also demonstrate in vitro that HOXA1 can inhibit ERα activity. This inhibition is at least bimodal, requiring an intact HOXA1 DNA-binding homeodomain and involving the DNA-binding independent capacity of HOXA1 to activate NF-κB. We provide evidence that the HOXA1-PBX interaction known to be critical for the transcriptional activity of HOXA1 is not involved in the ERα inhibition. Finally, we reveal that HOXA1 and ERα can physically interact but that this interaction is not essential for the HOXA1-mediated inhibition of ERα. Like other HOX oncoproteins interacting with ERα, HOXA1 could be involved in endocrine therapy resistance.

HOXB8 Counteracts MAPK/ERK Oncogenic Signaling in a Chicken Embryo Model of Neoplasia

HOX transcription factors are members of an evolutionarily conserved family of proteins required for the establishment of the anteroposterior body axis during bilaterian development. Although they are often deregulated in cancers, the molecular mechanisms by which they act as oncogenes or tumor suppressor genes are only partially understood. Since the MAPK/ERK signaling pathway is deregulated in most cancers, we aimed at apprehending if and how the Hox proteins interact with ERK oncogenicity. Using an in vivo neoplasia model in the chicken embryo consisting in the overactivation of the ERK1/2 kinases in the trunk neural tube, we analyzed the consequences of the HOXB8 gain of function at the morphological and transcriptional levels. We found that HOXB8 acts as a tumor suppressor, counteracting ERK-induced neoplasia. The HOXB8 tumor suppressor function relies on a large reversion of the oncogenic transcriptome induced by ERK. In addition to showing that the HOXB8 protein controls the transcriptional responsiveness to ERK oncogenic signaling, our study identified new downstream targets of ERK oncogenic activation in an in vivo context that could provide clues for therapeutic strategies.

Developmental Robustness: The Haltere Case in Drosophila

Developmental processes have to be robust but also flexible enough to respond to genetic and environmental variations. Different mechanisms have been described to explain the apparent antagonistic nature of developmental robustness and plasticity. Here, we present a “self-sufficient” molecular model to explain the development of a particular flight organ that is under the control of the Hox gene Ultrabithorax (Ubx) in the fruit fly Drosophila melanogaster. Our model is based on a candidate RNAi screen and additional genetic analyses that all converge to an autonomous and cofactor-independent mode of action for Ubx. We postulate that this self-sufficient molecular mechanism is possible due to an unusually high expression level of the Hox protein. We propose that high dosage could constitute a so far poorly investigated molecular strategy for allowing Hox proteins to both innovate and stabilize new forms during evolution.