Homeobox (HOX) genes encode highly conserved homeotic transcription factors that play a crucial role in organogenesis and tissue homeostasis. Their deregulation impacts the function of several regulatory molecules contributing to tumor initiation and progression. A functional bridge exists between altered gene expression of individual HOX genes and tumorigenesis. This review focuses on how deregulation in the HOX-associated signaling pathways contributes to the metastatic progression in cancer. We discuss their functional significance, clinical implications and ascertain their role as a diagnostic and prognostic biomarker in the various cancer types. Besides, the mechanism of understanding the theoretical underpinning that affects HOX-mediated therapy resistance in cancers has been outlined. The knowledge gained shall pave the way for newer insights into the treatment of cancer. Graphical abstract

HOX genes are members of the homeotic transcription factor family, organized into four paralogous clusters. HOX complexes are believed to have arisen by genome-wide duplications during evolution. In humans, there are about 200 homeobox genes of which 39 are HOX genes, which are segregated onto four chromosomes, HOXA -7p15, HOXB -17q21.2, HOXC -12q13, and HOXD -2q31 (Figure 1). 1,2 The protein product of the HOX gene is a transcription factor that contains a conserved homeodomain region. 2 The homeodomain consists of the helix-turn-helix protein motif responsible for sequence-specific DNA binding. HOX genes are the pivotal regulators of growth and development. They regulate events such as differentiation, metabolism, apoptosis, autophagy, and their deregulation leads to various disorders and diseases including cancer. 3

The objective of the study is to understand the role of experimentally validated microRNAs (miRNAs) contributing to the acquisition of oncogenic phenotype in oral submucous fibrosis (OSF) by computational analysis. A comprehensive review was carried out to corroborate and summarize altered miRNA expression in OSF by retrieving relevant publications querying MEDLINE, Web of Science, Embase, and Scopus. The association between the miRNA‐mRNA was performed using miRTarBase 8.0. The visualization of the miRNA‐mRNA interaction was plotted using Cytoscape. MIENTURNET was used for the pathway analysis. Enrichment analysis was carried out for elucidating the hierarchical functions of miRNAs related to the acquisition of biological processes involved in the development of cancer. Thirteen miRNAs (hsa‐miR‐499a, hsa‐miR‐200b, hsa‐miR‐200c, hsa‐miR‐1246, hsa‐miR‐31, hsa‐miR‐10b, hsa‐miR‐21, hsa‐miR‐203, hsa‐miR‐455, hsa‐miR‐760, hsa‐miR‐623, hsa‐miR‐610, and hsa‐miR‐509‐3‐5p) were found to be deregulated in OSF. A total of 371 experimentally validated genes were shown to be interacting with the OSF‐associated miRNAs. The targets of antifibrotic and profibrotic miRNAs were enriched in the cancer‐related pathways. Dysregulated miRNA and its target genes illustrate the physiological role of miRNAs in fibrosis. Understanding the miRNA‐mediated fibrotic signaling and targetting the specific miRNA‐target gene interaction might provide relevant cues to ameliorate the fibrotic disease.

Alterations in homeobox (HOX) gene expression are involved in the progression of several cancer types including head and neck squamous cell carcinoma (HNSCC). However, regulation of the entire HOX cluster in the pathophysiology of HNSCC is still elusive. By using different comprehensive databases, we have identified the significance of differentially expressed HOX genes (DEHGs) in stage stratification and HPV status in the cancer genome atlas (TCGA)-HNSCC datasets. The genetic and epigenetic alterations, druggable genes, their associated functional pathways and their possible association with cancer hallmarks were identified. We have performed extensive analysis to identify the target genes of DEHGs driving HNSCC. The differentially expressed HOX cluster-embedded microRNAs (DEHMs) in HNSCC and their association with HOX-target genes were evaluated to construct a regulatory network of the HOX cluster in HNSCC. Our analysis identified sixteen DEHGs in HNSCC and determined their importance in stage stratification and HPV infection. We found a total of 55 HNSCC driver genes that were identified as targets of DEHGs. The involvement of DEHGs and their targets in cancer-associated signaling mechanisms have confirmed their role in pathophysiology. Further, we found that their oncogenic nature could be targeted by using the novel and approved anti-neoplastic drugs in HNSCC. Construction of the regulatory network depicted the interaction between DEHGs, DEHMs and their targets genes in HNSCC. Hence, aberrantly expressed HOX cluster genes function in a coordinated manner to drive HNSCC. It could provide a broad perspective to carry out the experimental investigation, to understand the underlying oncogenic mechanism and allow the discovery of new clinical biomarkers for HNSCC.

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