Identification of HOX signatures contributing to oral cancer phenotype

Abstract

The role of evolutionarily conserved homeobox-containing HOX genes as transcriptional regulators in the developmental specification of organisms is well known. The contribution of HOX genes involvement in oral cancer phenotype has yet to be fully ascertained. TCGA-HNSC HTSeq-counts and clinical data were retrieved from the GDC portal for oral cavity neoplasms. GEO datasets (GSE72627, GSE30784, GSE37991) were accessed and analyzed using GEO2R. Differential HOX gene expression was profiled using the DESeq2 R package with a log2 fold change cut-off (− 1 and + 1) and Benjamini–Hochberg p-adjusted value at ≤ 0.01. Gene set over-representation analysis and semantic analysis associated with the disease ontology was performed using the ClusterProfiler R package, and pathway over-representation analysis was performed using IMPaLa. HOX protein interaction network was constructed using the Pathfind R package. HOX phenotype associations were performed using Mammalian Phenotype Ontology, Human Phenotype Ontology, PhenGenI associations, Jensen tissues, and OMIM entries. Drug connectivity mapping was carried out with Dr. Insight R package. HOXA2 was upregulated in oral dysplasia but silenced during tumor progression. Loss of HOXB2 expression was consistent in the potentially malignant oral lesions as well as in the primary tumor. HOXA7, HOXA10, HOXB7, HOXC6, HOXC10, HOXD10, and HOXD11 were consistently upregulated from premalignancy to malignancy and were notably associated with risk factors. Overrepresentation analysis suggested HOXA10 was involved in the transcriptional misregulation contributing to the oral cancer phenotype. HOX genes subnetwork analysis showed crucial interactions with cell cycle regulators, growth responsive elements, and proto-oncogenes. Phenotype associations specific to the oral region involving HOX genes provide intrinsic cues to tumor development. The 5′ HOX genes were aberrantly upregulated during oral carcinogenesis reflecting their posterior prevalence.

Mitogen‐activated protein kinase inhibition augments the T cell response against HOXB7‐expressing tumor through human leukocyte antigen upregulation

“…The relationship between HOXB7 overexpression and poor prognosis has been reported in various types of cancer 16,21,36–38 . As in previous reports, the present study also found an association between HOXB7 and alcohol consumption 39 . The overexpression of HOXB7 increases the proliferation, invasion, and migration of tumor cell lines, 27,36,38 and HOXB7 knockdown inhibits the proliferation of HNSCC cells.…”

“… 16 , 21 , 36 , 37 , 38 As in previous reports, the present study also found an association between HOXB7 and alcohol consumption. 39 The overexpression of HOXB7 increases the proliferation, invasion, and migration of tumor cell lines, 27 , 36 , 38 and HOXB7 knockdown inhibits the proliferation of HNSCC cells. Liao et al reported that HOXB7 might be a useful prognostic biomarker for colorectal cancer.…”

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“…In contrast to other methods, the present study identified 3 candidate biomarker genes (P13, KRT16, and EGR3), and further validation revealed that only EGR3 was the most enriched gene and had a similar expression pattern in the analyzed datasets. Additionally, several previous studies report the wellknown association of EGR family genes with SCC (Padam et al, 2022). Thus, considering previous reports, the results of our study encourage us to infer that EGR3 is a novel CSCC-related biomarker gene with featured functions that are vital for early diagnosis and efficient treatment of cancer in clinical disease management.…”

Spatial transcriptomics reveals distinct and conserved tumor core and edge architectures that predict survival and targeted therapy response

“…Conversely, the upregulation of several TFs including cellular development and differentiation-regulatory genes TP63 and HOXB2 (refs. 36 , 37 ), and EMT regulatory genes CREB3L1 , TCF4 , and NFATC4 (refs. 38 – 40 ) were observed in the LE (Supplementary Fig.…”