Pan-cancer exploration of oncogenic and clinical impacts revealed that HOXA9 is a diagnostic indicator of tumorigenesis.

Homeodomain transcription factor A9 (HOXA9) is a member of the HOX cluster family of transcription factors that are crucially involved in embryo implantation, morphogenesis, body axis development, and endothelial cell differentiation. Despite numerous reports on its aberrant expression in a few malignancies, the molecular and functional complexity of HOXA9 across cancers remains obscure. We aimed to analyze the dynamic role of HOXA9 across cancers by identifying, analyzing, and understanding its multiple modes of regulation and functional implications and identifying possible therapeutic avenues. We conducted a comprehensive analysis to determine the role of HOXA9 across cancers. This approach involved the integration of large-scale datasets from public repositories such as the Genomic Data Commons, specifically the Cancer Genome Atlas (GDC-TCGA), across 33 different cancer types. The multiple modes of HOXA9 regulation by genetic and epigenetic factors were determined using online tools, which comprised experimentally validated observations. Furthermore, downstream pathways were identified by predicting the targets of HOXA9 and by performing functional enrichment analysis. We also assessed the clinical significance of HOXA9 in terms of prognosis and stage stratification. This study evaluated the correlation between HOXA9 and tumor-infiltrating molecules and discussed its association with therapeutically approved antineoplastic drugs. HOXA9 was significantly upregulated in 9 tumors and downregulated in 2 cancers. The deregulation of HOXA9 is primarily attributed to epigenetic factors, including promoter DNA methylation and noncoding RNAs (ncRNAs). The HOXA9 transcription factor interacts with PBX/MEIS cofactors and regulates multiple genes involved in cancer-associated EMT, autophagy, the cell cycle, metabolic pathways, Wnt signaling, TGF-ß signaling, the AMPK pathway, PI3K/AKT signaling, and NF-κB signaling, thereby establishing control over downstream mechanisms. Differential expression in various clinical stages across cancers was shown to have prognostic significance and to be correlated with tumor-infiltrating immune molecules. The assessment of the correlation of HOXA9 expression with approved antineoplastic drugs revealed that targeting HOXA9 could be the most reliable strategy for preventing cancer progression. HOXA9 is upregulated in the majority of malignancies and drives cancer progression by regulating multiple signaling mechanisms. Hence, HOXA9 could be a reliable diagnostic indicator and a potential therapeutic candidate for solid cancer types.

HOXA9 transcription factor is a double-edged sword: from development to cancer progression.

The HOXA9 transcription factor serves as a molecular orchestrator in cancer stemness, epithelial-mesenchymal transition (EMT), metastasis, and generation of the tumor microenvironment in hematological and solid malignancies. However, the multiple modes of regulation, multifaceted functions, and context-dependent interactions responsible for the dual role of HOXA9 as an oncogene or tumor suppressor in cancer remain obscure. Hence, unravelling its molecular complexities, binding partners, and interacting signaling molecules enables us to comprehend HOXA9-mediated transcriptional programs and molecular crosstalk. However, it is imperative to understand its central role in fundamental biological processes such as embryogenesis, foetus implantation, hematopoiesis, endothelial cell proliferation, and tissue homeostasis before designing targeted therapies. Indeed, it presents an enormous challenge for clinicians to selectively target its oncogenic functions or restore tumor-suppressive role without altering normal cellular functions. In addition to its implications in cancer, the present review also focuses on the clinical applications of HOXA9 in recurrence and drug resistance, which may provide a broader understanding beyond oncology, open new avenues for clinicians for accurate diagnoses, and develop personalized treatment strategies. Furthermore, we have also discussed the existing therapeutic options and accompanying challenges in HOXA9-targeted therapies in different cancer types.

HOX cluster-embedded lncRNAs and epithelial-mesenchymal transition in cancer: Molecular mechanisms and therapeutic opportunities.

Although there has been substantial improvement in the treatment modalities, cancer remains the major cause of fatality worldwide. Metastasis, recurrence, and resistance to oncological therapies are the leading causes of cancer mortality. Epithelial-mesenchymal transition (EMT) is a complex biological process that allows cancer cells to undergo morphological transformation into a mesenchymal phenotype to acquire invasive potential. It encompasses reversible and dynamic ontogenesis by neoplastic cells during metastatic dissemination. Hence, understanding the molecular landscape of EMT is imperative to identify a reliable clinical biomarker to combat metastatic spread. Accumulating evidence reveals the role of HOX (homeobox) cluster-embedded long non-coding RNAs (lncRNAs) in EMT and cancer metastasis. They play a crucial role in the induction of EMT, modulating diverse biological targets. The present review emphasizes the involvement of HOX cluster-embedded lncRNAs in EMT as a molecular sponge, chromatin remodeler, signaling regulator, and immune system modulator. Furthermore, the molecular mechanisms behind therapy resistance and the potential use of novel drugs targeting HOX cluster-embedded lncRNAs in the clinical management of distant metastasis will be discussed.

Integrated computational analysis reveals HOX genes cluster as oncogenic drivers in head and neck squamous cell carcinoma.

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.

Molecular implications of HOX genes targeting multiple signaling pathways in cancer.

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.

In silico interaction of HOX cluster-embedded microRNAs and long non-coding RNAs in oral cancer.

The essential role HOX-associated non-coding RNAs play in chromatin dynamics and gene regulation has been well documented. The potential roles of these microRNAs and long non-coding RNAs in oral cancer development, with their attendant involvement in various cellular processes including proliferation, invasion, migration, epithelial-mesenchymal transition and metastasis is gaining credence. An interaction network of HOX-embedded non-coding RNAs was constructed to identify the RNA interaction landscape using the arena-Idb platform and visualized using Cytoscape. The miR-10a was shown to interact with HOXA1, miR-10b with HOXD10, miR-196a1 with HOXA5, HOXA7, HOXB8, HOXC8, HOXD8, and miR-196a2 with HOXA5. The lncRNAs, HOTAIR interacted with HOXC11, HOTAIRM1 with HOXA1 and HOXA4, HOTTIP with HOXA13, HOXA-AS2 with HOXA3, HOXA11-AS with HOXA11 and HOXD-AS1 with HOXB8. Changes in the HOX cluster-embedded non-coding RNAs have implications for prognosis and overall disease survival. Our review aims to analyze the functional significance and clinical relevance of non-coding RNAs within the HOX cluster in the context of oral carcinogenesis. Elucidating these interactions between the non-coding RNAs and HOX genes in oral cancer development and progression could pave the way for the identification of reliable biomarkers and potential therapeutic targets.