Homeobox genes function as master regulatory transcription factors during development, and their expression is often altered in cancer. The HOX gene family was initially studied intensively to understand how the expression of each gene was involved in forming axial patterns and shaping the body plan during embryogenesis. More recent investigations have discovered that HOX genes can also play an important role in cancer. The literature has shown that the expression of HOX genes may be increased or decreased in different tumors and that these alterations may differ depending on the specific HOX gene involved and the type of cancer being investigated. New studies are also emerging, showing the critical role of some members of the HOX gene family in tumor progression and variation in clinical response. However, there has been limited systematic evaluation of the various contributions of each member of the HOX gene family in the pathways that drive the common phenotypic changes (or "hallmarks") and that underlie the transformation of normal cells to cancer cells. In this review, we investigate the context of the engagement of HOX gene targets and their downstream pathways in the acquisition of competence of tumor cells to undergo malignant transformation and tumor progression. We also summarize published findings on the involvement of HOX genes in carcinogenesis and use bioinformatics methods to examine how their downstream targets and pathways are involved in each hallmark of the cancer phenotype.

https://journals.sagepub.com/doi/pdf/10.1177/1010428320918050

Contributions of HOX genes to cancer hallmarks: Enrichment pathway analysis and review.

Recent studies have indicated that homeobox A3 (HOXA3) functions as a carcinogen in colon cancer and the methylation level of HOXA3 is significantly increased in lung adenocarcinoma (LUAD) tissues. However, at least to the best of our knowledge, few studies to date have been performed on HOXA3 in non-small cell lung cancer (NSCLC). Therefore, further studies on HOXA3 expression in NSCLC and the potential regulatory mechanisms are urgently required. In this study, HOXA3 expression in 55 tissues of cases of NSCLC and corresponding non-lung cancer tissues was detected by reverse transcription-quantitative PCR (RT-qPCR). In addition, the clinical significance of HOXA3 expression in NSCLC was evaluated using the Cancer Genome Atlas (TCGA) database. Bioinformatics analysis was then performed to elucidate the potential molecular mechanisms of action of HOXA3. Furthermore, the potential target microRNAs (miRNAs or miRs) of HOXA3 were predicted using miRWalk2.0. Based on Gene Expression Omnibus (GEO) and TGCA databases, standardized mean difference (SMD) and sROC methods were used for meta-analyses of the expression of potential target miRNAs of HOXA3 in NSCLC to evaluate their association with HOXA3. The results revealed that the HOXA3 expression levels in NSCLC, LUAD and lung squamous cell carcinoma (LUSC) were 0.1130±0.1398, 0.1295±0.16890 and 0.0906±0.0846, respectively. These values were all decreased compared with the normal tissues (0.1877±0.1975, 0.2337±0.2405 and 0.1249±0.0873, respectively, P<0.05). The TCGA database also revealed the low expression trend of HOXA3. The downregulation of HOXA3 may play an important role in the progression and the poor prognosis of LUAD. The TCGA database also suggested that HOXA3 in LUAD and LUSC tissues exhibited certain mutational levels. In addition, the methylation levels in the NSCLC, LUAD and LUSC tissues significantly increased [NSCLC: fold change (FC), 1.3226; P<0.001; LUAD: FC, 1.2712; P<0.001; and LUSC: FC, 1.3786; P<0.001]. According to the analyses using the Kyoto Encyclopedia of Genes and Genomes (KEGG), we found that the co-expression HOXA3 genes were mainly associated with the focal adhesion signalling pathway and the ECM-receptor interaction signalling pathway. Furthermore, the predicted miRNA, miR-372-3p, exhibited a high expression in both the NSCLC and LUAD tissues (P<0.05). On the whole, the findings of this study indicate that low HOXA3 expression may play a certain role in LUAD; however, its association with LUSC still requires further investigation. HOXA3 function may be achieved through different pathways or target miRNAs. However, the specific underlying mechanisms need to be confirmed through various functional studies.

/pdf/downregulation-of-hoxa3-in-lung-adenocarcinoma-and-its-nkgwz6243k.pdf

Downregulation of HOXA3 in lung adenocarcinoma and its relevant molecular mechanism analysed by RT-qPCR, TCGA and in silico analysis.

INTRODUCTION Galbanic acid (GA) is a natural bioactive compound abundantly distributed in Ferula species (Apiaceae), with a wide range of biological functions. METHODS The present study investigated the anticancer properties of GA in human breast carcinoma MCF-7 and MDA-MB-231 cell lines using MTT (3,4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide) assay. Further, the antioxidant activity of GA was determined in vitro. The plausible mechanisms of action of GA were further investigated using flow cytometry and gene expression analysis. RESULTS Our study indicated that treatment with GA resulted in inhibition of proliferation and induction of apoptosis in MDA-MB-231 cells. The obtained results indicated that GA has strong cytotoxicity on MDA-MB-231 cells (IC50  = 48.75 µg/mL) compare to MCF-7 (IC50  = 56.65 µg/mL) and decrease cancer cell viability in the dose- and time-dependent manner. Meanwhile, microscopic examination and flow cytometry analysis confirmed the apoptosis cell death upon treatment with GA. The gene expression analysis revealed that GA could induce apoptosis-mediated proliferation inhibition in MDA-MB-231 cells through upregulation of bax and caspase-3 and downregulation of bcl2 genes. Besides, the GA exhibited free radical-scavenging activity and enhanced the cellular redox state in human dermal fibroblasts. The elevation of cellular redox status was confirmed by upregulating superoxide dismutase, catalase, and glutathione peroxidase genes. CONCLUSION The results obtained in this study indicated that GA could be considered as a promising anticancer agent in breast cancer therapy and a bioactive antioxidant compound to be used in pharmaceutical and cosmetic industries.

Galbanic acid: Induced antiproliferation in estrogen receptor-negative breast cancer cells and enhanced cellular redox state in the human dermal fibroblasts.

Retinoic acid (RA), the biologically active metabolite of vitamin A, regulates a vast spectrum of biological processes, such as cell differentiation, proliferation, apoptosis, and morphogenesis. microRNAs (miRNAs) play a crucial role in regulating gene expression by binding to messenger RNA (mRNA) which leads to mRNA degradation and/or translational repression. Like RA, miRNAs regulate multiple biological processes, including proliferation, differentiation, apoptosis, neurogenesis, tumorigenesis, and immunity. In fact, RA regulates the expression of many miRNAs to exert its biological functions. miRNA and RA regulatory networks have been studied in recent years. In this manuscript, we summarize literature that highlights the impact of miRNAs in RA-regulated molecular networks included in the PubMed.

Retinoic acid and microRNA.

Background The prognosis of homeobox A9 (HOXA9) methylation have been assessed in a variety of cancers; nevertheless, the results remain undetermined due to discrete outcome and the limitations of small sample size. Therefore, we conducted a meta-analysis to explore the effect of HOXA9 methylation on the prognostic outcomes of patients with solid tumors. Methods Qualified studies were verified by searching PubMed, Excerpta Medica Database and Web of Science until September, 2020. Clinicopathological factors and hazard ratio (HR) of 95% confidence interval (95% CI) were selected. Subgroup analysis including carcinoma category, analysis method and sample size were adopted. Results In the meta-analysis 1,031 patients with solid carcinoma from 7 eligible investigations were involved. Among human cancer we discovered that the high HOXA9 methylation level was negative correlative with overall survival (OS) (HR =2.36; 95% CI: 1.70–3.26). In the subgroup analysis, we found HOXA9 methylation over-expression had statistical significance with poorer OS in lung cancer patients (HR =3.08, 95% CI: 1.70–5.55, P=0.002) and non-lung cancer (HR =2.10, 95% CI: 1.42–3.10, P=0.0002). Similar result was found in sample size. Greater than or equal to 100 (HR =2.31, 95% CI: 1.54–3.45, P<0.0001) and less than 100 (HR =2.45, 95% CI: 1.42–4.23, P=0.001). Discussion HOXA9 methylation has a significantly estimable biomarker of predicting poor prognosis and a potential target for therapy in solid malignant carcinoma from our meta-analysis.

/pdf/the-prognostic-value-of-homeobox-a9-hoxa9-methylation-in-3k4vj2rqnr.pdf

The prognostic value of homeobox A9 (HOXA9) methylation in solid tumors: a systematic review and meta-analysis

Progress in the understanding of the molecular mechanism for acute myeloid leukaemia is of great significance to generate new potential targets for treatment. Recent studies showed that HOXA9, a homeodomain-containing transcription factor, is commonly deregulated in acute leukaemia. In this study, we elucidated the direct correlation between HoxA9 expression and progression of leukaemia using 2 different types of leukaemia cells HL-60 and MOLT-3. The HoxA9 expression level was decreased in leukaemia cells with the treatment of all-trans retinoic acid or arsenic trioxide (As2 O3 ). Downregulation of HoxA9 could impair the proliferation and promote the leukaemia cell death. HoxA9 silencing also potentiated the differentiation of leukaemia cells, and in vivo studies demonstrated that HoxA9 downregulation could interfere the tumour growth. Interestingly, HoxA9 silencing also led to the alteration in miRNA expression, mediating the promoting effect on the leukaemia cell differentiation. Therefore, this work provided a promising and potentially efficient target to leukaemia treatment, indicating that HoxA9 is likely to be an ideal candidate in the gene therapy against acute myeloid leukaemia. In this study, we elucidated the critical role of HoxA9 in the proliferation and differentiation of leukaemia cells both in vitro and in vivo. The effect of HoxA9 modulation was correlated with the clinical effect of all-trans retinoic acid and As2 O3 . Furthermore, HoxA9 also regulated the miRNA expression, controlling the leukaemia cell differentiation. Therefore, this work provided new insights into molecular mechanism underlying the leukaemia treatment, potentially putting forward a brand new target to the gene therapy against leukaemia.

HOXA9 is critical in the proliferation, differentiation, and malignancy of leukaemia cells both in vitro and in vivo

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HOXA9 is critical in the proliferation, differentiation, and malignancy of leukaemia cells both in vitro and in vivo