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

Abstract

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.

Methylation in HOX Clusters and Its Applications in Cancer Therapy

“…For HOXA3, differential methylation profiles were found in glioma, lung and penile carcinomas, leading to its consideration as part of the methylome signature associated with these diseases [72,80,84,106].…”

Combined Analysis of the Aberrant Epigenetic Alteration of Colorectal Cancer

“…This result also suggested the feasibility of our present results. While other genes have not been reported to be associated with COAD/READ/CRC, their associations with other cancers have also been reported, such as APBB1, HHIP, and HOXA3 with lung cancer [30][31][32][33];TCF7L1, HOXB3, and ABCC2 with pancreatic cancer [34][35][36][37]; SALL1 with neck cancer [38,39];C2CD4A with breast cancer [40]. These results suggest both their relevance and their role as prognostic genes for corresponding cancers.Based on the results of our study and the relationship between those genes and other kind of cancers found in previous studies, it is suggested that those genes mentioned above may be used as prognostic genes for colorectal cancer.…”

Upregulated expression of SAC3D1 is associated with progression in gastric cancer

“…The co-expressed genes of SAC3D1 were obtained from the Multi Experiment Matrix (https://biit.cs.ut.ee/mem/index. cgi) (19) and COXPRESdb (http://coxpresdb.jp) (20). In the Multi Experiment Matrix, P<0.05 was regarded as statistically significant.…”