Abstract
BackgroundHyaluronan-mediated motility receptor (HMMR) plays a pivotal role in cell proliferation in various cancers, including lung cancer. However, its function and biological mechanism in lung adenocarcinoma (LUAD) remain unclear.MethodsData on HMMR expression from several public databases were extensively analyzed, including the prognosis of HMMR in the Gene Expression Profiling Interactive Analysis (GEPIA) database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed using DAVID and gene set enrichment analysis (GSEA) software. The correlation between HMMR expression and immune cell infiltration was analyzed in the Tumor Immune Estimation Resource (TIMER) database, and the gene and protein networks were examined using the GeneMANIA and STRING databases. Experimentally, the expression of HMMR in LUAD and lung cancer cell lines was determined using immunohistochemistry and quantitative RT-PCR assays. Besides, the function of HMMR on cancer cell proliferation and migration was examined using cell growth curve and colony formation, Transwell, and wound healing assays.ResultsIn this study, we found that HMMR was elevated in LUAD and that its high expression was associated with poor clinicopathological features and adverse outcomes in LUAD patients. Furthermore, our results demonstrated that the expression of HMMR was positively correlated with immune cell infiltration and immune modulation. Interestingly, diverse immune cell infiltration affects the prognosis of LUAD. In the functional assay, depletion of HMMR significantly repressed the cancer cell growth and migration of LUAD. Mechanically, we found that that the DNA methylation/TMPO-AS1/let-7b-5p axis mediated the high expression of HMMR in LUAD. Depletion of TMPO-AS1 and overexpression of let-7b-5p could result in the decreased expression of HMMR in LUAD cells. Furthermore, we found that TMPO-AS1 was positively correlated with HMMR, yet negatively correlated with let-7b-5p expression in LUAD.ConclusionsOur findings elucidated that the DNA methylation/TMPO-AS1/let-7b-5p axis mediated the high expression of HMMR, which may be considered as a biomarker to predict prognosis in LUAD.
Highlights
Lung cancer is one of the main causes of cancer death and has brought huge public health burden worldwide [1]
The results indicated that Hyaluronan-mediated motility receptor (HMMR) was elevated in pan-cancer, including bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), esophageal carcinoma (ESCA), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), thyroid carcinoma (THCA), and uterine corpus endometrial carcinoma (UCEC) (Figure 1A)
To further verify the results, we used Gene Expression Profiling Interactive Analysis (GEPIA) database analysis and found that HMMR was significantly overexpressed in adrenocortical carcinoma (ACC), BLCA, BRCA, cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), COAD, lymphoid neoplasm diffuse large B-cell lymphoma (DLBC), ESCA, glioblastoma multiforme (GBM), HNSC, LIHC, LUAD, LUSC, ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), READ, skin cutaneous melanoma (SKCM), STAD, thymoma (THYM), UCEC, and uveal melanoma (UVM) compared to matched normal tissues
Summary
Lung cancer is one of the main causes of cancer death and has brought huge public health burden worldwide [1]. We developed a new method called cross-value association analysis (CVAA), which functions without a normalization and distribution assumption We applied this method to large-scale pan-cancer transcriptome data generated by The Cancer Genome Atlas (TCGA) project and successfully discovered numerous new differentially expressed genes (DEGs). HMMR, named as RHAMM (receptor for hyaluronan-mediated motility), plays a pivotal role in cell proliferation [6]. A previous study indicated that HMMR was essential to maintain the stemness of glioblastoma stem cells [14]. He et al found that HMMR was upregulated in bladder cancer and correlated with poor prognosis. Hyaluronan-mediated motility receptor (HMMR) plays a pivotal role in cell proliferation in various cancers, including lung cancer. Its function and biological mechanism in lung adenocarcinoma (LUAD) remain unclear
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