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Published on: July 22, 2020
Identification of hub genes and potential molecular mechanisms related to radiotherapy sensitivity in rectal cancer
Pengfei Zhao1, Hongchao Zhen2, Hong Zhao1
1Department of Radiotherapy, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, P.R. China.
Background:
Radiotherapy resistance is the main cause of low tumor regression for locally advanced rectum adenocarcinoma (READ). The biomarkers correlated to radiotherapy sensitivity and potential molecular mechanisms have not been completely elucidated.
Methods:
A mRNA expression profile and a gene expression dataset of READ (GSE35452) were acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Differentially expressed genes (DEGs) between radiotherapy responder and non-responder of READ were screened out. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis for DEGs were performed. Random survival forest analysis was used to identified hub genes by randomForestSRC package. Based on CIBERSORT algorithm, Genomics of Drug Sensitivity in Cancer (GDSC) database, Gene set variation analysis (GSVA), enrichment analysis (GSEA), nomogram, motif enrichment and non-coding RNA network analyses, the associations between hub genes and immune cell infiltration, drug sensitivity, specific signaling pathways, prognosis prediction and TF - miRNA regulatory and ceRNA network were investigated. The expressions of hub genes in clinical samples were displayed with the online Human Protein Atlas (HPA).
Results:
In total, 544 up-regulated and 575 down-regulated DEGs in READ were enrolled. Among that, three hubs including PLAGL2, ZNF337 and ALG10 were identified. These three hub genes were significantly associated with tumor immune infiltration, different immune-related genes and sensitivity of chemotherapeutic drugs. Also, they were correlated with the expression of various disease-related genes. In addition, GSVA and GSEA analysis revealed that different expression levels of PLAGL2, ZNF337 and ALG10 affected various signaling pathways related to disease progression. A nomogram and calibration curves based on three hub genes showed excellent prognosis predictive performance. And then, a regulatory network of transcription factor (ZBTB6) - mRNA (PLAGL2) and a ceRNA network of miRNA (has-miR-133b) - lncRNA were established. Finally, the results from HPA online database demonstrated the protein expression levels of PLAGL2, ZNF337 and ALG10 varied widely in READ patients.
Conclusion:
These findings indicated that up-regulation of PLAGL2, ZNF337 and ALG10 in READ associated with radiotherapy response and involved in multiple process of cellular biology in tumor. They might be potential predictive biomarkers for radiotherapy sensitivity and prognosis for READ.
Insights
Radiotherapy resistance in rectum adenocarcinoma (READ) is a challenge. Three genes, PLAGL2, ZNF337, and ALG10, were identified as potential biomarkers for predicting treatment response and patient prognosis.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Radiotherapy resistance limits tumor regression in locally advanced rectum adenocarcinoma (READ).
- Biomarkers for radiotherapy sensitivity and underlying molecular mechanisms in READ remain unclear.
Purpose of the Study:
- To identify novel biomarkers for predicting radiotherapy response in READ.
- To elucidate the molecular mechanisms associated with radiotherapy sensitivity in READ.
Main Methods:
- Utilized TCGA and GEO datasets to identify differentially expressed genes (DEGs) in READ responders versus non-responders.
- Performed bioinformatics analyses including GO, KEGG, random survival forest, CIBERSORT, GSVA, GSEA, and constructed regulatory networks.
- Validated hub gene expression in clinical samples using the Human Protein Atlas (HPA).
Main Results:
- Identified three hub genes (PLAGL2, ZNF337, ALG10) significantly associated with radiotherapy response.
- These genes correlate with tumor immune infiltration, drug sensitivity, and disease-related gene expression.
- A nomogram based on these hub genes demonstrated excellent prognostic predictive performance.
Conclusions:
- PLAGL2, ZNF337, and ALG10 are upregulated in READ and linked to radiotherapy response.
- These genes are involved in cellular processes critical to tumor progression and may serve as predictive biomarkers for radiotherapy sensitivity and prognosis in READ.
