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. 2024 Jan 20;60(1):181.
doi: 10.3390/medicina60010181.

Deciphering the Role of ERBB3 Isoforms in Renal Cell Carcinoma: A Comprehensive Genomic and Transcriptomic Analysis

Mingyu Kim  1 , Hyung Ho Lee  1 , So Dam Won  1 , YeonSue Jang  2 , Baek Gil Kim  2 , Nam Hoon Cho  2 , Young Deuk Choi  3 , Jin Soo Chung  1 , Hyun Ho Han  3
Affiliations

Deciphering the Role of ERBB3 Isoforms in Renal Cell Carcinoma: A Comprehensive Genomic and Transcriptomic Analysis

Mingyu Kim et al. Medicina (Kaunas). .

Abstract

ERBB3, a key member of the receptor tyrosine kinase family, is implicated in the progression and development of various human cancers, affecting cellular proliferation and survival. This study investigated the expression of ERBB3 isoforms in renal clear cell carcinoma (RCC), utilizing data from 538 patients from The Cancer Genome Atlas (TCGA) Firehose Legacy dataset. Employing the SUPPA2 tool, the activity of 10 ERBB3 isoforms was examined, revealing distinct expression patterns in RCC. Isoforms uc001sjg.3 and uc001sjh.3 were found to have reduced activity in tumor tissues, while uc010sqb.2 and uc001sjl.3 demonstrated increased activity. These variations in isoform expression correlate with patient survival and tumor aggressiveness, indicating their complex role in RCC. The study, further, utilizes CIBERSORTx to analyze the association between ERBB3 isoforms and immune cell profiles in the tumor microenvironment. Concurrently, Gene Set Enrichment Analysis (GSEA) was applied, establishing a strong link between elevated levels of ERBB3 isoforms and critical oncogenic pathways, including DNA repair and androgen response. RT-PCR analysis targeting the exon 21-23 and exon 23 regions of ERBB3 confirmed its heightened expression in tumor tissues, underscoring the significance of alternative splicing and exon utilization in cancer development. These findings elucidate the diverse impacts of ERBB3 isoforms on RCC, suggesting their potential as diagnostic markers and therapeutic targets. This study emphasizes the need for further exploration into the specific roles of these isoforms, which could inform more personalized and effective treatment modalities for renal clear cell carcinoma.

Keywords: ERBB3 isoforms; TCGA; renal cell carcinoma.

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Conflict of interest statement

The authors have no conflicts of interest.

Figures

Figure 1
Figure 1
Comparative analysis of ERBB3 isoform expression in normal and tumor tissues of renal clear cell carcinoma patients. (A) ERBB3 isoform analysis in renal clear cell carcinoma from TCGA Firehose Legacy Dataset overview of the 10 ERBB3 isoforms identified in the UCSC Genome Browser, evaluated using the SUPPA2 tool. The analysis includes data from 538 individuals with renal clear cell carcinoma, focusing on the initial dataset and the specific ERBB3 isoforms under investigation. (B) The differential expression of ERBB3 isoforms in normal vs. tumor tissues shows how the expression levels of ERBB3 isoforms change in renal clear cell carcinoma patients’ normal tissues compared to their tumor tissues. It specifically contrasts the expression patterns of uc001sjg.3 and uc001sjh.3 (reduced expression in tumor tissues) against uc010sqb.2 and uc001sjl.3 (increased expression in tumor tissues).
Figure 2
Figure 2
The impact of uc001sjh.3 isoform expression on patient survival and tumor characteristics. Illustration of the correlation between the expression level of the uc001sjh.3 isoform and both the patient’s lifespan and the characteristics of tumors in malignant tissues. The graph illustrates a significant correlation between elevated levels of uc001sjh.3 expression (in the top quartile, Q1) and increased patient survival rates. Over 70% of the patients achieved a survival rate exceeding 150 months. Moreover, it demonstrates that malignancies exhibiting elevated levels of uc001sjh.3 expression exhibit a slower growth rate and smaller tumor size. The data points are classified into quartiles, where Q1 denotes the highest levels of expression. To demonstrate these associations, we present the survival curve, tumor size distribution, and malignancy advancement rate. The blue dots in the picture showing tumor size represent each patient.
Figure 3
Figure 3
The correlation of uc001sjl.3 isoform expression with decreased survival rates and tumor aggressiveness illustrates the correlation between elevated levels of the uc001sjl.3 isoform and both patient survival and the aggressiveness of tumors in malignant tissues. Evidence demonstrates that increased levels of uc001sjl.3 (upper quartile, Q1) expression are associated with considerably reduced survival rates, especially when less than 20% of patients survive beyond 130 months. The image also illustrates the correlation between elevated uc001sjl.3 expression and heightened tumor aggressiveness and size. The data are partitioned into quartiles, with Q1 denoting the greatest levels of expression. These findings are visually represented using a survival curve, as well as graphs illustrating tumor size and aggressiveness. The blue dots in the picture showing tumor size represent each patient.
Figure 4
Figure 4
Exploring ERBB3 isoform expression and its impact on immune cell profiles and gene set enrichment in renal cell carcinoma. (A) CIBERSORTx analysis exploring the relationship between the expression levels of ERBB3 isoforms (uc001sjh.3 and uc001sjl.3) and the proportional representation of immune cells in the cancer samples. The deconvolution values from CIBERSORTx, confirmed via Spearman correlation analysis, revealed distinct immune cell profiles associated with each isoform. For uc001sjh.3, a negative association was noted with regulatory T cells (Tregs), activated NK cells, follicular helper T cells, and CD8 T cells, while a positive correlation was seen with CD4 memory resting T cells, neutrophils, M2 macrophages, resting mast cells, and monocytes. In contrast, uc001sjl.3 showed inverse relationships, indicating its potential role in diminishing innate immunity, which could contribute to increased cancer growth and aggressiveness. Nine different types of immune cells, each exhibiting varying relationships with the two isoforms, are highlighted in yellow to emphasize these correlations. (B) Gene set enrichment analysis (GSEA) explores the association between the overexpression of ERBB3 isoforms and the enrichment of specific gene sets in renal cell carcinoma. Fifty genes from the C2 gene family were found to be significantly linked to the upregulation of ERBB3 isoforms. The most active gene sets were related to DNA repair, protein secretion, and androgen response, indicating the key biological pathways impacted by ERBB3 isoform expression changes in renal cell carcinoma.
Figure 5
Figure 5
Assessment of ERBB3 expression in specific exon regions of renal cell carcinoma tissues via RT-PCR and quantitative analysis. (A) RT-PCR analysis was performed on specific exon regions (exons 21–23 and exon 23) of the ERBB3 gene in both normal and tumor tissues from patients with renal cell carcinoma. We wanted to confirm whether the gene would be expressed even if alternative splicing was performed on a specific region of ERBB3 rather than the entire gene. (B) In both areas, the amount of ERBB3 expression was higher in tumor tissue compared to normal tissue. ImageJ software was used to analyze the quantified RT-PCR results for ERBB3 expression in normal tissue and tumor tissue. This confirms that the observed changes in ERBB3 expression between normal and tumor tissues are statistically significant. ** p < 0.01, *** p < 0.001, indicating a significant difference from the normal group.
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