Overexpression of MAX dimerization protein 3 (MXD3) predicts poor prognosis in clear cell renal cell carcinoma

Fangyuan Zhang; Liansheng Liu; Pengjie Wu; Shengwen Li; Dong Wei

doi:10.21037/tau-20-1187

Overexpression of MAX dimerization protein 3 (MXD3) predicts poor prognosis in clear cell renal cell carcinoma

Transl Androl Urol. 2021 Feb;10(2):785-796. doi: 10.21037/tau-20-1187.

Authors

Fangyuan Zhang¹, Liansheng Liu^{2

3}, Pengjie Wu⁴, Shengwen Li¹, Dong Wei⁴

Affiliations

¹ School of Clinical Medicine, Tsinghua University, Beijing, China.
² Key Laboratory of Regenerative Biology of the Chinese Academy of Sciences and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
³ Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.
⁴ Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.

Abstract

Background: Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of malignant kidney tumor. The molecular mechanism of ccRCC is complicated, and few effective prognostic predictors have been applied to clinical practice. MAX dimerization protein 3 (MXD3) is generally considered a transcription factor of the MYC/MAX/MAD transcriptional network. This study aimed to investigate the impact of MXD3 in ccRCC.

Methods: Gene expression profiles and clinical data of ccRCC were downloaded from The Cancer Genome Atlas (TCGA) database. MXD3 expression levels between tumors and adjacent normal tissues were compared. The influence of MXD3 on overall survival (OS) was evaluated using the Kaplan-Meier method. Associations between MXD3 expression and clinical features were assessed with the Kruskal test and Wilcoxon test. Univariate and multivariate Cox analyses were performed to observe the impact of MXD3 expression and clinical features on prognosis. The correlation between MXD3 and ccRCC immune infiltration was estimated with TIMER. The DNA methylation levels of the MXD3 promoter were obtained from UALCAN. Gene set enrichment analysis (GSEA) was conducted to explore the biological signaling pathways.

Results: MXD3 was overexpressed in ccRCC tumor tissues compared with adjacent normal kidney tissues. High expression of MXD3 was significantly correlated with poor prognosis. MXD3 expression levels were associated with tumor grade, tumor stage, tumor (T) classification and metastasis (M) classification. Univariate and multivariate Cox analyses showed that high expression of MXD3 was an independent risk factor for OS in ccRCC. MXD3 expression was positively correlated with the infiltrating levels of B cells and myeloid dendritic cells, and negatively correlated with macrophages. The MXD3 promoter region tended to be hypomethylated in ccRCC compared with normal tissues. GSEA identified homologous recombination, base excision repair, and glycerophospholipid metabolism as differentially enriched in ccRCC with high MXD3 expression.

Conclusions: This study suggests that high expression of MXD3 is an independent risk factor for poor prognosis in ccRCC. MXD3 expression potentially contributes to regulation of immune infiltration and cell proliferation in ccRCC, and the aberrant expression of MXD3 in tumor tissues could be caused by hypomethylation of gene promoter. MXD3 could be an effective prognostic biomarker and potential therapeutic target for ccRCC.

Keywords: MAX dimerization protein 3 (MXD3); biomarkers, prognosis; renal cell carcinoma (RCC).