A pan-cancer analysis of MARCH8: molecular characteristics, clinical relevance, and immuno-oncology features

Abstract

Membrane-associated RING-CH8 (MARCH8) is a member of the recently discovered MARCH family of ubiquitin ligases. MARCH8 has been shown to participate in immune responses. However, the role of MARCH8 in prognosis and immunology in human cancers remains largely unknown. The expression of MARCH8 protein was detected via immunohistochemistry in non-small cell lung cancer (NSCLC) and non-cancerous lung tissues. The study investigated the role of MARCH8 in tumor immunity through pan-cancer analysis of multiple databases. MARCH8 genetic alternations and expression were explored with the cBioPortal, GTEx, and TCGA databases. We investigated the role of MARCH8 expression in clinical relevance, prognosis, tumor immune microenvironment, immune checkpoint (ICP) with a series of bioinformatics tools and methods, such as TISIDB database, ESTIMATE, and CIBERSORT method. MARCH8 expression showed cancer-specific dysregulation and was associated with the prognosis of patients in various cancers. MARCH8 was related to the tumor microenvironment and participated in tumor immune regulation. Furthermore, low expression of MARCH8 was associated with poor prognosis and might serve as an independent prognostic biomarker for NSCLC patients. The comprehensive pan-cancer analysis revealed the potential of MARCH8 in tumor-targeted therapy, and suggested MARCH8 as a promising prognostic and immunological pan-cancer biomarker.

Keywords: E3-ubiquitin ligase; MARCH8; NSCLC; pan-cancer analysis; tumor immune infiltrating.

Figure 1.

Genetic alterations and expression pattern of MARCH8 across cancer types. (a) Distribution of the CNA alterations of MARCH8 in cancers harboring the highest alteration rates (green: mutation, red: amplification, blue: deep deletion). (b) The CNV alteration expression (Mean±sd) distribution of MARCH8 across cancer types. (c) The mRNA expression of MARCH8 gene across cancer types (red) and normal tissues (blue). Differences among groups were analyzed by Wilcoxon rank sum and signed rank tests between two individual groups, and by Kruskal-Wallis tests for multiple groups. ⁻p > .05, *p < .05, **p < .01, ***p < .001, ****p < .0001.

Figure 2.

The relationship between MARCH8 expression and different immune subtypes and molecular subtypes across cancer types. (a-p) The relationship between MARCH8 expression and different immune subtypes across cancer types. (q-x) The relationship between MARCH8 expression and different molecular subtypes across cancer types. (Spearman’s correlation, all p < .05).

Figure 3.

The prognostic potential of MARCH8 across cancer types. (a) The relationship between MARCH8 expression and OS across cancer types, using univariate survival analysis (only P-values < 0.05 shown). Kaplan-Meier OS curves of MARCH8 expression in KIRC (b) and LGG patients (c).

Figure 4.

Correlation analysis between expression of MARCH8 and immune cell infiltration and ICP genes across cancer types. (a) Correlation analysis between expression of MARCH8 and immune cells across cancer types by CIBERSORT, and immune infiltration score based on estimate. (b) Correlation analysis between expression of MARCH8 and ICP gene expression across cancer types. *p < .05, **p < .01, ***p < .001.

Figure 5.

The expression of MARCH8 protein and prognosis potential in NSCLC tissues. (a) The expression of MARCH8 protein in LUAD, LUSC, and noncancerous lung tissues detected by IHC (DAB staining, original magnification 200×and 40×). (b) The expression of MARCH8 in LUSC, and LUAD compared to the noncancerous lung tissues. *p < .05, ***p < .001. (c) Kaplan-Meier overall survival analysis of NSCLC patients based on MARCH8 proteins expression (log-rank test, p = .044). (d) The univariate survival analysis of OS and MARCH8 protein expression and clinical-pathological features in NSCLC patients.