Multi-omics analysis of the oncogenic value of copper Metabolism-Related protein COMMD2 in human cancers

Abstract

Background: The copper metabolism MURR1 domain (COMMD) protein family is involved in tumorigenicity of malignant tumors. However, as the member of COMMD, the role of COMMD2 in human tumors remains unknown.

Methods: We used The Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx), Human Protein Atlas (HPA) database, Cancer Cell Line Encyclopedia (CCLE) platform, univariate Cox regression analysis, Kaplan-Meier curve, cBioPortal, UALCAN database, Sangerbox online platform, GSCA database gene set enrichment analysis (GSEA), and GeneMANIA to analyze the expression of COMMD2, its prognostic values, genomic alteration patterns, and the correlation with tumor stemness, tumor mutational burden (TMB), microsatellite instability (MSI), and immune infiltrates, drug sensitivity, and gene function enrichment in pan-cancer. qRT-PCR, CCK-8, EdU, wound healing, and transwell migration assays were performed to confirm the function of COMMD2.

Results: COMMD2 was strongly expressed in most cancer types. Elevated COMMD2 expression affects the prognosis, clinicopathological stage, and molecular or immune subtypes of various tumors. Moreover, promoter hypomethylation and mutations in the COMMD2 gene may be associated with its high expression and poor survival. Additionally, we discovered that COMMD2 expression was linked to tumor stemness, TMB, MSI, immune cell infiltration, immune-checkpoint inhibitors, and drug sensitivity in pan-cancer. Furthermore, the COMMD2 gene co-expression network is constructed with GSEA analysis, displaying significant interaction of COMMD2 with E2F targets, G2-M checkpoint, and mitotic spindle in bladder cancer (BLCA). Finally, RNA interference data showed suppression of COMMD2 prevented proliferation and migration of BLCA and uterine corpus endometrial carcinoma (UCEC) cells.

Conclusion: Our findings shed light on the COMMD2 functions in human cancers and demonstrate that it is a promising prognostic biomarker and therapeutic target in pan-cancer.

Keywords: COMMD2; bioinformatics; immune infiltration; pan-cancer; prognostic biomarker.

FIGURE 1

Expression of COMMD2 in tumor and normal tissue. (A) Differential expression of COMMD2 between tumor tissues and paired non‐tumor tissues in the TCGA database. (B) Differential expression of COMMD2 in tumor and non‐tumor tissues in the SangerBox database. (C) Differential expression of COMMD2 in TCGA combined with the GTEx database. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001.

FIGURE 2

Immunohistochemistry staining of COMMD2 protein in normal and tumor tissues based on the HPA database.

FIGURE 3

Survival analysis of COMMD2 in pan‐cancer. COMMD2 expression with OS survival curves of BLCA (A), LIHC (B), PAAD (C), LGG (D), UCEC (E), HNSC (F), and SARC (G). COMMD2 expression and survival curve of DSS in BLCA (H), LIHC (I), PAAD (J), LGG (K), UCEC (L), HNSC (M), and SARC (N). ROC curves for the relationship of COMMD2 expression and the malignant progression of BLCA (O), LIHC (P), PAAD (Q), LGG (R), UCEC (S), HNSC (T), and SARC (U).

FIGURE 4

Relationship of COMMD2 expression and tumor stage and grade. COMMD2 expression and tumor stage in UCEC (A), PAAD (B), and TGCT (C). COMMD2 expression and tumor grade in UCEC (D), PAAD (E), and LIHC (F).

FIGURE 5

Relationship of COMMD2 expression with immune subtype in BLCA (A), UCEC (B), LUAD (C), LIHC (D), LUSC (E), BRCA (F), STAD (G), OV (H), and KICH (I). Association of COMMD2 expression with the molecular subtype in BRCA (G), HNSC (K), and LGG (L).

FIGURE 6

Methylation and genetic alterations of COMMD2 in pan‐cancer. (A) Methylation level of COMMD2 in BLCA (A), LIHC (B), HNSC (C), LUSC (D), TGCT (E), COAD (F), BRCA (G) and ESCA (H). (I) Mutation frequency of COMMD2 in different cancers. (J) Putative copy‐number alterations of COMMD2 from GISTI. (K) Genetic alterations of COMMD2 and OS. (L) Genetic alterations of COMMD2 and DSS.

FIGURE 7

Relationship of COMMD2 expression and TMB (A), MSI (B), mDNAsi (C), and mRNAsi (D) in pan‐cancer.

FIGURE 8

Association of COMMD2 expression and immune infiltration and ESTIMATE Score. The relationship between COMMD2 expression and immune cell infiltration evaluated via the TIMER algorithm (A), MCPCOUNTER algorithm (B), and QUANTISEQ algorithm(C). (D) COMMD2 expression and ESTIMATEScore, ImmuneScore and StromalScore in COAD, UCEC, PAAD, and TGCT. *p < 0.05, **p < 0.01, and ***p < 0.001.

FIGURE 9

Analysis of the relevance between COMMD2 expression and immune checkpoint inhibitors and drug sensitivity. (A) Co‐expression of COMMD2 and immune checkpoint inhibitors. (B) GDSC drug sensitivity and COMMD2 mRNA expression. (C) CTRP drug sensitivity and COMMD2 mRNA expression. *p < 0.05, **p < 0.01, and ***p < 0.001.

FIGURE 10

GSEA analysis and pathway analysis of COMMD2 in BLCA. Ridge plot of GSEA analysis respectively taken from the “c5.bp.v7.2.symbols.gmt” gene set (A) and “h.all.v7.2.symbols.gmt” gene set (B) as the references in BLCA. (C‐H) Association of COMMD2 and pathways related with tumor in BLCA.

FIGURE 11

COMMD2's biological roles in bladder cancer and uterine corpus endometrial carcinoma cells. (A) In UMUC3 and HEC‐1‐A, verification of COMMD2 knockdown efficiency. CCK‐8 (B), EdU assay (C), colony formation assay (D), wound healing (E), and transwell assay (F) were performed to confirm the biological function of COMMD2 in bladder cancer and uterine corpus endometrial carcinoma cells. **p < 0.01, ***p < 0.001, and ###p < 0.001.