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. 2021 Sep 7;21(1):1001.
doi: 10.1186/s12885-021-08699-3.

Transcriptional analysis of the expression, prognostic value and immune infiltration activities of the COMMD protein family in hepatocellular carcinoma

Xiaobo Wang #  1   2   3 , Shujiao He #  1   2   3 , Xin Zheng  4 , Shanzhou Huang  5 , Honghui Chen  1   2   3 , Huadi Chen  1   2   3 , Weixin Luo  1   2   3 , Zhiyong Guo  6   7   8 , Xiaoshun He  9   10   11 , Qiang Zhao  12   13   14
Affiliations

Transcriptional analysis of the expression, prognostic value and immune infiltration activities of the COMMD protein family in hepatocellular carcinoma

Xiaobo Wang et al. BMC Cancer. .

Abstract

Background: The copper metabolism MURR1 domain (COMMD) protein family involved in tumor development and progression in several types of human cancer, but little is known about the function of COMMD proteins in hepatocellular carcinoma (HCC).

Methods: The ONCOMINE and the UALCAN databases were used to evaluate the expression of COMMD1-10 in HCC and the association of this family with individual cancer stage and tumor grade. Kaplan-Meier (K-M) Plotter and Cox analysis hint the prognostic value of COMMDs. A network comprising 50 most similar genes and COMMD1-10 was constructed with the STRING database. Gene set enrichment analysis (GSEA) was performed using LinkedOmics database. The correlations between COMMD expression and the presence of immune infiltrating cells were also analyzed by the tumor immune estimation resource (TIMER) database. GSE14520 dataset and 80 HCC patients were used to validated the expression and survival value of COMMD3. Human HCC cell lines were also used for validating the function of COMMD3.

Results: The expression of all COMMD family members showed higher expression in HCC tissues than that in normal tissues, and is associated with clinical cancer stage and pathological tumor grade. In HCC patients, the transcriptional levels of COMMD1/4 are positively correlated with overall survival (OS), while those of COMMD2/3/7/8/9 are negatively correlated with OS. Multivariate analysis indicated that a high level of COMMD3 mRNA is an independent prognostic factor for shorter OS in HCC patients. However, the subset of patients with grade 3 HCC, K-M survival curves revealed that high COMMD3/5/7/8/9 expression and low COMMD4/10 expression were associated with shorter OS. In addition, the expression of COMMD2/3/10 was associated with tumor-induced immune response activation and immune infiltration in HCC. The expression of COMMD3 from GSE14520 dataset and 80 patients are both higher in tumor than that in normal tissue, and a higher level of COMMD3 mRNA is associated with shorter OS. Knockdown of COMMD3 inhibits human HCC cell lines proliferation in vitro.

Conclusions: Our study indicates that COMMD3 is an independent prognostic biomarker for the survival of HCC patients. COMMD3 supports the proliferation of HCC cells and contributes to the poor OS in HCC patients.

Keywords: COMMD protein family; Hepatocellular carcinoma; Immune infiltration; Prognosis; Transcription; mRNA.

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Conflict of interest statement

The authors declared that they have no competing interests.

Figures

Fig. 1
Fig. 1
Differences in transcriptional expression in different cancers from ONCOMINE database. The cutoff values for the inclusion criteria were as follows: p-value, 0.01; fold change, 1.5; gene rank, 10%; and data type, mRNA
Fig. 2
Fig. 2
Transcriptional expression of COMMD genes in HCC tissues and normal tissues. A-J mRNA expression of the10 COMMD family members was higher in primary HCC tissues than in normal samples (UALCAN). *** p < 0.001
Fig. 3
Fig. 3
Relationship between the mRNA expression of COMMD genes and individual cancer stage of HCC patients. A-J The mRNA expression of the 10 COMMD genes was correlated with the patients’ individual cancer stage. * p < 0.05, ** p < 0.01, *** p < 0.001
Fig. 4
Fig. 4
Relationship between the mRNA expression of COMMD genes and tumor grade of HCC patients. A-J The mRNA expression of 10 COMMD genes was correlated with patient tumor grade. * p < 0.05, ** p < 0.01, *** p < 0.001
Fig. 5
Fig. 5
Prognostic value of the mRNA expression of COMMD genes in HCC patients (K-M Plotter). A-J K-M OS curves comparing all HCC patients stratified by high and low expression of COMMD1–10. *p < 0.05
Fig. 6
Fig. 6
Prognostic value of the mRNA expression of COMMD proteins in patients with grade III HCC (K-M Plotter). A-J K-M OS curves comparing high and low expression of COMMD1–10 in patients with grade III HCC. p < 0.05
Fig. 7
Fig. 7
Correlation of COMMD expression with the level of immune infiltration in HCC. A-J Comparison of COMMD expression between the high and low immune score groups comprising HCC patients. K-M COMMD2/3/10 were related to tumor purity and immune infiltration levels of HCC by TIMER analysis. ** p < 0.01
Fig. 8
Fig. 8
Genetic mutations, network, and GSEA of COMMD proteins. A Genetic mutation analysis of COMMD proteins (cBioPortal). B Relationship between genetic mutations in COMMD proteins and OS. C Relationship between genetic mutations in COMMD proteins and DFS. D Relationship between genetic mutations in COMMD proteins and PFS. E Network comprising COMMD1–10 and their most closely associated genes (STRING). F GSEA of the COMMD protein family members
Fig. 9
Fig. 9
The expression and prognostic value of COMMD3 was validated in GSE14520 and HCC patients. A COMMD3 expression in GSE14520 datasets between one thirds of the highest expression and two thirds of the lowest expression. B K-M OS curves in GSE14520 datasets stratified by COMMD3 expression. C COMMD3 expression in normal and tumor tissue of 80 HCC patients. D K–M OS curves in 80 HCC patients stratified by COMMD3 expression. E CCK-8 cell proliferation assay results in Hep3B and HepG2 cells transfected with si-COMMD3, or negative control (NC). F EdU cell proliferation assay results in Hep3B and HepG2 cells transfected with si-COMMD3, or NC. * p < 0.05, *** p < 0.001
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