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

Wang, Xiaobo; He, Shujiao; Zheng, Xin; Huang, Shanzhou; Chen, Honghui; Chen, Huadi; Luo, Weixin; Guo, Zhiyong; He, Xiaoshun; Zhao, Qiang

doi:10.1186/s12885-021-08699-3

Cited by 18 publications

(26 citation statements)

References 47 publications

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“…COMMD8 can also bind to the coiled-coil domain containing 22 (CCDC22 protein), which can promote the ubiquitination and degradation of the NF-κB inhibitor, IκBα [ 146 ]. The expression of COMMD8 protein negatively correlates with patient overall survival [ 147 ]. On the other hand, HBx can interact with Cullin 4–RING E3 ubiquitin ligase complex (CRL4 complex) through its interaction with DDB1 protein (CRL4-adaptor protein) [ 41 , 148 ].…”

Section: Discussionmentioning

confidence: 99%

Canonical and Divergent N-Terminal HBx Isoform Proteins Unveiled: Characteristics and Roles during HBV Replication

et al. 2021

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Hepatitis B virus (HBV) X protein (HBx) is a viral regulatory and multifunctional protein. It is well-known that the canonical HBx reading frame bears two phylogenetically conserved internal in-frame translational initiation codons at Met2 and Met3, thus possibly generating divergent N-terminal smaller isoforms during translation. Here, we demonstrate that the three distinct HBx isoforms are generated from the ectopically expressed HBV HBx gene, named XF (full-length), XM (medium-length), and XS (short-length); they display different subcellular localizations when expressed individually in cultured hepatoma cells. Particularly, the smallest HBx isoform, XS, displayed a predominantly cytoplasmic localization. To study HBx proteins during viral replication, we performed site-directed mutagenesis to target the individual or combinatorial expression of the HBx isoforms within the HBV viral backbone (full viral genome). Our results indicate that of all HBx isoforms, only the smallest HBx isoform, XS, can restore WT levels of HBV replication, and bind to the viral mini chromosome, thereby establishing an active chromatin state, highlighting its crucial activities during HBV replication. Intriguingly, we found that sequences of HBV HBx genotype H are devoid of the conserved Met3 position, and therefore HBV genotype H infection is naturally silent for the expression of the HBx XS isoform. Finally, we found that the HBx XM (medium-length) isoform shares significant sequence similarity with the N-terminus domain of the COMMD8 protein, a member of the copper metabolism MURR1 domain-containing (COMMD) protein family. This novel finding might facilitate studies on the phylogenetic origin of the HBV X protein. The identification and functional characterization of its isoforms will shift the paradigm by changing the concept of HBx from being a unique, canonical, and multifunctional protein toward the occurrence of different HBx isoforms, carrying out different overlapping functions at different subcellular localizations during HBV genome replication. Significantly, our current work unveils new crucial HBV targets to study for potential antiviral research, and human virus pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Canonical and Divergent N-Terminal HBx Isoform Proteins Unveiled: Characteristics and Roles during HBV Replication

et al. 2021

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“…They recruit GPCR-kinases to activate β-arrestin mediated immune response in B-cells. COMMD5 reduces the upregulation of proinflammatory cytokines and chemokines, such as TNF-α, IL-1β, and monocyte chemotactic protein (MCP)-1 in mice kidney after trauma acting as immunosuppressor [ 31 ]. COMMD7 induces CXCL expression to inflict immune response [ 71 ].…”

Section: Immune Response Regulationmentioning

confidence: 99%

“…The overexpression of COMMD6 can either improve or worsen the cancer prognosis depending on the cancer type [ 33 ]. Survival from hepatocellular carcinoma is improved with high expression of COMMD1/4/10 and on the other hand, overexpression of COMMD2/3/5/7/8/9 decreased the survival [ 31 ].…”

Section: Cell Cycle and Cancermentioning

confidence: 99%

“…COMMD5 is a tumor suppressor as it promotes cell proliferation and kidney regeneration in mice after trauma [ 81 ]. This happens via p53 independent p21 activation, where inhibition of G1/S phase transition prevents cell growth [ 31 , 32 ]. Tumorigenesis of COMMD5 deficiency is ascribed by cell growth, but also uncontrolled cell invasion as COMMD5 is required for cell migration regulation [ 50 ].…”

Section: Cell Cycle and Cancermentioning

confidence: 99%

“…Later, COMMD1 were found to control Na+ homeostasis via regulating the human epithelial sodium channel (ENaC) [ 13 ], and the commander complex has been subsequently linked to the regulation of several ubiquitous fundamental cellular functions: ion and lipid homeostasis [ 14 , 15 , 16 , 17 , 18 ], embryogenesis [ 4 ], immune response [ 9 , 19 , 20 , 21 , 22 , 23 ], cell growth [ 24 ] and cell cycle [ 23 , 25 , 26 , 27 ]. Changes in COMMD protein function have been connected to developmental disorders [ 4 ] and several diseases like Wilson’s disease [ 28 ], Parkinson’s disease [ 29 ], atherosclerosis [ 17 ], viral protein recycling [ 10 , 30 ], and most importantly cancer [ 31 , 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

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Commander Complex—A Multifaceted Operator in Intracellular Signaling and Cargo

Laulumaa

Varjosalo

2021

Cells

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Commander complex is a 16-protein complex that plays multiple roles in various intracellular events in endosomal cargo and in the regulation of cell homeostasis, cell cycle and immune response. It consists of COMMD1–10, CCDC22, CCDC93, DENND10, VPS26C, VPS29, and VPS35L. These proteins are expressed ubiquitously in the human body, and they have been linked to diseases including Wilson’s disease, atherosclerosis, and several types of cancer. In this review we describe the function of the commander complex in endosomal cargo and summarize the individual known roles of COMMD proteins in cell signaling and cancer. It becomes evident that commander complex might be a much more important player in intracellular regulation than we currently understand, and more systematic research on the role of commander complex is required.

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

et al. 2022

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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.

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

Cited by 18 publications

References 47 publications

Canonical and Divergent N-Terminal HBx Isoform Proteins Unveiled: Characteristics and Roles during HBV Replication

Canonical and Divergent N-Terminal HBx Isoform Proteins Unveiled: Characteristics and Roles during HBV Replication

Commander Complex—A Multifaceted Operator in Intracellular Signaling and Cargo

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

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