COMMD6 Human

What is the genomic location and structure of COMMD6?

COMMD6 is located at chromosome 13q22.2 in humans. Its gene structure includes a 5′UTR exon, three CDS exons, a 3′UTR exon, and four introns . The protein structure is characterized primarily by the copper metabolism gene MURR1 domain (COMMD), which is crucial for its biological functions . Phylogenetic analysis divides COMMD family members into three clusters, with COMMD6 falling into cluster 2 alongside COMMD7, COMMD8, and COMMD10 .

How conserved is COMMD6 across different species?

COMMD6 demonstrates remarkable conservation across mammalian species. Sequence comparison analysis reveals that Homo sapiens COMMD6 shares 84% identity with Mus musculus, 85% with Sus scrofa, 88% with Felis catus, 88% with Bos taurus, and 87% with Ovis aries . This high degree of conservation suggests that COMMD6 likely serves fundamental biological functions that have been preserved throughout mammalian evolution.

What is the expression pattern of COMMD6 in normal human tissues?

COMMD6 expression varies significantly across different human tissues. Based on UCSC database analysis, COMMD6 mRNA is highly expressed in human breast tissues and kidney cortex tissues . It shows moderate expression in colon, lung, and stomach tissues, while displaying relatively low expression in liver tissues—interestingly contrasting with the higher expression observed in liver specimens via immunohistochemistry (IHC) assays . This tissue-specific expression pattern provides insight into potential tissue-specific functions of COMMD6.

How is COMMD6 expression detected in laboratory settings?

Researchers typically employ several complementary techniques to detect COMMD6 expression:

• Real-time PCR (qRT-PCR): Total RNA is extracted using Trizol reagent and reverse transcribed to generate cDNA. COMMD6-specific primers (Forward: 5′-GGAAACTGGGTATGGCTGTGA-3′, Reverse: 5′-TGTGGAATCGTCATTTCAAAGCA-3′ for Homo sapiens) are used for amplification, and relative expression is calculated using the comparative Ct method (ΔΔCt) .

• Immunohistochemistry (IHC): Tissues are fixed in paraformaldehyde, embedded in paraffin, sectioned, and then incubated with COMMD6-specific antibodies. The visualization signal is developed with 3,3-diaminobenzidine tetrahydrochloride staining. COMMD6 expression is quantified based on the percent positivity of stained cells and staining intensity .

What molecular mechanisms underlie COMMD6's role in tumorigenesis?

COMMD6 appears to promote tumorigenesis through several distinct molecular mechanisms:

• ceRNA Network in Head and Neck Squamous Cell Carcinoma: COMMD6 functions within a TEX41-miR-340-COMMD6 competing endogenous RNA network . In this mechanism, the long non-coding RNA TEX41 likely acts as a sponge for miR-340, thereby regulating COMMD6 expression levels.

• Transcriptional Network in Cholangiocarcinoma: COMMD6 participates in a miR-218-CDX1-COMMD6 transcriptional network . This suggests that miR-218 may regulate the transcription factor CDX1, which in turn modulates COMMD6 expression.

• NF-κB Pathway Regulation: COMMD6 may modulate the ubiquitination and degradation of NF-κB subunits . Given that aberrant activation of the NF-κB signaling pathway is observed in many human cancers and contributes to unlimited tumor growth and progression, COMMD6's involvement in this pathway is particularly significant.

• Regulation of Ribonucleoprotein and Spliceosome Complex Biogenesis: COMMD6 appears to regulate these processes in tumors, potentially affecting RNA processing and gene expression .

How do genetic alterations of COMMD6 correlate with cancer phenotypes?

Analysis of COMMD6 in cancer cell lines using the Cancer Cell Line Encyclopedia (CCLE) database reveals significant variations in genetic alterations across different cancer types:

• mRNA Expression and Copy Number Variation (CNV): Both are highest in acute myelocytic leukemia (AML), meningioma, colorectal cancer, and diffuse large B-cell lymphoma (DLBCL) cell lines . This suggests that COMMD6 overexpression may contribute to these malignancies.

• Methylation Status: COMMD6 methylation is highest in lymphocyte malignancies and lowest in soft tissue cancer, osteosarcoma, leukemia, giant cell tumor, Ewing's sarcoma, and esophagus cancer cell lines . These methylation patterns may influence COMMD6 expression and function in different tumor contexts.

• Mutation Frequency: COSMIC database analysis indicates that COMMD6 is highly mutated in skin cancer and soft tissue cancers, suggesting potential roles in these tumor types .

How does COMMD6 interact with the WASH complex and retromer in endosomal sorting?

COMMD6 colocalizes with the WASH complex and retromer in a sub-compartment of the endosome and participates in the CCC-WASH axis in endosomal sorting of receptors . This interaction suggests that COMMD6 may contribute to protein trafficking and recycling within cells, potentially affecting the surface expression of growth factor receptors and other molecules relevant to cancer cell behavior.

What bioinformatics tools are most effective for analyzing COMMD6 expression and function?

Multiple bioinformatics resources have proven valuable for COMMD6 research:

• Genomic Analysis Tools:

  • GeneCards (https://www.genecards.org/) for chromosome location analysis

  • Uniprot (https://www.uniprot.org/) for protein sequence analysis

  • Illustrator for Biological Sequences (IBS, http://ibs.biocuckoo.org/) for visual representation of protein structure

• Expression Analysis Tools:

  • UCSC database (https://genome.ucsc.edu/) for expression profiling in normal human tissues

  • CCLE database (https://portals.broadinstitute.org/ccle) for analyzing expression, CNV, and methylation in cancer cell lines

  • COSMIC database (https://cancer.sanger.ac.uk/cosmic) for mutation analysis in tumor cell lines

• Survival and RNA-Sequencing Analysis:

  • GEPIA database (http://gepia.cancer-pku.cn/index.html) for analyzing RNA-sequencing data and patient survival based on The Cancer Genome Atlas (TCGA)

• Network Analysis Tools:

  • miRanda, miRDB, miRwalk, DIANAmT, and Targetscan databases for microRNA prediction

  • DIANA databases for lncRNA prediction

  • GCBI database (https://www.gcbi.com.cn) for transcription factor prediction

  • Cytoscape software for constructing ceRNA networks

• R Packages:

  • "limma", "edgeR", "pheatmap", and "ggplot2" for creating heatmaps of differentially expressed molecules

  • "clusterProfiler", "org.Hs.eg.db", "enrichplot" for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis

What statistical approaches are recommended for analyzing COMMD6 expression data?

For rigorous analysis of COMMD6 expression data, the following statistical approaches are recommended:

• Two-group Comparisons: Student's t-test is appropriate for comparing COMMD6 expression between two groups

• Multi-group Comparisons: One-way analysis of variance (ANOVA) followed by LSD comparison test is suitable for comparing expression levels across three or more groups

• Non-parametric Analysis: For immunohistochemistry scoring data, which may not follow normal distributions, nonparametric tests are more appropriate

• Correlation Analysis: Pearson correlation method is recommended for assessing correlations between COMMD6 expression and other variables

• Significance Threshold: P-values less than 0.05 are generally considered statistically significant

How does COMMD6 expression contribute to cancer prognosis?

COMMD6 expression has been found to predict prognosis in cancer patients, though the specific impact appears to vary by cancer type . Kaplan-Meier analysis applied to evaluate the prognosis of COMMD6 in tumors reveals significant associations with patient outcomes . The prognostic value of COMMD6 may be related to its involvement in critical cellular processes including NF-κB signaling, which has established roles in cancer progression.

What experimental models are most suitable for studying COMMD6 function in cancer?

Based on the research methodologies described in the literature, several experimental models appear suitable for studying COMMD6 function in cancer:

• BALB/c mice: These commonly used laboratory animals provide a valuable in vivo model for investigating COMMD6 expression patterns across multiple tissues

• Human cancer cell lines: Analysis of CCLE data suggests that AML, meningioma, colorectal cancer, and DLBCL cell lines, which exhibit high COMMD6 expression and CNV, may serve as appropriate in vitro models

• TCGA patient datasets: These provide valuable clinical correlation data linking COMMD6 expression to patient outcomes across multiple cancer types

• Molecular manipulation models: Given COMMD6's involvement in specific ceRNA and transcriptional networks, models that allow manipulation of these regulatory relationships (e.g., through miR-340 or miR-218 modulation) would be particularly informative

How does COMMD6's interaction with NF-κB signaling impact tumor biology?

COMMD6 has been reported to be involved in inhibiting NF-κB pathway activity in HEK-293 cells . The activation of NF-κB can be completely abolished by mutation of amino acid residues Trp24 and Pro41 in the COMM domain of COMMD6 . Since aberrant activation of the NF-κB signaling pathway occurs in many human cancers and drives unlimited tumor growth and progression, COMMD6's role in this pathway is particularly significant.

Mechanistically, COMMD6 may modulate the ubiquitination and degradation of NF-κB subunits, thereby regulating their activity and stability . This suggests that COMMD6 could function as either a tumor suppressor or promoter depending on the cellular context and the specific effects on NF-κB signaling components.

What are the most promising therapeutic implications of COMMD6 research?

The current understanding of COMMD6 suggests several promising therapeutic directions:

• Biomarker Development: COMMD6 expression patterns could serve as potential biomarkers for tumor prevention and therapy, helping to stratify patients and guide treatment decisions

• Targeted Therapy Approaches: Given COMMD6's role in NF-κB regulation, therapeutic approaches that modulate this interaction could potentially suppress tumor growth in cancers where NF-κB signaling is aberrantly activated

• microRNA-based Therapies: The involvement of COMMD6 in ceRNA networks suggests that microRNA-based therapies targeting miR-340 or miR-218 could potentially regulate COMMD6 expression and function in specific cancer types

• Combination Therapies: Understanding how COMMD6 interacts with other cancer pathways could inform the development of combination therapies that target multiple oncogenic mechanisms simultaneously

What are the key challenges in translating COMMD6 research findings to clinical applications?

Despite promising research findings, several challenges must be addressed before COMMD6 research can be effectively translated to clinical applications:

• Tissue-Specific Effects: COMMD6 exhibits varying expression patterns across different tissues and cancer types, suggesting that its functions may be context-dependent

• Mechanistic Complexity: COMMD6 appears to function through multiple mechanisms (ceRNA networks, transcriptional regulation, NF-κB modulation), complicating the development of targeted interventions

• Limited Functional Validation: While bioinformatic analyses have revealed potential roles for COMMD6 in cancer, more extensive functional validation studies are needed to confirm these roles and evaluate therapeutic potential

• Therapeutic Targeting Challenges: As a primarily regulatory protein involved in multiple cellular processes, developing specific interventions that modulate COMMD6 function without disrupting essential cellular processes presents significant challenges