ABSTRACT
COMMD10, a member of COMMD protein, has been proved to target p65 NF-kappaB (nuclear factor-kappaB) subunit and reduce its nuclear translocation, thereby leading to the inactivation of NF-kappaB pathway and suppression of colorectal cancer invasion and metastasis. The aim of this study is to explore its expression pattern and tissue distribution in human normal tissues and other tumor tissues and to investigate the relevant mechanism. We firstly provided the expression profile and histological distribution of COMMD10 in various BALB/c mice tissues and identified the biological distribution of COMMD10 in different kinds of human normal and tumor tissues. We verified the expression profile of COMMD10 using TCGA database. The interacting genes of COMMD10 were predicted by using STRING using. Finally, we performed database, and the microRNAs targeting COMMD10 were predicted using miRDB, miRWalk, TargetScan and microRNA. GO and KEGG pathway analyses were performed to predict the biological function of COMMD10 and its interacting genes. mRNA expression of COMMD10 showed the highest level in the lung and spleen, and the lowest level in the heart and brain. Immunohistochemistry detection revealed that COMMD10 was expressed in different tissues with different degrees and was was located mainly in the cytoplasm. Subsequently, we showed that COMMD10 displayed various degrees of expression in different human normal tissues that mainly located in cytoplasm, while COMMD10 of liver cells resided in both nucleus and cytoplasm. All the tumor tissues except breast small cell carcinoma, breast phyllodes tumor, lung adenocarcinoma, thymoma, cervical cancer and bladder urothelial carcinoma showed that COMMD10 was positive staining in cytoplasm. Kaplan-Meier plotter indicated that renal clear cell carcinoma patients with increased expression level of COMMD10 exhibited longer survival. STRING database revealed that COMMD10 had 41 interacting genes, and data from 4 different databases indicated that hsa-miR-590-3p may be the potential regulator of COMMD10. GO analysis demonstrated that COMMD10 and its interacting genes were mainly enriched in Cullin-RING ubiquitin ligase complexes, binding and transport of copper ions, the transport and steady-state maintenance of copper ions, transcription, translation and transport of proteins, and negatively regulate the activity of NF-kappaB transcription factors. KEGG pathway showed that COMMD10 and its interacting genes were mainly involved in renal cell carcinoma, HIF-1 signaling pathways, ubiquitination-mediated proteolysis, endocytosis and mineral absorption. COMMD10 may play a tumor suppressive role in renal clear cell carcinoma through the miR-590-3p-COMMD10-Cul2-RBX1-NF-κB/HIF/NRF2 pathway and regulate the chemotherapy resistance of various tumor cells to cisplatin.
Subject(s)
Biomarkers, Tumor/genetics , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , MicroRNAs/metabolism , Neoplasms/genetics , Animals , Apoptosis/genetics , Cell Line, Tumor , Chemotherapy, Adjuvant/methods , Cisplatin/pharmacology , Cisplatin/therapeutic use , Computational Biology , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , Humans , Kaplan-Meier Estimate , Male , Mice , Mice, Inbred BALB C , Neoplasms/diagnosis , Neoplasms/mortality , Neoplasms/therapy , Prognosis , Signal Transduction/genetics , Tissue DistributionABSTRACT
OBJECTIVE: By means of observing the clinical development of asymptomatic chronic HBsAg carriers (AsC) to explore the clinical rule of development of chronic hepatitis B (CHB) to liver cirrhosis (LC) to hepatocellular carcinoma (HCC) and to seek effective method for blocking the procedure. METHODS: AsCs were selected from health examination according to the diagnostic standard from the National Program for Prevention and Treatment of Viral Hepatitis, by periodical or non-periodical conventional examination of liver diseases, mixed infection of HCV was excluded. A 16-year systematic observation on clinical process of HBV infection series was completed. RESULTS: In the 217 AsCs observed, 21 cases (9.68%) with the HBsAg negatively converted, the average year negative conversion rate being 0.58%, among them, 13/21 cases (61.9%) had production of anti-HBs antigen; 20 cases were clinically cured; 1 case transferred to HCC; 124 cases (57.14%) remained asymptomatic carriers; 73 transferred to chronic liver disease, showing a tendency of gradually developing from CHB to LC to HCC, the year transferring rate from AsC to LC and HCC being 1.04% and 0.40%, respectively. Fifteen patients died of liver diseases, in which one died of severe CHB, 3 of LC and 11 of HCC. CONCLUSION: Different clinical end-results may reveal in AsCs according to their age and regulation on immune response to HBV. Few of the HCC and LC patients were HBeAg (e+) positive, they often reveal HBeAg (e-) negative or anti-HBe positive. HCC always develops on the basis of liver fibrosis or cirrhosis, which are the prophase of HCC, and patients with liver fibrosis or cirrhosis are the high risk group of developing HCC. HCC is not only the terminal pathologic stage of hepatopathy, but also one of the most important factors that causes death of chronic hepatopathy. From the viewpoint of integrative medicine in typing hepatopathy to observe the clinical speciality of AsC developing to CHB, LC and HCC, it is considered that the degree of blood stasis is in accordance with the development of hepatopathy.