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Downregulation of C1R promotes hepatocellular carcinoma development by activating HIF-1α-regulated glycolysis.
- Source :
-
Molecular carcinogenesis [Mol Carcinog] 2024 Nov; Vol. 63 (11), pp. 2237-2253. Date of Electronic Publication: 2024 Aug 16. - Publication Year :
- 2024
-
Abstract
- C1R has been identified to have a distinct function in cutaneous squamous cell carcinoma that goes beyond its role in the complement system. However, it is currently unknown whether C1R is involved in the progression of hepatocellular carcinoma (HCC). HCC tissues were used to examine C1R expression in relation to clinical and pathological factors. Malignant characteristics of HCC cells were assessed through in vitro and in vivo experiments. The mechanism underlying the role of C1R in HCC was explored through RNA-seq, methylation-specific PCR, immuno-precipitation, and dual-luciferase reporter assays. This study found that the expression of C1R decreased as the malignancy of HCC increased and was associated with poor prognosis. C1R promoter was highly methylated through DNMT1 and DNMT3a, resulting in a decrease in C1R expression. Downregulation of C1R expression resulted in heightened malignant characteristics of HCC cells through the activation of HIF-1α-mediated glycolysis. Additionally, decreased C1R expression was found to promote xenograft tumor formation. We found that C-reactive protein (CRP) binds to C1R, and the free CRP activates the NF-κB signaling pathway, which in turn boosts the expression of HIF-1α. This increase in HIF-1α leads to higher glycolysis levels, ultimately promoting aggressive behavior in HCC. Methylation of the C1R promoter region results in the downregulation of C1R expression in HCC. C1R inhibits aggressive behavior in HCC in vitro and in vivo by inhibiting HIF-1α-regulated glycolysis. These findings indicate that C1R acts as a tumor suppressor gene during HCC progression, opening up new possibilities for innovative therapeutic approaches.<br /> (© 2024 Wiley Periodicals LLC.)
- Subjects :
- Humans
Animals
Mice
Promoter Regions, Genetic
Male
Cell Line, Tumor
Mice, Nude
Female
Prognosis
Cell Proliferation
C-Reactive Protein genetics
C-Reactive Protein metabolism
Signal Transduction
DNA Methyltransferase 3A metabolism
DNA Methyltransferase 3A genetics
Mice, Inbred BALB C
Carcinoma, Hepatocellular genetics
Carcinoma, Hepatocellular pathology
Carcinoma, Hepatocellular metabolism
Liver Neoplasms genetics
Liver Neoplasms pathology
Liver Neoplasms metabolism
Glycolysis genetics
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Gene Expression Regulation, Neoplastic
Down-Regulation
DNA Methylation
Subjects
Details
- Language :
- English
- ISSN :
- 1098-2744
- Volume :
- 63
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Molecular carcinogenesis
- Publication Type :
- Academic Journal
- Accession number :
- 39150096
- Full Text :
- https://doi.org/10.1002/mc.23806