下调 C1R 可激活 HIF-1α 调节的糖酵解,从而促进肝细胞癌的发展。

IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Carcinogenesis Pub Date : 2024-11-01 Epub Date: 2024-08-16 DOI:10.1002/mc.23806
Yuying Ma, Yuehua Wang, Peng Tuo, Zhongji Meng, Bin Jiang, Yahong Yuan, Yan Ding, Abid Naeem, Xingrong Guo, Xiaoli Wang
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引用次数: 0

摘要

已发现 C1R 在皮肤鳞状细胞癌中具有独特的功能,这种功能超出了它在补体系统中的作用。然而,目前尚不清楚 C1R 是否参与了肝细胞癌(HCC)的进展。我们利用肝癌组织来研究 C1R 表达与临床和病理因素的关系。通过体外和体内实验评估了 HCC 细胞的恶性特征。通过RNA-seq、甲基化特异性PCR、免疫沉淀和双荧光素酶报告实验探讨了C1R在HCC中的作用机制。研究发现,C1R的表达随着HCC恶性程度的增加而降低,并与不良预后相关。C1R 启动子通过 DNMT1 和 DNMT3a 被高度甲基化,导致 C1R 表达下降。通过激活 HIF-1α 介导的糖酵解,C1R 表达的下调导致 HCC 细胞恶性特征增强。此外,研究还发现 C1R 表达的降低会促进异种移植肿瘤的形成。我们发现,C反应蛋白(CRP)会与C1R结合,游离的CRP会激活NF-κB信号通路,进而促进HIF-1α的表达。HIF-1α 的增加会导致糖酵解水平升高,最终促进 HCC 的侵袭行为。C1R 启动子区域的甲基化会导致 C1R 在 HCC 中的表达下调。C1R通过抑制HIF-1α调控的糖酵解,抑制体外和体内HCC的侵袭行为。这些研究结果表明,C1R 是 HCC 进展过程中的肿瘤抑制基因,为创新治疗方法提供了新的可能性。
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Downregulation of C1R promotes hepatocellular carcinoma development by activating HIF-1α-regulated glycolysis.

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.

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来源期刊
Molecular Carcinogenesis
Molecular Carcinogenesis 医学-生化与分子生物学
CiteScore
7.30
自引率
2.20%
发文量
112
审稿时长
2 months
期刊介绍: Molecular Carcinogenesis publishes articles describing discoveries in basic and clinical science of the mechanisms involved in chemical-, environmental-, physical (e.g., radiation, trauma)-, infection and inflammation-associated cancer development, basic mechanisms of cancer prevention and therapy, the function of oncogenes and tumors suppressors, and the role of biomarkers for cancer risk prediction, molecular diagnosis and prognosis.
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