Wu Dandan, Sun Xinning, Li Xin, Zuo Zongchao, Yan Dong, Yin Wu
State Key Lab of Pharmaceutical Biotechnology (SKLPB), College of Life Sciences in Nanjing University (Xianlin Campus), Nanjing University, Nanjing 210046, China.
The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, China.
Genes (Basel). 2024 Dec 6;15(12):1575. doi: 10.3390/genes15121575.
Hepatocellular carcinoma (HCC) is a type of malignant tumor with high morbidity and mortality. Untimely treatment and high recurrence are currently the major challenges for HCC. The identification of potential targets of HCC progression is crucial for the development of new therapeutic strategies.
Bioinformatics analyses have been employed to discover genes that are differentially expressed in clinical cases of HCC. A variety of pharmacological methods, such as MTT, colony formation, EdU, Western blotting, Q-PCR, wound healing, Transwell, cytoskeleton F-actin filaments, immunohistochemistry (IHC), hematoxylin-eosin (HE) staining, and dual-luciferase reporter assay analyses, were utilized to study the pharmacological effects and potential mechanisms of ribonucleotide reductase regulatory subunit M2 (RRM2) in HCC.
RRM2 expression is significantly elevated in HCC, which is well correlated with poor clinical outcomes. Both in vitro and in vivo experiments demonstrated that RRM2 promoted HCC cell growth and metastasis. Mechanistically, RRM2 modulates the EMT phenotype of HCC, and further studies have shown that RRM2 facilitates the activation of the TGF-β/Smad signaling pathway. SB431542, an inhibitor of TGF-β signaling, significantly inhibited RRM2-induced cell migration. Furthermore, RRM2 expression was correlated with diminished survival in HBV-associated HCC patients. RRM2 knockdown decreased the levels of HBV RNA, pgRNA, cccDNA, and HBV DNA in HepG2.2.15 cells exhibiting sustained HBV infection, while RRM2 knockdown inhibited the activity of the HBV Cp, Xp, and SpI promoters.
RRM2 is involved in the progression of HCC by activating the TGF-β/Smad signaling pathway. RRM2 increases HBV transcription in HBV-expressing HCC cells. Targeting RRM2 may be of potential value in the treatment of HCC.
肝细胞癌（HCC）是一种发病率和死亡率都很高的恶性肿瘤。治疗不及时和高复发率是目前HCC面临的主要挑战。识别HCC进展的潜在靶点对于开发新的治疗策略至关重要。
采用生物信息学分析来发现HCC临床病例中差异表达的基因。利用多种药理学方法，如MTT、集落形成、EdU、蛋白质免疫印迹法、定量聚合酶链反应、伤口愈合实验、Transwell实验、细胞骨架F-肌动蛋白丝、免疫组织化学（IHC）、苏木精-伊红（HE）染色以及双荧光素酶报告基因检测分析，研究核糖核苷酸还原酶调节亚基M2（RRM2）在HCC中的药理作用和潜在机制。
RRM2在HCC中的表达显著升高，这与不良临床结局密切相关。体外和体内实验均表明RRM2促进HCC细胞生长和转移。机制上，RRM2调节HCC的上皮-间质转化表型，进一步研究表明RRM2促进转化生长因子-β（TGF-β）/Smad信号通路的激活。TGF-β信号抑制剂SB431542显著抑制RRM2诱导的细胞迁移。此外，RRM2表达与乙肝相关HCC患者生存率降低相关。在持续感染乙肝的HepG2.2.15细胞中，敲低RRM2可降低乙肝RNA、pgRNA、cccDNA和乙肝DNA水平，而敲低RRM2可抑制乙肝核心启动子（Cp）、X蛋白启动子（Xp）和表面启动子（SpI）的活性。
RRM2通过激活TGF-β/Smad信号通路参与HCC的进展。RRM2增加表达乙肝的HCC细胞中的乙肝转录。靶向RRM2在HCC治疗中可能具有潜在价值。
