苹果酸酶2通过调控SHCBP1促进肝癌的发生发展

doi:10.16352/j.issn.1001-6325.2025.06.0741

基础医学与临床 ›› 2025, Vol. 45 ›› Issue (6): 741-747.doi: 10.16352/j.issn.1001-6325.2025.06.0741

苹果酸酶2通过调控SHCBP1促进肝癌的发生发展

秋昱翀^1,2, 杜文静^1*

1.中国医学科学院基础医学研究所北京协和医学院基础学院细胞生物学系重大疾病共性机制研究全国重点实验室,北京 100005;
2.中国医学科学院北京协和医学院临床医学专业试点班,北京 100730

收稿日期:2025-03-12 修回日期:2025-04-03 出版日期:2025-06-05 发布日期:2025-05-26
通讯作者: ^*wenjingdu@ibms.pumc.edu.cn
基金资助:
国家自然科学基金(32470829);中国医学科学院医学与健康科技创新工程(2021-I2M-1-016)

Malic enzyme 2 promotes liver cancer progression by regulating SHCBP1

QIU Yuchong^1,2, DU Wenjing^1*

1. State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Cell Biology, Institute of Basic Medical Sciences CAMS, School of Basic Medicine PUMC, Beijing 100005;
2. 4+4 Medical Doctor Program, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China

Received:2025-03-12 Revised:2025-04-03 Online:2025-06-05 Published:2025-05-26

摘要/Abstract

摘要： 目的筛选苹果酸酶2(ME2)调控的基因并探究其在肝癌发生发展中的作用与机制。方法对ME2敲降细胞的RNA-seq数据进行差异基因分析、聚类分析、GO和KEGG富集分析;在HepG2细胞中通过荧光定量PCR检测ME2敲降或者过表达后候选靶基因SHCBP1 mRNA的水平;Western blot检测ME2对下游信号通路的影响;通过细胞增殖、划痕与集落形成实验检测SHCBP1对肝癌细胞增殖与迁移的影响;利用TCGA LIHC数据库中肝癌患者的生存数据分析SHCBP1对肝癌患者预后的影响。结果敲降ME2后差异基因富集于PI3K-Akt信号通路、细胞周期、丝氨酸磷酸化等生物过程。在HepG2中敲降ME2后SHCBP1的mRNA水平降低,过表达ME2后SHCBP1的mRNA水平升高,两者呈正相关。Western blot 结果显示ME2通过SHCBP1激活PI3K-Akt信号通路。荧光定量PCR结果显示SHCBP1在肝癌细胞系中表达显著高于正常肝细胞,并促进肝癌细胞的增殖与迁移,且与不良预后相关。结论 ME2正向调控SHCBP1并激活PI3K-Akt信号通路,SHCBP1高表达促进肝癌的发生发展,为肝癌治疗提供了新的靶点。

关键词: 苹果酸酶2(ME2), PI3K-Akt信号通路, SHCBP1, 肝癌

Abstract: Objective To identify genes regulated by ME2 and to explore their roles as well as underlying mechanisms in liver cancer progression. Methods RNA-seq data of siME2-transfected cells were subjected to differential expression analysis, clustering, GO and KEGG enrichment analyses. The mRNA level of the potential target gene SHCBP1 was measured by quantitative real-time PCR (qPCR) following ME2 knockdown or overexpression in HepG2 cells. The effect of ME2 and SHCBP1 on the downstream pathway was examined by Western blot. Cell proliferation, wound healing, and colony formation assays were conducted to evaluate SHCBP1's role in liver cancer cell proliferation and migration. Survival analysis of the TCGA-LIHC cohort was performed to determine the prognostic value of SHCBP1 in liver cancer patients. Results Differentially expressed genes in siME2-transfected cells were significantly enriched in biological processes including the PI3K-Akt signaling pathway, cell cycle, and serine phosphorylation. In HepG2 cells, ME2 knockdown led to a reduction in SHCBP1 mRNA level, whereas ME2 over-expression resulted in enhanced SHCBP1 mRNA level, demonstrating a positive correlation between ME2 and SHCBP1 expression. Western blot analysis revealed that ME2 enhanced PI3K-Akt signaling pathway activation through SHCBP1. qPCR results confirmed that SHCBP1 was significantly over-expressed in liver cancer cells and promoted both proliferation and migration, contributing to poor prognosis in liver cancer patients. Conclusions ME2 promotes liver cancer progression by regulating SHCBP1 to activate the PI3K-Akt signaling pathway, presenting a novel therapeutic target for liver cancer treatment.

Key words: malic enzyme 2 (ME2), PI3K-Akt signaling pathway, SHCBP1, liver cancer

中图分类号:

R735.7

秋昱翀, 杜文静. 苹果酸酶2通过调控SHCBP1促进肝癌的发生发展[J]. 基础医学与临床, 2025, 45(6): 741-747.

QIU Yuchong, DU Wenjing. Malic enzyme 2 promotes liver cancer progression by regulating SHCBP1[J]. Basic & Clinical Medicine, 2025, 45(6): 741-747.

参考文献 11

[1]	Llovet JM, Kelley RK, Villanueva A, et al. Hepato-cellular carcinoma[J]. Nat Rev Dis Primers, 2021, 7:7. doi: 10.1038/s41572-021-00245-6.
[2]	Wang H, Cui W, Yue S, et al.Malic enzymes in cancer: Regulatory mechanisms, functions, and therapeutic implications[J]. Redox Biol, 2024, 75:103273. doi: 10.1016/j.redox.2024.103273.
[3]	Wang YP, Sharda A, Xu SN, et al. Malic enzyme 2 connects the Krebs cycle intermediate fumarate to mitochon-drial biogenesis[J]. Cell Metab, 2021, 33:1027-1041 e8.doi:10.1016/j.cmet.2021.03.003.
[4]	Yang Y, Zhang Z, Li W, et al. alphaKG-driven RNA polymerase Ⅱ transcription of cyclin D1 licenses malic enzyme 2 to promote cell-cycle progression[J]. Cell Rep, 2023, 42:112770. doi: 10.1016/j.celrep.2023.112770.
[5]	Qi G, Ma H, Teng K, et al. SHCBP1 promotes cisplatin resistance of ovarian cancer through AKT/mTOR/Autophagy pathway[J]. Apoptosis, 2025, 30: 83-98.
[6]	Shi W, Zhang G, Ma Z, et al. Hyperactivation of HER2-SHCBP1-PLK1 axis promotes tumor cell mitosis and impairs trastuzumab sensitivity to gastric cancer[J]. Nat Commun, 2021,12:2812.doi: 10.1038/s41467-021-23053-8.
[7]	Yin H, Zhang C, Wei Z, et al. EGF-induced nuclear translocation of SHCBP1 promotes bladder cancer progression through inhibiting RACGAP1-mediated RAC1 inactivation[J]. Cell Death Dis, 2022,13:39. doi: 10.1038/s41419-021-04479-w.
[8]	Wang N, Zhu L, Wang L, et al. Identification of SHCBP1 as a potential biomarker involving diagnosis, prognosis, and tumor immune microenvironment across multiple cancers[J]. Comput Struct Biotechnol J, 2022,20: 3106-3119.
[9]	Chen KC, Hsiao IH, Huang YN, et al. Targeting human mitochondrial NAD(P)(+)-dependent malic enzyme (ME2) impairs energy metabolism and redox state and exhibits antileukemic activity in acute myeloid leukemia[J]. Cell Oncol (Dordr), 2023, 46:1301-1316.
[10]	Chen T, Xie S, Cheng J, et al. AKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis[J]. Nat Commun, 2024, 15: 686. doi: 10.1038/s41467-024-44772-8.
[11]	Feng W, Li HC, Xu K, et al. SHCBP1 is over-expressed in breast cancer and is important in the proliferation and apoptosis of the human malignant breast cancer cell line[J]. Gene, 2016, 587: 91-97.

[1]	贾会文, 刘赟, 徐赟, 杨启, 杨科. 原发性肝癌血清miR-409-3p和miR-325-3p与介入治疗疗效相关[J]. 基础医学与临床, 2025, 45(3): 341-345.
[2]	郝思嘉, 杨振丽, 卞晓翠, 侯昱宏, 刘玉琴. Luc2-tdT标记的小鼠肝癌细胞系的建立及鉴定[J]. 基础医学与临床, 2025, 45(3): 317-322.
[3]	李顺乐, 李蓉, 田亚亚, 冉小丽, 赵延培, 徐蒙. 血清KLF5和actinin-4水平与肝细胞肝癌肝动脉化疗栓塞术治疗预后的关系[J]. 基础医学与临床, 2024, 44(9): 1284-1289.
[4]	安琪, 齐光照, 韩超. 桃叶珊瑚苷抑制人肝癌细胞系HepG2增殖[J]. 基础医学与临床, 2024, 44(3): 333-338.
[5]	郭鑫, 冀梦蝶, 王琦, 李雪媛, 陈阳. 鉴定顺铂对人肝癌细胞系转录物组的影响[J]. 基础医学与临床, 2024, 44(3): 352-360.
[6]	卢慧莹, 王建国. 下调去甲基化酶FTO抑制人肝癌细胞系HepG2增殖[J]. 基础医学与临床, 2024, 44(2): 185-191.
[7]	林钧, 李泽鹏, 余君莹. 有效白蛋白在慢性肝病中的作用[J]. 基础医学与临床, 2024, 44(12): 1707-1711.
[8]	杨雅倩, 潘艳芳, 屈梦扬, 方艳, 应小平, 张玫倩, 魏静. 外泌体在肝癌前病变发生发展中作用的研究进展[J]. 基础医学与临床, 2023, 43(9): 1453-1456.
[9]	孙全鹏, 樊超, 展德玺, 范怡明, 孙伟峰. 罗哌卡因抑制人肝癌细胞系Hep3B增殖、迁移和侵袭[J]. 基础医学与临床, 2022, 42(3): 448-453.
[10]	黄容, 张键, 车旭. SLC4A10表达水平对肝癌患者预后的影响[J]. 基础医学与临床, 2022, 42(3): 461-466.
[11]	米月, 蒋琦炜, 沈雁婕, 张德宇, 叶棋浓. 激活蛋白2家族基因真核表达载体的构建及其功能鉴定[J]. 基础医学与临床, 2022, 42(12): 1829-1834.
[12]	唐加峰, 何雪莲, 夏菁, 熊伟, 李小山. 熊果酸联合HDAC2抑制剂抑制人肝癌细胞系HepG2的增殖[J]. 基础医学与临床, 2021, 41(8): 1144-1150.
[13]	李长安, 刘春秀, 谢晓娟, 孙爱平. 下调Notch1基因促进人肝癌细胞系HepG2自噬[J]. 基础医学与临床, 2021, 41(4): 508-513.
[14]	吴娜, 王东, 李京敏, 白咸勇. 羟基红花黄色素A抑制人肝癌细胞系Huh7发生上皮-间质转化[J]. 基础医学与临床, 2021, 41(10): 1423-1427.
[15]	田小星, 秦溧嫔, 李茜. 长链非编码RNA TINCR通过miR-7调控肝癌细胞系Huh7侵袭和迁移[J]. 基础医学与临床, 2020, 40(8): 1041-1046.

苹果酸酶2通过调控SHCBP1促进肝癌的发生发展

Malic enzyme 2 promotes liver cancer progression by regulating SHCBP1

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献 11

相关文章 15

编辑推荐

Metrics

本文评价