Zeste 12抑制基因在肝细胞癌中的功能及机制

doi:10.3969/j.issn.1674-8115.2025.09.006

上海交通大学学报（医学版） ›› 2025, Vol. 45 ›› Issue (9): 1138-1148.doi: 10.3969/j.issn.1674-8115.2025.09.006

Zeste 12抑制基因在肝细胞癌中的功能及机制

李倩玉¹^,², 钱逸斐¹^,², 李松玲³, 朱子俊¹^,², 覃雯莉¹^,², 刘艳丰¹(), 邱必军¹()

^1.上海交通大学医学院附属仁济医院肝脏外科，上海 200127
^2.上海交通大学医学院附属仁济医院临床干细胞研究中心，上海 200127
^3.上海交通大学生物医学工程学院Med-X研究院，上海 200030

收稿日期:2025-04-27 接受日期:2025-07-06 出版日期:2025-09-28 发布日期:2025-09-30
通讯作者: 刘艳丰，研究员，博士；电子信箱：lyf7858188@163.com。
邱必军，主治医师，博士；电子信箱：qiubijun2010@126.com。
基金资助:
国家自然科学基金(82272684);国家自然科学基金(82241221);上海市重中之重研究中心项目(2022ZZ01016);上海市中央引导地方科技发展资金资助项目(YDZX20243100002002);上海交通大学医学院“双百人”项目(20221704)

Function and mechanism of suppressor of zeste 12 in hepatocellular carcinoma

LI Qianyu¹^,², QIAN Yifei¹^,², LI Songling³, ZHU Zijun¹^,², QIN Wenli¹^,², LIU Yanfeng¹(), QIU Bijun¹()

^1.Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
^2.Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
^3.School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China

Received:2025-04-27 Accepted:2025-07-06 Online:2025-09-28 Published:2025-09-30
Contact: LIU Yanfeng, E-mail: lyf7858188@163.com.
QIU Bijun, E-mail: qiubijun2010@126.com.
Supported by:
National Natural Science Foundation of China(82272684);Project of Shanghai Key Research Center(2022ZZ01016);Central Government Guidance Fund for Local Science and Technology Development of Shanghai(YDZX20243100002002);“Two-Hundred Talents” Program of Shanghai Jiao Tong University School of Medicine(20221704)

摘要/Abstract

摘要：

目的·探究Zeste 12抑制基因（suppressor of zeste 12，SUZ12）在肝细胞癌（hepatocellular carcinoma，HCC）中的功能及潜在机制。方法·通过R语言分析肝癌数据集中SUZ12在HCC患者中的表达情况并绘制相关生存曲线。构建SUZ12稳定敲低的肝癌细胞系LM3和Huh7，采用实时荧光定量PCR（quantitative real-time PCR，qPCR）和Western blotting方法检测SUZ12的敲低效率；利用CCK-8方法和克隆形成检测细胞增殖能力。通过水动力尾静脉注射（hydrodynamic tail vein injection，HTVI）系统，将免疫完全的小鼠肝脏中的Suz12敲除，以探究其在体内的致瘤功能。利用癌症基因组图谱（the cancer genome atlas，TCGA）数据库探索SUZ12调控HCC的分子机制。利用R语言分析SUZ12与肿瘤干细胞（cancer stem cell，CSC）标志物及糖酵解关键基因表达之间的关系，并使用肝癌细胞系及小鼠肿瘤组织进行验证。结果·SUZ12在肝癌组织中的表达高于癌旁组织，且肿瘤分期越高，表达越高；SUZ12高表达的HCC患者的预后较差。在肝癌细胞系LM3及Huh7中，稳定敲低SUZ12后细胞的增殖能力减弱。在de novoMYC/Trp53^-/-小鼠肝癌模型中，内源性敲除Suz12后，小鼠肝脏的肿瘤数量、大小及肿瘤负荷均下降。TCGA肝癌数据集中SUZ12高表达组HCC患者富集到多条肿瘤增殖及代谢相关通路，且SUZ12与CSC标志物及糖酵解通路关键基因的表达呈正相关。稳定敲低SUZ12的肝癌细胞系及敲除Suz12的小鼠肝癌组织中CSC标志物及糖酵解通路关键基因的mRNA水平均下降。结论·SUZ12在HCC患者中表达显著升高，与患者的不良预后有关。稳定敲低SUZ12的肝癌细胞增殖能力减弱。小鼠体内敲除Suz12可抑制HCC的发生发展。SUZ12的高表达维持CSC群体，发生代谢重编程，促进HCC发生发展。SUZ12可以作为HCC预后不良的潜在生物标志物和潜在治疗新靶点。

关键词: Zeste12抑制基因, 肝细胞癌, 水动力尾静脉注射, 治疗靶点

Abstract:

Objective ·To explore the function and potential mechanism of suppressor of zeste 12 (SUZ12) in hepatocellular carcinoma (HCC). Methods ·The expression of SUZ12 in HCC patients was analyzed using R language in liver cancer datasets, and relevant survival curves were drawn. Stable knockdown of SUZ12 was established in the liver cancer cell lines LM3 and Huh7. The knockdown efficiency of SUZ12 was assessed using quantitative real-time PCR (qPCR) and Western blotting. Cell proliferation ability was assessed using CCK-8 assay and colony formation assay. Using the hydrodynamic tail vein injection (HTVI) method, Suz12 was knocked out in the livers of fully immunocompetent mice to explore its tumorigenic function in vivo. The molecular mechanism of SUZ12 regulating HCC was explored using The Cancer Genome Atlas (TCGA) database. R language was used to analyze the relationship between SUZ12 and the expression of cancer stem cell (CSC) markers as well as key glycolysis-related genes. Findings were validated in liver cancer cell lines and mouse tumor tissues. Results ·The expression of SUZ12 in liver cancer tissues was higher than in adjacent non-tumor tissues, and its expression increased with higher tumor stage. HCC patients with high SUZ12 expression had poorer prognoses. In LM3 and Huh7 liver cancer cell lines, stable knockdown of SUZ12 reduced cell proliferation ability. In the de novo MYC/Trp53^-/- mouse liver cancer model, tumor nodule number and size, and tumor burden in liver tissue were reduced after endogenous knockout of Suz12. TCGA analysis showed that high SUZ12 expression in HCC was enriched in multiple tumor proliferation- and metabolism-related pathways. The expression of SUZ12 was positively correlated with CSC markers and key genes in glycolysis pathway. The mRNA levels of CSC markers and key genes in glycolysis pathway were decreased in liver cancer cell lines with stable SUZ12 knockdown and Suz12 knockout mouse HCC tissues. Conclusion ·The expression of SUZ12 is significantly increased in HCC patients and is associated with poor prognosis. Stable knockdown of SUZ12 weakens the proliferative ability of liver cancer cells. Knockout of Suz12 in mice in vivo can suppress the occurrence and development of HCC. The high expression of SUZ12 maintains the CSC pool, induces metabolic reprogramming, and promotes the occurrence and progression of HCC. SUZ12 can serve as a potential biomarker for poor prognosis and a novel target for potential therapeutic intervention in HCC.

Key words: suppressor of zeste 12 (SUZ12), hepatocellular carcinoma (HCC), hydrodynamic tail vein injection, therapeutic target

中图分类号:

R735.7

李倩玉, 钱逸斐, 李松玲, 朱子俊, 覃雯莉, 刘艳丰, 邱必军. Zeste 12抑制基因在肝细胞癌中的功能及机制[J]. 上海交通大学学报（医学版）, 2025, 45(9): 1138-1148.

LI Qianyu, QIAN Yifei, LI Songling, ZHU Zijun, QIN Wenli, LIU Yanfeng, QIU Bijun. Function and mechanism of suppressor of zeste 12 in hepatocellular carcinoma[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(9): 1138-1148.

图/表 6

表1 引物序列

Tab 1 Primer sequence

Gene	Forward (5′→3′)	Reverse (5′→3′)
SUZ12	AGGCTGACCACGAGCTTTTC	GGTGCTATGAGATTCCGAGTTC
CD13	GACGCTGAGACCGTACCTC	TCAGTCTTGTCAATGTCGGGG
EpCAM	AATCGTCAATGCCAGTGTACTT	TCTCATCGCAGTCAGGATCATAA
CD24	CTCCTACCCACGCAGATTTATTC	AGAGTGAGACCACGAAGAGAC
PKM2	ATAACGCCTACATGGAAAAGTGT	TAAGCCCATCATCCACGTAGA
HK2	TTGACCAGGAGATTGACATGGG	CAACCGCATCAGGACCTCA
PGK1	TGGACGTTAAAGGGAAGCGG	GCTCATAAGGACTACCGACTTGG
ACTB	CATGTACGTTGCTATCCAGGC	CTCCTTAATGTCACGCACGAT
Cd13	ATGGAAGGAGGCGTCAAGAAA	CGGATAGGGCTTGGACTCTTT
Epcam	GCGGCTCAGAGAGACTGTG	CCAAGCATTTAGACGCCAGTTT
Cd24	GTTGCACCGTTTCCCGGTAA	CCCCTCTGGTGGTAGCGTTA
Cd34	AAGGCTGGGTGAAGACCCTTA	TGAATGGCCGTTTCTGGAAGT
Cd44	TCGATTTGAATGTAACCTGCCG	CAGTCCGGGAGATACTGTAGC
Pkm2	GCCGCCTGGACATTGACTC	CCATGAGAGAAATTCAGCCGAG
Hk2	TGATCGCCTGCTTATTCACGG	AACCGCCTAGAAATCTCCAGA
Pgk1	ATGTCGCTTTCCAACAAGCTG	GCTCCATTGTCCAAGCAGAAT
Actb	GGCTGTATTCCCCTCCATCG	CCAGTTGGTAACAATGCCATGT

图1 SUZ12 在HCC组织样本中的表达及其与预后的关系Note： A/B. SUZ12 expression levels in tumors versus adjacent normal tissues of liver cancer patients and in liver cancer patients across different clinical stages from the TCGA_LIHC dataset (A) and CHCC_HBV dataset (B). C. Kaplan-Meier survival curves for OS, DFI, PFI, and DSS in liver cancer patients stratified by low or high SUZ12 expression levels from the TCGA database.

Fig 1 Expression of SUZ12 in HCC samples and its correlation with prognosis

图2 SUZ12 敲低对肝癌细胞增殖的影响Note： A/B. Verification of SUZ12 knockdown efficiency in LM3 and Huh7 cells by qPCR (A) and Western blotting (B). C/D. Effects of LM3 (C) and Huh7 (D) cells after stable SUZ12 knockdown on the proliferation by CCK-8 (n=6). E/F. Clonal formation and statistical results of LM3 (E) and Huh7 (F) cells after stable SUZ12 knockdown. ①P=0.023, ②P=0.002, ③P=0.001, ④P<0.001, compared with SCR.

Fig 2 Effect of SUZ12 knockdown on the proliferation of liver cancer cells

图3 小鼠HTVI模型示意图Note： Delivery of CMV-SB13, pT3-EF1A-MYC-IRES-luciferase, pX330-sg-p53, and either lenti-CRISPR sgSuz12 (sgSuz12 group) or lenti-CRISPR v2 (sgCtrl group) via HTVI in mice.

Fig 3 Schematic diagram of the HTVI mouse model

图4 敲除 Suz12 小鼠的HCC形成情况Note： A. Protein expression of SUZ12 and β-actin in liver tumor tissues of mice in the sgCtrl and sgSuz12 groups. B. Representative images of HCC in the sgCtrl and sgSuz12 groups. C‒E. Tumor number (C), tumor number (>1 mm) (C), max size (D), and tumor burden (E) in the sgCtrl and sgSuz12 groups.

Fig 4 Formation of HCC in Suz12-knockout mice

图5 TCGA肝癌数据集 SUZ12 表达相关的生物信息学分析及肝癌细胞系、小鼠肿瘤组织mRNA水平验证Note： A. GSEA analysis of pathway enrichment between SUZ12 high- and low-expression groups. B. Correlation analysis between SUZ12 expression and CSC markers as well as key glycolysis-related genes. C/D. The mRNA expression levels of CSC markers and key glycolysis-related genes in LM3 (C) and Huh7 (D) cells. E. The mRNA expression levels of CSC markers and key glycolysis-related genes in mouse liver cancer tissues. NES—normalized enrichment score; FDR—false discovery rate; Cor—correlation coefficient.

Fig 5 Bioinformatic analysis of SUZ12 expression in the TCGA liver cancer dataset and validation of mRNA expression levels in liver cancer cell lines and mouse liver cancer tissues

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Zeste 12抑制基因在肝细胞癌中的功能及机制

Function and mechanism of suppressor of zeste 12 in hepatocellular carcinoma

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