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Exploring the potential of extrachromosomal DNA as a novel oncogenic driver

Science China Life Sciences 2025年第1期68卷 144-157页

作者： Huanbo Zhu Longtao Huangfu Junbing Chen Jiafu Ji Xiaofang Xing key laboratory of Carcinogenesis and Translational Research (Ministry of Education/beijing) Division of Gastrointestinal Cancer Translational Research LaboratoryPeking University Cancer Hospital & Institute Department of Gastrointestinal cancer Center Peking University Cancer Hospital & Institute Department of liver Surgery & Transplantation Liver Cancer InstituteZhongshan HospitalFudan University key laboratory of Carcinogenesis and cancer Invasion Ministry of Education State key laboratory of Holistic Integrative Management of Gastrointestinal cancers Beijing Key Laboratory of Carcinogenesis and Translational ResearchDivision of Gastrointestinal Cancer Translational Research LaboratoryPeking University Cancer Hospital & Institute

Extrachromosomal DNA(ecDNA) is a form of circular DNA mostly found in tumor cells. Unlike the typical chromosomal DNA, ecDNA is circular, self-replicating, and carries complete or partial gene fragments. Although ecDNA occurrence remains a rare event in cancer, recent studies have shown that oncogene amplification on ecDNA is widespread throughout many types of cancer, implying that ecDNA plays a central role in accelerating tumor evolution. ecDNA has also been associated with increased tumor mutation burden, chromosomal instability, and even tumor microenvironment remodeling. ecDNA may be crucial in influencing tumor heterogeneity, drug sensitivity,oncogenic senescence, and tumor immunogenicity, leading to a worsening prognosis for tumor patients. In this way, several clinical trials have been conducted to investigate the importance of ecDNA in clinical treatment. In this review, we summarize the biogenesis, characteristics, and current research methods of ecDNA, discuss the vital role of ecDNA-caused tumor heterogeneity in cancers, and highlight the potential role of ecDNA in cancer therapy.

关键词： extrachromosomal DNA cancer therapy tumor heterogeneity drug resistance tumor evolution

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AZD1775 synergizes with SLC7A11 inhibition to promote ferroptosis

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Science China Life Sciences 2025年第1期68卷 204-218页

作者： Chen Xiong Hong Ling Yingdan Huang Hanzhi Dong Bangxiang Xie Qian Hao Xiang Zhou Fudan University Shanghai cancer Center and Institutes of Biomedical Sciences Fudan University Department of Oncology Shanghai Medical CollegeFudan University Department of Breast Surgery Fudan University Shanghai Cancer CenterFudan University Department of Oncology First Affiliated Hospital of Nanchang University beijing Institute of Hepatology Beijing Youan HospitalCapital Medical University beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and liver cancer key laboratory of Breast cancer in Shanghai Fudan University Shanghai Cancer CenterFudan University Shanghai key laboratory of Medical Epigenetics International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology)Institutes of Biomedical SciencesFudan University

Tumor suppressor p53-mediated cell cycle arrest and DNA damage repair may exert cytoprotective effects against cancer therapies, including WEE1 inhibition. Considering that p53 activation can also lead to multiple types of cell death, the role of this tumor suppressor in WEE1 inhibitor-based therapies remains disputed. In this study, we reported that nucleolar stress-mediated p53 activation enhanced the WEE1 inhibitor AZD1775-induced ferroptosis to suppress lung cancer growth. Our findings showed that AZD1775 promoted ferroptosis by blocking cystine uptake, an action similar to that of Erastin. Meanwhile, inhibition of WEE1 by the WEE1 inhibitors or si RNAs induced compensatory upregulation of SLC7A11, which conferred resistance to ferroptosis. Mechanistically, AZD1775 prevented the enrichment of H3K9me3, a histone marker of transcriptional repression, on the SLC7A11 promoter by repressing the expression of the histone methyltransferase SETDB1, thereby enhancing NRF2-mediated SLC7A11 transcription. This finding was also validated using the H3K9me3 inhibitor BRD4770. Remarkably, we found that the nucleolar stress-inducing agent Actinomycin D(Act. D) inhibited SLC7A11 expression by activating p53, thus augmenting AZD1775-induced ferroptosis. Moreover, the combination of AZD1775 and Act. D synergistically suppressed wild-type p53-harboring lung cancer cell growth both in vitro and in vivo. Altogether, our study demonstrates that AZD1775 promotes ferroptosis by targeting cystine uptake but also mediates the adaptive activation of SLC7A11 through the WEE1-SETDB1 cascade and NRF2-induced transcription, and inhibition of SLC7A11 by Act. D boosts the anti-tumor efficacy of AZD1775 by enhancing ferroptosis in cancers with wild-type p53.

关键词： p53 NRF2 SLC7A11 WEE1 AZD1775 ferroptosis nucleolar stress

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Overexpression of chaperonin containing TCP1, subunit 3 predicts poor prognosis in hepatocellular carcinoma

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World Journal of Gastroenterology 2015年第28期21卷 8588-8604页

作者： Xiao Cui Zhi-Ping Hu Zhao Li Peng-Ji Gao Ji-Ye Zhu Department of Hepatobiliary Surgery Peking University People’s Hospital beijing key Surgical Basic Research laboratory of liver cirrhosis and liver cancer Peking University People’s Hospital

AIM:To investigate the value of chaperonin containing TCP1,subunit 3(CCT3) to predict the prognosis of patients with hepatocellular carcinoma(HCC) and determine its function in HCC ***:CCT3 expression levels were examined in human non-cancerous liver tissues and a variety of HCC cell lines by quantitative real-time PCR and ***3 expression was suppressed by small interfering *** effects of reducing CCT3 expression in HCC cells were ***3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide(MTT) assay,cell counting experiment,cell cycle assay,apoptosis assay and invasion assay were employed to evaluate cell functions in *** was performed on HCC *** addition,CCT3 expression in HCC specimens was also assessed at the protein and mRNA *** between clinicopathological characteristics and prognosis were analyzed,along with the possible mechanisms involved in CCT3's function in HCC ***:The expression levels of CCT3 mRNA and protein were upregulated in HCC cell lines in contrast to adjacent non-cancerous *** CCT3 expression not only suppressed cell proliferation in cell counts,MTT assay,cell cycle assay and induced cell apoptosis(P cancer cells in HCC specimens(58of 104 patients,55.8%) was associated with poor prognosis in HCC patients(3-year survival rate,55.5%vs 84.2%,P = 0.020) after *** analyses showed that signal transducer and activator of transcription 3(STAT3) activation was decreased even when stimulated by interleukin-6 after knocking down CCT3 in the HepG2 cell ***:Overexpression of CCT3 in the nuclei of cancerous cells is associated with HCC ***3 may be a target that affects the activation of STAT3 in HCC.

关键词： Hepatocellular carcinoma Chaperonin ContainingTCP1, Subunit 3 Cell growth Invasion Prognosis

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Concomitant extrahepatic autoimmune diseases do not compromise the long-term outcomes of primary biliary cholangitis

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Hepatobiliary & Pancreatic Diseases International 2022年第6期21卷 577-582页

作者： Sha Chen Meng-Qi Li Wei-Jia Duan Bu-Er Li Shu-Xiang Li Ting-Ting Lv Lin Ma Ji-Dong Jia liver Research Center Beijing Friendship HospitalCapital Medical UniversityBeijing Key Laboratory of Translational Medicine on Liver CirrhosisNational Clinical Research Center for Digestive Diseases95 Yong’an RoadBeijing 100050China

Background:Primary biliary cholangitis(PBC)patients often have concomitant extrahepatic autoimmune(EHA)diseases including Sjögren’s syndrome(SS),systemic sclerosis(SSc),rheumatoid arthritis(RA),and autoimmune thyroid *** present study aimed to describe the prevalence of EHA diseases in PBC and explore the impact of EHA diseases on the long-term outcomes of PBC in Chinese ***:Medical records of PBC patients diagnosed in our institute were retrospectively ***-tients were followed up by a standardized telephone *** endpoints were defined as liver-related death and/or liver ***:Totally 247 of the 985(25.1%)PBC patients enrolled in the study had at least one concomi-tant EHA ***ögren’s syndrome(n=140,14.2%)was the most frequent one,followed by rheuma-toid arthritis(RA)(n=56,5.7%)and Hashimoto’s thyroiditis(n=45,4.6%).Patients with EHA dis-eases were more common in females(P<0.001)and in those with a family history of autoimmune disease(P=0.017).Overall,no differences were found between PBC patients with and without EHA dis-eases in terms of biochemical response rates to ursodeoxycholic acid,the incidence of hepatic events,or transplant-free *** and EHA≥2 were protective factors for hepatic events in univariate Cox analysis,but the results became insignificant in multivariate ***:Concomitant EHA diseases were common in PBC patients but did not compromise the long-term outcomes of PBC.

关键词： Primary biliary cholangitis Extrahepatic autoimmune diseases Sjögren’s syndrome Rheumatoid arthritis Prognosis

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Hepatocellular carcinoma: Current situation and challenge

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Hepatobiliary & Pancreatic Diseases International 2019年第4期18卷 303-304页

作者： Zhao Li Ji-Ye Zhu Department of Hepatobiliary Surgery Peking University People’s HospitalBeijing 100044China Peking University Institute for Organ Transplantation Beijing 100044China beijing key laboratory of liver cirrhosis and liver cancer Beijing 100044China

Hepatocellular carcinoma(HCC)ranks the fourth cause of cancer-related death worldwide[1].More than 50%newly diagnosed HCC patients are in China,while 70%of them are at advanced stage when they are diagnosed[2].These patients have lost the opportunity of radical surgery and can only receive palliative ***,the modality for these advanced stage HCC patients mainly include:targeted therapy,interventional therapy,chemotherapy,radiotherapy,and immunotherapy.

关键词： chemotherapy patients therapy

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Control of Chronic Hepatitis B in China:Perspective of Diagnosis and Treatment

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China CDC weekly 2020年第31期2卷 596-600页

作者： Yu Wang Min Wang Guanhua Zhang Xiaojuan Ou Hong Ma Hong You Jidong Jia liver Research Center Beijing Friendship HospitalCapital Medical University/Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis/National Clinical Research Center for Digestive DiseasesBeijingChina

In the last three decades,China has made extraordinary effort and achieved great progress in the control of hepatitis *** to the adoption of universal administering of HBV vaccinations for newborns since 1992,the prevalence of hepatitis B surface antigen(HBsAg)in the population born after 1992 decreased significantly resulting in a decline in the general population from 9.75%to about 6%(1).

关键词： Chronic vaccination prevalence

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Overexpression of anillin is related to poor prognosis in patients with hepatocellular carcinoma

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Hepatobiliary & Pancreatic Diseases International 2021年第4期20卷 337-344页

作者： Long-Hui Zhang Dong Wang Zhao Li Gang Wang Ding-Bao Chen Qian Cheng Shi-Hua Hu Ji-Ye Zhu Department of Hepatobiliary Surgery Peking University People’s HospitalBeijing 100044China Peking University Institute for Organ Transplantation Beijing 100044China beijing key laboratory of liver cirrhosis and liver cancer Beijing 100044China Department of Pathology Peking University People’s HospitalBeijing 100044China

Background: Anillin(ANLN) is required for tumor growth. It has been proven that knockdown of ANLN effectively reduces the occurrence of hepatocellular carcinoma(HCC) in transgenic mice. However, the functional role of ANLN in HCC patients remains to be elucidated. Methods: Both microarray and TCGA project were used for the analyses of ANLN expression and regulation in HCC. The effect of ANLN on proliferation and cell cycle was detected by CCK-8, colony formation assay and flow cytometry. ANLN expression was measured by immunohistochemistry. Correlation between ANLN expression and clinicopathological features was assessed by Pearson Chi-square test and 5-year overall survival after liver resection was evaluated by Kaplan–Meier method. Results: Increased copy number, decreased methylation levels in the Cp G island and upregulated histone hypermethylation of ANLN were found in HCC. Knockdown of ANLN inhibited proliferation and induced G2/M phase arrest in SMMC-7721 cells. ANLN was mainly expressed in the nucleus and showed significantly higher expression levels in cancerous tissues than those in paired adjacent tissues. Moreover, nuclear ANLN expression levels in HCC metastases were significantly higher than those in primary HCC. The results of Cox proportional hazards regression model suggested that ANLN nuclear expression in HCC was an independent risk factor for poor 5-year overall survival of patients after liver resection. Conclusions: ANLN is a potential therapeutic target for HCC. Patients with nuclear ANLN overexpression in HCC tissue may need adjuvant therapy after liver resection.

关键词： Anillin DNA methylation Copy number variation Hepatocellular carcinoma Prognosis

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Adenovirus and severe acute hepatitis of unknown etiology in children:Offender or bystander?

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Hepatobiliary & Pancreatic Diseases International 2022年第4期21卷 354-355页

作者： Shan Shan Ji-Dong Jia liver Research Center Beijing Friendship HospitalCapital Medical University/Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis/National Clinical Research Center for Digestive DiseasesBeijing 100050China

On April 6,2022,the United Kingdom Health Security Agency(UKHSA)released an alert on cases of hepatitis of unknown etiology in children[1].On April 15,2022,World Health Organization(WHO)published the first notice of this condition[2].Later on,similar cases were reported from the UK,other European countries,and other parts of the world.

关键词： etiology hepatitis cases

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New perspectives in the definition and classification of acute-on-chronic liver failure

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中华医学杂志(英文版) 2024年第21期137卷 2521-2525页

作者： Xu Manman Chen Yu Fourth Department of liver Disease Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research Beijing You’an Hospital Capital Medical University Beijing China

The term “acute-on-chronic liver failure”(ACLF) was initially proposed nearly 30 years ago. ACLF is distinct from decompensated cirrhosis and acute liver failure, representing an independent clinical syndrome result...

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“Treat-all”Strategy for Patients with Chronic Hepatitis B Virus Infection in China:Are We There Yet?

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Journal of Clinical and Translational Hepatology 2024年第6期12卷 589-593页

作者： Mengyang Zhang Yuanyuan Kong Xiaoqian Xu Yameng Sun Jidong Jia Hong You liver Research Center Beijing Friendship HospitalCapital Medical UniversityBeijing Key Laboratory of Translational Medicine on Liver CirrhosisNational Clinical Research Center of Digestive DiseasesState Key Lab of Digestive HealthBeijingChina Clinical Epidemiology and EBM Unit Beijing Friendship HospitalCapital Medical UniversityBeijing Clinical Research InstituteBeijingChina

Chronic hepatitis B remains the primary cause of liver-related events in *** World Health Organization set a goal to eliminate viral hepatitis as a public health threat by ***,achieving this goal appears challenging due to the current low rates of diagnosis and ***“Treat-all”strategy,which proposes treating all patients with detectable hepatitis B virus(HBV)DNA or even all patients with positive HBsAg,has been suggested to simplify anti-HBV *** 2022,the Chinese Society of Hepatology and the Chinese Society of Infectious Diseases updated the guidelines for the prevention and treatment of chronic hepatitis B in China,expanding antiviral indications and simplifying the treatment *** to this latest guideline,nearly 95%of patients with detectable HBV DNA are eligible for antiviral *** review aimed to provide a detailed interpretation of the treatment indications outlined in the Chinese Guidelines for the Prevention and Treatment of Chronic Hepatitis B(version 2022)and to identify gaps in achieving the“Treat-all”strategy in China.

关键词： Chronic hepatitis B Antiviral therapy Treatment indication Expanding treatment Treatment rate “Treat-all”strategy

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