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AZD1775 synergizes with SLC7A11 inhibition to promote ferroptosis

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 UniversityShanghai 200032China Department of Oncology Shanghai Medical CollegeFudan UniversityShanghai 200032China Department of Breast Surgery Fudan University Shanghai Cancer CenterFudan UniversityShanghai 200032China Department of Oncology First Affiliated Hospital of Nanchang UniversityNanchang 330006China Beijing Institute of Hepatology Beijing Youan HospitalCapital Medical UniversityBeijing 100069China Beijing Engineering Research center for Precision Medicine and Transformation of hepatitis and liver cancer Beijing 100069China Key Laboratory of Breast cancer in Shanghai Fudan University Shanghai Cancer CenterFudan UniversityShanghai 200032China Shanghai Key Laboratory of Medical Epigenetics International Co-laboratory of Medical Epigenetics and Metabolism(Ministry of Science and Technology)Institutes of Biomedical SciencesFudan UniversityShanghai 200032China

Tumor suppressor p53-mediated cell cycle arrest and DNA damage repair may exert cytoprotective effects against cancer therapies,including WEE1 *** that p53 activation can also lead to multiple types of cell death,the role of this tumor suppressor in WEE1 inhibitor-based therapies remains *** this study,we reported that nucleolar stress-mediated p53 activation enhanced the WEE1 inhibitor AZD1775-induced ferroptosis to suppress lung cancer *** findings showed that AZD1775 promoted ferroptosis by blocking cystine uptake,an action similar to that of ***,inhibition of WEE1 by the WEE1 inhibitors or siRNAs induced compensatory upregulation of SLC7A11,which conferred resistance to ***,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 *** finding was also validated using the H3K9me3 inhibitor ***,we found that the nucleolar stress-inducing agent Actinomycin D(Act.D)inhibited SLC7A11 expression by activating p53,thus augmenting AZD1775-induced ***,the combination of AZD1775 and Act.D synergistically suppressed wild-type p53-harboring lung cancer cell growth both in vitro and in ***,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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Sequential living donor liver transplantation after liver resection optimizes outcomes for patients with high-risk hepatocellular carcinoma

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Hepatobiliary & Pancreatic Diseases International 2025年第1期24卷 50-56页

作者： Itsuko Chih-Yi Chen Leona Bettina P Dungca Chee-Chien Yong Chao-Long Chen liver Transplantation center Department of SurgeryKaohsiung Chang Gung Memorial Hospital123 Ta-Pei RoadNiao-SungKaohsiungTaiwanChina

Background:Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. While liver transplantation (LT) provides the best long-term survival, it is constrained by organ scarcity and strict criteria. liver resection (LR) is often the initial treatment for patients with solitary tumors and preserved liver function. The high recurrence rates associated with LR has prompted the exploration of sequential living donor liver transplantation (seq LDLT) after LR as a strategy for HCC patients with high-risk of ***:We analyzed data from 27 adult patients who underwent seq LDLT after LR for HCC at Kaohsiung Chang Gung Memorial Hospital (KCGMH) between June 1994 and December 2023. Patients were selected based on high-risk histopathological features post-LR or as part of downstaging strategy. Outcomes measured included overall survival (OS) and disease-free survival (DFS).Results:Among 765 HCC patients who underwent LDLT, 204 received LR before LDLT, and 27 underwent seqL DLT. Five patients (19%) underwent living donor liver transplantation (LDLT) following LR as a downstaging strategy while the rest received seqL DLT as a preemptive strategy. The median age was 53.5 years with 85%males. Chronic hepatitis B was the predominant underlying disease (74%). The 1-, 3-, and 5-year OS and DFS rates were 100%, 96.0%, 96.0%and 100%, 96.2%, 96.2%, respectively, with two patients experiencing HCC recurrence. One patient died from HCC recurrence. High-risk histopathological features included microvascular invasion (52%), satellite nodules (15%), multiple tumors (26%), tumors> 5 cm(19%), and a total tumor diameter> 10 cm (7%).Conclusions:Seq LDLT offers a promising, tailored approach for managing HCC with adverse histopathologic features. Combining seq LDLT, downstaging strategies, and multidisciplinary treatments can achieve satisfactory OS and DFS in carefully selected patients, highlighting the need for refined criteria to identify the best candidates.

关键词： Living donor liver transplantation liver resection High-risk hepatocellular carcinoma Sequential living donor liver transplantation Salvage living donor liver transplantation

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Mitochondrial mt12361A>G increased risk of metabolic dysfunctionassociated steatotic liver disease among non-diabetes

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World Journal of Gastroenterology 2025年第10期31卷 38-50页

作者： Ming-Ying Lu Yu-Ju Wei Chih-Wen Wang Po-Cheng Liang Ming-Lun Yeh Yi-Shan Tsai Pei-Chien Tsai Yu-Min Ko Ching-Chih Lin Kuan-Yu Chen Yi-Hung Lin Tyng-Yuan Jang Ming-Yen Hsieh Zu-Yau Lin Chung-Feng Huang Jee-Fu Huang Chia-Yen Dai Wan-Long Chuang Ming-Lung Yu hepatitis center and Hepatobiliary Division Department of Internal MedicineKaohsiung Medical University HospitalKaohsiung 80708Taiwan School of Medicine and Doctoral Program of Clinical and Experimental Medicine College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver DiseaseNational Sun Yat-sen UniversityKaohsiung 80708Taiwan

BACKGROUND Insulin resistance,lipotoxicity,and mitochondrial dysfunction contribute to the pathogenesis of metabolic dysfunction-associated steatotic liver disease(MASLD).Mitochondrial dysfunction impairs oxidative phosphorylation and increases reactive oxygen species production,leading to steatohepatitis and hepatic *** intelligence(AI)is a potent tool for disease diagnosis and risk *** To investigate mitochondrial DNA polymorphisms in susceptibility to MASLD and establish an AI model for MASLD *** Multiplex polymerase chain reaction was performed to comprehensively genotype 82 mitochondrial DNA variants in the screening dataset(n=264).The significant mitochondrial single nucleotide polymorphism was validated in an independent cohort(n=1046)using the Taqman®allelic discrimination *** forest,eXtreme gradient boosting,Naive Bayes,and logistic regression algorithms were employed to construct an AI model for *** In the screening dataset,only mt12361A>G was significantly associated with ***12361A>G showed borderline significance in MASLD patients with 2-3 cardiometabolic traits compared with controls in the validation dataset(P=0.055).Multivariate regression analysis confirmed that mt12361A>G was an independent risk factor of MASLD[odds ratio(OR)=2.54,95%confidence interval(CI):1.19-5.43,P=0.016].The genetic effect of mt12361A>G was significant in the non-diabetic group but not in the diabetic ***12361G carriers had a 2.8-fold higher risk than A carriers in the non-diabetic group(OR=2.80,95%CI:1.22-6.41,P=0.015).By integrating clinical features and mt12361A>G,random forest outperformed other algorithms in detecting MASLD[training area under the receiver operating characteristic curve(AUROC)=1.000,validation AUROC=0.876].CONCLUSION The mt12361A>G variant increased the severity of MASLD in non-diabetic *** supports the screening and management of MASLD in primary care settings.

关键词： Metabolic dysfunction-associated steatotic liver disease Mitochondrial DNA Artificial intelligence Machine learning Algorithm

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High-dose hepatitis B immunoglobulin therapy in hepatocellular carcinoma with hepatitis B virus-DNA/hepatitis B e antigen-positive patients after living donor liver transplantation

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World Journal of Gastroenterology 2016年第14期22卷 3803-3812页

作者： Eung Chang Lee Seong Hoon Kim Seung Duk Lee Hyeongmin Park Soon-Ae Lee Sang-Jae Park center for liver cancer National Cancer Center

AIM: To investigate the impact of high-dose hepatitis B immunoglobulin(HBIG) on hepatocellular carcinoma(HCC) and hepatitis B virus(HBV) recurrence and overall survival after living donor liver transplantation(LDLT).METHODS: We investigated 168 patients who underwent LDLT due to HCC, and who were HBV-DNA/hepatitis B e antigen(HBe Ag)-positive, from January 2008 to December 2013. After assessing whether the patients met the Milan criteria, they were assigned to the low-dose HBIG group and high-dose HBIG group. Using the propensity score 1:1 matching method, 38 and 18 pairs were defined as adhering to and not adhering to the Milan criteria. For each pair, HCC recurrence, HBV recurrence and overall survival were analyzed by the Kaplan-Meier method and the log rank test according to the HBIG dose. RESULTS: Among those who met the Milan criteria, the 6-mo, 1-year, and 3-year HCC recurrence-free survival rates were 88.9%, 83.2%, and 83.2% in the low-dose HBIG group and 97.2%, 97.2%, and 97.2% in the high-dose HBIG group, respectively(P = 0.042).In contrast, among those who did not meet the Milan criteria, HCC recurrence did not differ according to the HBIG dose(P = 0.937). Moreover, HBV recurrence and overall survival did not differ according to the HBIG dose among those who met(P = 0.317 and 0.190, respectively) and did not meet(P = 0.350 and 0.987, respectively) the Milan criteria. CONCLUSION: High-dose HBIG therapy can reduce HCC recurrence in HBV-DNA/HBe Ag-positive patients after LDLT.

关键词： hepatitis B immune globulin Hepatocellular carcinoma hepatitis B virus-DNA liver transplantation hepatitis B e antigen

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Acute liver failure and death predictors in patients with dengueinduced severe hepatitis

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World Journal of Gastroenterology 2020年第33期26卷 4983-4995页

作者： Tongluk Teerasarntipan Roongruedee Chaiteerakij Piyawat Komolmit Pisit Tangkijvanich Sombat Treeprasertsuk Department of Medicine Division of GastroenterologyFaculty of MedicineChulalongkorn Universityand Thai Red CrossBangkok 10330Thailand Department of Biochemistry Center of Excellence in Hepatitis and Liver CancerFaculty of MedicineChulalongkorn UniversityBangkok 10330Thailand

BACKGROUND liver injury in patients with dengue infection is *** patients have mild and transient *** liver failure(ALF)in dengue infection is rare but results in an extremely poor *** To identify prognostic predictors of ALF and death in patients with dengueinduced severe hepatitis(DISH).METHODS We retrospectively reviewed 2311 serologically confirmed adolescent and adult dengue patients who were hospitalized during a 12-year study period(between 2007 and 2019)at the university hospital of King Chulalongkorn Memorial Hospital,Bangkok,*** with DISH[n=134(5.80%)],defined as a baseline transaminase>10 times the normal reference cut-off level,and DISH with subsequent ALF as defined by the American Association for the Study of the liver Diseases 2011 criteria[n=17(0.74%)],were *** of ALF and in-hospital death were identified using logistic regression *** Of the 151 dengue-infected patients with severe liver injury or ALF,51%were female,with a mean age of 27.9±14.5 *** leakage syndrome(CLS)occurred in 68.2%(n=103)of DISH and 100%of ALF *** mortality rate was low in DISH patients(0.8%)but was remarkably high if ALF developed(58.8%).In univariate analysis,age,sex,hematocrit,white blood count,atypical lymphocyte count,platelet count,international normalized ratio(INR),bilirubin,serum glutamate-oxaloacetate transaminase,serum glutamate-pyruvate transaminase,alkaline phosphatase,albumin,creatinine,Model for End-Stage liver Disease(MELD)score,presence of liver comorbidity and presence of CLS were identified as potential prognostic parameters for ALF or *** multivariate analysis,the MELD score remained the only predictor of ALF with an adjusted odds ratio(aOR)of 1.3[95%confidence interval(CI):1.1-1.5;P=<0.001].An initial MELD score≥15 was associated with ALF from DISH with an area under the receiver operating characteristic(AUROC)of 0.91,88.2%sensitivity and 87.3%***

关键词： Dengue liver failure hepatitis Prognosis Mortality Predictor

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Successful living donor liver transplantation with a graft-to-recipient weight ratio of 0.41 without portal flow modulation:A case report

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World Journal of Clinical Cases 2022年第16期10卷 5414-5419页

作者： Seong Hoon Kim center for liver cancer National Cancer CenterGoyang 10408GyeonggidoSouth Korea

BACKGROUND There have been numerous efforts to lower the limit of minimum graft size to meet the metabolic demand of recipients in adult-to-adult living donor liver transplantation(LDLT).We experienced a successful case of LDLT using a verysmall-for-size graft without portal flow modulation such as splenectomy or portocaval *** SUMMARY A 49-year-old man(weighing 91 kg)suffering hepatocellular carcinoma accompanied with hepatitis B virus related cirrhosis underwent *** one and only voluntary donor was his 17-year-old daughter whose body weight was 50 kg with a body mass index(BMI)of *** procured right liver graft was 411 g with a real graft-to-recipient weight ratio(GRWR)of 0.41%,the smallest to be reported in the *** the recipient and donor had an uneventful recovery and were discharged on days 15 and 8,respectively,with normal liver *** father and daughter have had no complication so far and are still in good health with normal liver function 81 mo after *** Satisfactory outcomes can be achieved in LDLT with a GRWR as low as 0.41%even without using portal flow modulation in highly selected patients.

关键词： Small-for-size graft Living donor liver transplantation Graft-to-recipient weight ratio Case report

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Long non-coding RNA H19 promotes proliferation inhepatocellular carcinoma cells via H19/miR-107/CDK6 axis

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Oncology Research 2023年第6期31卷 989-1005页

作者： ARCHITTAPON NOKKEAW PANNATHON THAMJAMRASSRI NAPHAT CHANTARAVISOOT PISIT TANGKIJVANICH CHAIYABOOT ARIYACHET Department of Biochemistry Faculty of MedicineChulalongkorn UniversityBangkok10330Thailand center of excellence in hepatitis and liver cancer Faculty of MedicineChulalongkorn UniversityBangkok10330Thailand Department of Biochemistry Medical Biochemistry ProgramFaculty of MedicineChulalongkorn UniversityBangkok10330Thailand center of excellence in Systems Biology Faculty of MedicineChulalongkorn UniversityBangkok10330Thailand

Hepatocellular carcinoma (HCC) is the leading cause of cancer death worldwide;nevertheless, currenttherapeutic options are limited or ineffective for many patients. Therefore, elucidation of molecular mechanisms inHCC biology could yield important insights for the intervention of novel therapies. Recently, various studies havereported dysregulation of long non-coding RNAs (lncRNAs) in the initiation and progression of HCC, including H19;however, the biological function of H19 in HCC remains unclear. Here, we show that knockdown of H19 disruptedHCC cell growth, impaired the G1-to-S phase transition, and promoted apoptosis, while overexpression of H19yielded the opposite results. Screening for expression of cell cycle-related genes revealed a significant downregulationof CDK6 at both RNA and protein levels upon H19 suppression. Bioinformatic analysis of the H19 sequence and the3′ untranslated region (3′ UTR) of CDK6 transcripts showed several binding sites for microRNA-107 (miR-107), andthe dual luciferase reporter assay confirmed their direct interaction with miR-107. Consistently, blockage of miR-107activity alleviated the growth suppression phenotypes induced by H19 downregulation, suggesting that H19 serves asa molecular sponge for miR-107 to promote CDK6 expression and cell cycle progression. Together, this studydemonstrates a mechanistic function of H19 in driving the proliferation of HCC cells and suggests H19 suppressionas a novel approach for HCC treatment.

关键词： HCC H19 Long-noncoding RNA MicroRNA Cyclin-dependent kinase CDK6

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Delta-like ligand 4 in hepatocellular carcinoma intrinsically promotes tumour growth and suppresses hepatitis B virus replication

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World Journal of Gastroenterology 2018年第34期24卷 3861-3870页

作者： Areerat Kunanopparat Jiraphorn Issara-Amphorn Asada Leelahavanichkul Anapat Sanpavat Suthiluk Patumraj Pisit Tangkijvanich Tanapat Palaga Nattiya Hirankarn center of excellence in Immunology and Immune Mediated Diseases Department of Microbiology Faculty of Medicine Chulalongkorn University Department of Pathology Faculty of Medicine Chulalongkorn University center of excellence for Microcirculation Department of Physiology Faculty of Medicine Chulalongkorn University Research Unit of hepatitis and liver cancer Department of Biochemistry Faculty of Medicine Chulalongkorn University Department of Microbiology Faculty of Science Chulalongkorn University

AIM To investigate the role of Delta-like ligand 4(DLL4) on tumour growth in hepatitis B virus(HBV)-associated hepatocellular carcinoma(HCC) in *** We suppressed DLL4 expression in an HBV expressing HCC cell line, HepG2.2.15 and analysed the growth ability of cells as subcutaneous tumours in nude mice. The expression of tumour angiogenesis regulators, VEGF-A and VEGF-R2 in tumour xenografts were examined by western blotting. The tumour proliferation and neovasculature were examined by immunohistochemistry. The viral replication and viral protein expression were measured by quantitative PCR and western blotting, *** Eighteen days after implantation, tumour volume in mice implanted with sh DLL4 HepG2.2.15 was significantly smaller than in mice implanted with control HepG2.2.15(P < 0.0001). The levels of angiogenesis regulators, VEGF-A and VEGF-R2 were significantly decreased in implanted tumours with suppressed DLL4 compared with the control group(P < 0.001 and P < 0.05, respectively). Furthermore, the suppression of DLL4 expression in tumour cells reduced cell proliferation and the formation of new blood vessels in tumours. Unexpectedly, increased viral replication was observed after suppression of DLL4 in the *** This study demonstrates that DLL4 is important in regulating the tumour growth of HBV-associated HCC as well as the neovascularization and suppression of HBV replication.

关键词： hepatocellular carcinoma Notch signalling Delta-like ligand 4 HepG2.2.15

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Clinicopathological features and prognosis of combined hepatocellular carcinoma and cholangiocarcinoma after surgery

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Hepatobiliary & Pancreatic Diseases International 2014年第6期13卷 594-601页

作者： Seung Duk Lee Sang-Jae Park Sung-Sik Han Seong Hoon Kim Young-Kyu Kim Soon-Ae Lee Young Hwan Ko Eun Kyung Hong center for liver cancer Research Institute and Hospital National Cancer Center Goyang-si Gyeonggi-do Republic of Korea

BACKGROUND： Combined hepatocellular carcinoma and cholangiocarcinoma （cHCC-CC） is a rare subtype of primary liver cancer consisting of both hepatocellular carcinoma （HCC） and cholangiocarcinoma （CC）. Because of the rarity of this tumor, its feature is poorly understood. The present study aimed to evaluate the clinicopathological features and long-term prognosis of patients with cHCC-CC after surgery and to compare with those of the patients with stage-matched HCC and CC. METHODS： The dinicopathological features of the patients who underwent surgery for cHCC-CC at our center during the period of 2001-2010 were retrospectively analyzed and compared with those of stage-matched HCC and CC patients. cancer staging was performed according to the AJCC cancer Staging Manual （6th ed.）. Overall survival and disease-free survival were compared among the groups and prognostic factors of cHCC-CC were evaluated. RESULTS： Significant differences were observed in clinico- pathological features among 42 patients with cHCC-CC, 90 patients with HCC and 45 patients with CC. Similar to HCC patients, cHCC-CC patients had frequent hepatitis B virus antigen positivity, microscopic vessel invasion, cirrhosis and high level of serum alpha-fetoprotein. Similar to CC patients, cHCC-CC patients showed increased bile duct invasion and decreased capsule. The 1-, 3-, and 5-year overall survival and disease- free survival of patients with cHCC-CC were not significantly different from those with stage-matched patients with CC;but significantly poorer than those with HCC. In subanalysis of patients with stage Ⅱ, the overall survival in patients with cHCC-CC or CC was significantly poorer than that in patients with HCC. We did not find the difference in patients with other stages. Univariate analysis of overall and disease-free survival of patients with cHCC-CC showed that the vascular invasion and intrahepatic metastasis were the significant predictive factors. CONCLUSION： Patients with cHCC-CC showe

关键词： hepatocellular carcinoma cholangiocarcinoma stage prognosis

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Neoadjuvant and Adjuvant Therapy in Intrahepatic Cholangiocarcinoma

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Journal of Clinical and Translational Hepatology 2022年第3期10卷 553-563页

作者： Xing Chen Jinpeng Du Jiwei Huang Yong Zeng Kefei Yuan Department of liver Surgery and liver Transplantation Laboratory of Liver SurgeryState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina

Intrahepatic cholangiocarcinoma(ICC)is the second most common primary liver cancer and causes major economic and health burdens throughout the *** the incidence of ICC is relatively low,an upward trend has been seen over the past few *** to the lack of specific manifestations and tools for early diagnosis,most ICC patients have relatively advanced disease at ***,neoadjuvant therapy is necessary to evaluate tumor biology and downstage these patients so that appropriate candidates can be selected for radical liver ***,even after radical resection,the recurrence rate is relatively high and is a main cause leading to death after surgery,which makes adjuvant therapy *** of its low incidence,studies in both neoadjuvant and adjuvant settings of ICC are lagging compared with other types of *** standard neoadjuvant and adjuvant regimens are not available in the current guidelines due to a lack of high-level evidence,some progress has been achieved in recent *** this review,the available literature on advances in neoadjuvant and adjuvant strategies in ICC are evaluated,and possible challenges and opportunities for clinical and translational investigations in the near future are discussed.

关键词： Intrahepatic cholangiocarcinoma Neoadjuvant therapy Adjuvant therapy Recurrence liver resection liver transplant

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