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Heat shock protein inhibitor, quercetin, as a novel adjuvant agent to improve radiofrequency ablation-induced tumor destruction and its molecular mechanism

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Chinese Journal of Cancer Research 2016年第1期28卷 19-28页

作者： Wei Yang Ming Cui Jungchieh Lee Wei Gong Song Wang Jingjing Fu Gongxiong Wu Kun Yan key laboratory of carcinogenesis and Translational Research (Ministry of Education/Beijing) Department of Ultrasound Peking University Cancer Hospital & Institute key laboratory of carcinogenesis and Translational Research (Ministry of Education/Beijing) Department of Gastrointestinal Surgery IV Peking University Cancer Hospital & Institute state key laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology department of Cardiovascular and Neurovascular Guangzhou Medical University department of oncology The first Affiliated Hospital Zhengzhou University

Background： We investigated the effect of a small molecular inhibitor of heat shock protein （HSP）, qnercetin, on tumor radiofrequency （RF） ablation, and explored the underlying molecular mechanisms. Methods： In in vivo study, rats with R3230 breast adenocarcinoma were sacrificed 24 h post-treatment and gross coagulation areas were compared, and next, randomized into four treatment arms （control, quercetin alone, RF alone, and combination） for Kaplan-Meier analysis of defined endpoint survival. Then the distribution and expression levels of heat shock protein 70 （HSP70）, cleaved caspase-3 and heat shock factor 1 （HSF1） were analyzed after different treatments. In in vitro study, we used quercetin to promote SK- HEP-I （hepatic） and MCF-7 （breast） cancer cell apoptosis in heat shock cell model, and siRNA was used to block c-Jun and to explore the role of activating protein-1 （AP-1） signaling pathways. Results： We found the effects of quercetin plus RFA resulted in increase on the tumor destruction/ endpoint survival （26.5±3.4 d） in vivo, compared with RF alone （17.6±2.5 d） and quercetin alone （15.7±3.1 d）. Most importantly, quercetin-induced cancer cell death required the presence of HSF1 in animal model. Furthermore, quercetin directly down-regulated expression of HSF1 in vitro, which our findings have revealed, required the activation of AP-1 signaling pathways by loss-of-function analysis using siRNA mediated targeting of c-Jun. Conclusions： These results indicated a protective role of quercetin in tumor ablation and highlighted a novel mechanism involving HSP70 with HSF1 pathway in thermal ablation of solid tumors.

关键词： Radiofrequency ablation (RFA) heat shock protein (HSP) quercetin solid tumor

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Single-cell profiling of the copy-number heterogeneity in colorectal cancer

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Chinese Medical Journal 2023年第6期136卷 707-718页

作者： Shiyu Song Lin Feng Kexing Xi Zhigang Sun Deyang Kong Zhenkai Luo Wei Pei Haizeng Zhang department of Colorectal Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China state key Lab of molecular oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China state key laboratory of molecular oncology Department of Etiology and CarcinogenesisNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

Background:With functionally heterogeneous cells,tumors comprise a complex ecosystem to promote tumor adaptability and evolution under strong selective pressure from the given *** tumor cells or intra-tumor heterogeneity is essential for tumor growth,invasion,and immune ***,no reliable method to classify tumor cell subtypes is yet *** this study,we introduced the single-cell sequencing combined with copy number characteristics to identify the types of tumor cells in microsatellite stable(MSS)colorectal cancer(CRC).Methods:To characterize the somatic copy number alteration(SCNA)of MSS CRC in a single cell profile,we analyzed 26 tissue samples from 19 Korean patients(GSE132465,the Samsung Medical Center[SMC]dataset)and then verified our findings with 15 tissue samples from five Belgian patients(GSE144735,the Katholieke Universiteit Leuven 3[KUL3]dataset).The Cancer Genome Atlas(TCGA)cohort,GSE39582 cohort,and National Cancer Center(NCC)cohort(24 MSS CRC patients were enrolled in this study between March 2017 and October 2017)were used to validate the clinical features of prognostic ***:We employed single cell RNA-sequencing data to identify three types of tumor cells in MSS CRC by their SCNA *** these three types of tumor cells,C1 and C3 had a higher SCNA burden;C1 had significant chromosome 13 and 20 amplification,whereas C3 was the polar opposite of C1,which exhibited deletion in chromosome 13 and *** three types of tumor cells exhibited various functions in the tumor microenvironment and harbored different mutations.C1 and C2 were linked to the immune response and hypoxia,respectively,while C3 was critical for cell adhesion activity and tumor ***,one gene(OLFM4)was identified as epithelium-specific biomarker of better prognosis of CRC(TCGA cohort:P=0.0110;GSE39582 cohort:P=0.0098;NCC cohort:P=0.0360).Conclusions:On the basis of copy number characteristics,we ill

关键词： Somatic copy number alteration Microsatellite stable Colorectal cancer Single cell RNA-sequencing Intra-tumor genetic heterogeneity

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Mitogen-activated protein kinase signaling pathway and invasion and metastasis of gastric cancer

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World Journal of Gastroenterology 2015年第41期21卷 11673-11679页

作者： Mei Yang Chang-Zhi Huang department of etiology and carcinogenesis & state key laboratory of molecular oncology Cancer Institute and Hospital Chinese Academy of Medical Sciences and Peking Union Medical College

The mortality rate of gastric cancer worldwide is as high as 70%, despite the development of novel therapeutic strategies. One reason for the high mortality is the rapid and uninhibited spread of the disease, such that the majority of patients are diagnosed at a stage when efficient therapeutic treatment is not available. Therefore, in-depth research is needed to investigate the mechanism of gastric cancer metastasis and invasion to improve outcomes and provide biomarkers for early diagnosis. The mitogen-activated protein kinase(MAPK) signaling pathway is widely expressed in multicellular organisms, with critical roles in multiple biological processes, such as cell proliferation, death, differentiation, migration, and invasion. The MAPK pathway typically responds to extracellular stimulation. However, the MAPK pathway is often involved in the occurrence and progression of cancer when abnormally regulated. Many studies have researched the relationship between the MAPK signaling pathway and cancer metastasis and invasion, but little is known about the important roles that the MAPK signaling pathway plays in gastric cancer. Based on an analysis of published data, this review aims to summarize the important role that the MAP kinases play in the invasion and metastasis of gastric cancer and attempts to provide potential directions for further research and clinical treatment.

关键词： Mitogen-activated protein kinase Gastric cancer Si

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Comparison of dimension reduction-based logistic regression models for case-control genome-wide association study:principal components analysis *** least squares

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The Journal of Biomedical Research 2015年第4期29卷 298-307页

作者： Honggang Yi Hongmei Wo Yang Zhao Ruyang Zhang Junchen Dai Guangfu Jin Hongxia Ma Tangchun Wu Zhibin Hu Dongxin Lin Hongbing Shen Feng Chen department of Epidemiology and Biostatistics School of Public Health department of Public Service Management School of KangDa Section of Clinical Epidemiology Jiangsu Key Laboratory of Cancer BiomarkersPrevention and TreatmentCancer Center Institute of Occupational Medicine and Ministry of Education Key Laboratory for Environment and HealthSchool of Public HealthTongji Medical CollegeHuazhong University of Science and Technology state key laboratory of Reproductive Medicine Nanjing Medical University state key laboratory of molecular oncology and department of etiology and carcinogenesis Cancer Institute and HospitalChinese Academy of Medical Sciences and Peking Union Medical College

With recent advances in biotechnology, genome-wide association study （GWAS） has been widely used to identify genetic variants that underlie human complex diseases and traits. In case-control GWAS, typical statistical strategy is traditional logistical regression （LR） based on single-locus analysis. However, such a single-locus analysis leads to the well-known multiplicity problem, with a risk of inflating type I error and reducing power. Dimension reduction-based techniques, such as principal component-based logistic regression （PC-LR）, partial least squares-based logistic regression （PLS-LR）, have recently gained much attention in the analysis of high dimensional genomic data. However, the perfor- mance of these methods is still not clear, especially in GWAS. We conducted simulations and real data application to compare the type I error and power of PC-LR, PLS-LR and LR applicable to GWAS within a defined single nucleotide polymorphism （SNP） set region. We found that PC-LR and PLS can reasonably control type I error under null hypothesis. On contrast, LR, which is corrected by Bonferroni method, was more conserved in all simulation settings. In particular, we found that PC-LR and PLS-LR had comparable power and they both outperformed LR, especially when the causal SNP was in high linkage disequilibrium with genotyped ones and with a small effective size in simulation. Based on SNP set analysis, we applied all three methods to analyze non-small cell lung cancer GWAS data.

关键词： principal components analysis partial least squares-based logistic regression genome-wide association study,type I error power

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Post-surgical resection prognostic value of combined OPN, MMP7, and PSG9 plasma biomarkers in hepatocellular carcinoma

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Frontiers of Medicine 2019年第2期13卷 250-258页

作者： Weiqi Rong Yang Zhang Lei Yang Lin Feng Baojun Wei Fan Wu Liming Wang Yanning Gao Shujun Cheng Jianxiong Wu Ting Xiao department of Abdominal Surgery National Cancer Center/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China state key laboratory of molecular oncology Department of Etiology and CarcinogenesisNational Cancer Center/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Clinical laboratory National Cancer Center/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

Biomarkers for hepatocellular carcinoma (HCC) following curative resection are not currently sufficient for prognostic indication of overall survival (OS) and disease-free survival (DFS). The aim of this study was to investigate the prognostic performance of osteopontin (OPN), matrix metalloproteinase 7 (MMP7), and pregnancy specific glycoprotein 9 (PSG9) in patients with HCC. A total of 179 prospective patients with HCC provided plasma before hepatectomy. Plasma OPN, MMP7, and PSG9 levels were determined by enzyme-linked immunosorbent assay. Correlations between plasma levels, clinical parameters, and outcomes (OS and DFS) were overall analyzed. High OPN (≥149.97 ng/mL), MMP7 (≥2.28 ng/mL), and PSG9 (≥45.59 ng/mL) were prognostic indicators of reduced OS (Pcarcinogenesis.

关键词： biomarkers OPN MMP7 PSG9 HCC prognosis

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Elevated expression of lung development-related protein HSP9O0 indicates poor prognosis in non-small cell lung cancer through affecting the cell cycle and apoptosis

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Signal Transduction and Targeted Therapy 2021年第3期6卷 611-613页

作者： Xiang Wang Yaru Wang Lin Feng Minghui Wang Kaitai Zhang Yousheng Mao Ting Xiao Shujun Cheng state key laboratory of molecular oncology Department of Etiology and CarcinogenesisNational Cancer Center/National Clinical Research Center for Cancer/Concer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina department of Thoracic Surgery National CancerCenter/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina

Dear Editor,Oncogenesis was considered to be similar to the early embryonic development process in a variety of ways.1 Using normal development samples as research models will help us understand tumors and identify potential ***-shock protein 90 beta(HSP90P,HSP90AB1)is one of the major isoforms of HSP90 and is involved in embryonic development,signal transduction,and cellular adaptability.

关键词： HSP90 lung prognosis

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PSG9 promotes angiogenesis by stimulating VEGFA production and is associated with poor prognosis in hepatocellular carcinoma

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Science China(Life Sciences) 2017年第5期60卷 528-535页

作者： Weiqi Rong Lei Yang Liyuan Yin Yanning Gao Ting Xiao Shujun Cheng state key laboratory of molecular oncology Beijing Key Laboratory for Carcinogenesis and Cancer Prevention National Cancer Center/Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100021 China department of Abdominal Surgery National Cancer Center/Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100021 China

Hepatocellular carcinoma(HCC) is a common malignant solid tumor characterized by rich vascularization. Pregnancy-specific glycoprotein 9(PSG9) is a member of the carcinoembryonic antigen(CEA)/PSG family and is produced at high levels during pregnancy. We previously identified PSG9 as an HCC-related protein. However, the expression of PSG9 and its regulation during HCC carcinogenesis remain poorly explored. In the present study, we first found that the levels of PSG9 protein were significantly increased in the plasma of HCC patients. PSG9 overexpression also increased the proliferation ability of an HCC cell line. High expression of PSG9 was associated with angiogenesis by accelerating VEGFA expression. In addition, Cox's proportional hazards model analysis revealed that the plasma level of PSG9 was an independent prognostic factor for overall survival. We propose that PSG9 is a novel indicator of prognosis in patients with HCC and could serve as a novel therapeutic target for HCC. Furthermore,our results indicate that PSG9 protein may facilitate the development of HCC by fostering angiogenesis via promoting VEGFA production in cancer cells.

关键词： hepatocellular carcinoma (HCC) PSG9 VEGFA angiogenesis

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An Oncolytic Adenovirus Expressing Herpes Simplex Virus-Thymidine Kinase for Targeting Cancer Therapy:An in vitro Evaluation

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Chinese Journal of Cancer Research 2009年第2期21卷 90-96页

作者： Fei-qun Zheng Yin Xu Yi-de Qin Ren-jie Yang Jun Han key laboratory of carcinogenesis and Translational Research （Ministry of Education） Department oflnterventional therapy Peking University School of Oncology Beijing Cancer Hospital ＆ Institute Beijing100142 China department of Biochemistry and molecular Biology Anhui Medical University Hefei 230032 AnhuiProvince China state key laboratory for Infectious Disease Prevention and Control National Institute for Viral DiseaseControl and Prevention Chinese Center for Disease Control and Prevention Beijing 100052 China

Objective： Oncolytic adenovirus, also called conditionally replicating adenovirus （CRAD）, has been developed for the treatment of cancer. However, there is a tremendous need to enhance their antitumor efficacy. Here we wish to evaluate whether a strategy that combines the herpes simplex virus-thymidine kinase with oncolytic effects offers a therapeutic advantage. Methods： A novel adenovirus Ad-ETK containing a sequentially positioned promoter of human telomerase reverse transcriptase （hTERT）, the coding sequence of E1A gene, an internal ribosome entry site sequence （IRES） and the coding sequence of herpes simplex virus-thymidine kinase （HSV-TK） was constructed. Infection of various cells with Ad-ETK followed by RT-PCR confirmed the expression of E1A and HSV-TK. The oncolytic ability and synergism between oncolytic effects and HSV-TK system was measured. The infection efficiency was determined by flow cytometry. Results： Ad-ETK deliverys E1A and HSV-TK gene, which selectively replicates in hTERT-positive tumor cells, and the progeny virus can reach up to 150 IU/cell. Our in vitro study showed that Ad-ETK plus ganciclovir （GCV） induced an obvious cell death. Conclusion： An oncolytic adenovirus plus the HSV-TK/GCV suicide gene system resulted in a significant improvement in treatment efficacy and it may offer important considerations in the development and preclinical assessments of oncolytic virotherapy.

关键词： Conditionally replicative adenovirus Cancer gene therapy Herpex simplex virus-thymidine kinase

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Association of the Asp312Asn and Lys751 Gln polymorphisms in the XPD gene with the risk of non-Hodgkin's lymphoma:evidence from a meta-analysis

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Chinese Journal of Cancer 2015年第3期34卷 108-114页

作者： Shen Chen Jin-Hong Zhu Fang Wang Shao-Yi Huang Wen-Qiong Xue Zhuo Cui Jing He Wei-Hua Jia state key laboratory of oncology in South China Collaborative Innovation Center for Cancer MedicineDepartment of Experimental ResearchSun Yat-sen University Cancer Center molecular Epidemiology Lab and laboratory Medicine Harbin Medical University Cancer Hospital department of Statistics University of California

Polymorphisms in DNA repair genes may alter DNA repair capacity and,consequently,lead to genetic instability and *** studies have investigated the association of the Asp312 Asn and Lys751 Gln polymorphisms in the xeroderma pigmentosum complementation group D {XPD) gene with the risk of non-Hodgkin's lymphoma(NHL),but the conclusions have been ***,we performed this meta-analysis to more precisely estimate these relationships.A systematic literature search was performed using the PubMed,Embase,and Chinese Biomedical(CBM) ***,6 studies of Asp312 Asn,comprising 3,095 cases and 3,306 controls,and 7studies of Lys751 Gln,consisting of 3,249 cases and 3,676 controls,were *** odds ratios(ORs) and 95%confidence intervals(CIs) were calculated to assess the strength of each ***,no association was observed between the Asp312 Asn polymorphism and NHL risk(homozygous:OR = 1.11,95%CI = 0.94-1.32;heterozygous:OR = 1.00,95%CI = 0.89-1.11;recessive:OR = 1.12,95%CI = 0.95-1.31;dominant:OR = 1.02,95%CI = 0.92-1.13;and allele comparison:OR = 1.04,95%CI = 0.96-1.12) or between the Lys751 Gln polymorphism and NHL risk(homozygous:OR = 0.97,95%CI = 0.83-1.15;heterozygous:OR = 0.96,95%CI = 0.86-1.06;recessive:OR = 1.00,95%CI = 0.86-1.16;dominant:OR = 0.96,95%CI = 0.87-1.06;and allele comparison:OR = 0.98,95%CI = 0.91-1.05).Furthermore,subgroup analyses did not reveal any association between these polymorphisms and ethnicity,the source of the controls,or the NHL *** results indicated that neither the Asp312 Asn nor Lys751 Gln XPD polymorphism was related to NHL *** and well-designed prospective studies are required to confirm this finding.

关键词：多态性淋巴瘤 D基因风险关联 DNA修复基因金证据

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VAV2 is required for DNA repair and implicated in cancer radiotherapy resistance

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Signal Transduction and Targeted Therapy 2021年第9期6卷 2906-2919页

作者： Weiling Liu Chuanwang Miao Shaosen Zhang Yachen Liu Xiangjie Niu Yiyi Xi Wenjia Guo Jiahui Chu Ai Lin Hongjin Liu Xinyu Yang Xinjie Chen Ce Zhong Yuling Ma Yuqian Wang Shihao Zhu Shuning Liu Wen Tan Dongxin Lin Chen Wu department of etiology and carcinogenesis National Cancer Center/National Clinical Research Center/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina Cancer Institute Affiliated Cancer Hospital of Xinjiang Medical UniversityUrumqiChina key laboratory of oncology of Xinjiang Uygur Autonomous Region UrumqiChina department of pharmacy Qilu HospitalCheeloo College of MedicineShandong UniversityJinanChina Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaGuangzhouChina Jiangsu key laboratory of Cancer Biomarkers Prevention and TreatmentCollaborative Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingChina CAMS key laboratory of Genetics and Genomic Biology Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina

Radiotherapy remains the mainstay for treatment of various types of human cancer;however,the clinical efficacy is often limited by radioresistance,in which the underlying mechanism is largely ***,using esophageal squamous cell carcinoma(ESCC)as a model,we demonstrate that guanine nucleotide exchange factor 2(VAV2),which is overexpressed in most human cancers,plays an important role in primary and secondary *** have discovered for the first time that VAV2 is required for the Ku70/Ku80 complex formation and participates in non-homologous end joining repair of DNA damages caused by ionizing radiation.

关键词： cancer clinical resistance

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