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Tumor initiation and early tumorigenesis:molecular mechanisms and interventional targets

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Signal Transduction and Targeted Therapy 2024年第7期9卷 2900-2935页

作者： Shaosen Zhang Xinyi Xiao Yonglin Yi Xinyu Wang lingxuan Zhu Yanrong Shen 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 College100021 BeijingChina Key Laboratory of Cancer Genomic Biology Chinese Academy of Medical Sciences and Peking Union Medical College100021 BeijingChina Changping Laboratory 100021 BeijingChina Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Medical UniversityNanjing 211166China Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaGuangzhou 510060China CAMS Oxford Institute Chinese Academy of Medical Sciences100006 BeijingChina

Tumorigenesis is a multistep process,with oncogenic mutations in a normal cell conferring clonal advantage as the initial ***,despite pervasive somatic mutations and clonal expansion in normal tissues,their transformation into cancer remains a rare event,indicating the presence of additional driver events for progression to an irreversible,highly heterogeneous,and invasive ***,researchers are emphasizing the mechanisms of environmental tumor risk factors and epigenetic alterations that are profoundly influencing early clonal expansion and malignant evolution,independently of inducing ***,clonal evolution in tumorigenesis reflects a multifaceted interplay between cell-intrinsic identities and various cell-extrinsic factors that exert selective pressures to either restrain uncontrolled proliferation or allow specific clones to progress into ***,the mechanisms by which driver events induce both intrinsic cellular competency and remodel environmental stress to facilitate malignant transformation are not fully *** this review,we summarize the genetic,epigenetic,and external driver events,and their effects on the co-evolution of the transformed cells and their ecosystem during tumor initiation and early malignant evolution.A deeper understanding of the earliest molecular events holds promise for translational applications,predicting individuals at high-risk of tumor and developing strategies to intercept malignant transformation.

关键词： alterations mechanisms restrain

Aberrant epithelial cell interaction promotes esophageal squamous-cell carcinoma development and progression

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Signal Transduction and Targeted Therapy 2024年第1期9卷 279-294页

作者： Liping Chen Shihao Zhu Tianyuan Liu Xuan Zhao Tao Xiang Xiao Hu Chen Wu dongxin lin Department of Etiology and Carcinogenesis National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Key Laboratory of Cancer Genomic Biology Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Medical UniversityNanjing 211166China CAMS Oxford Institute Chinese Academy of Medical SciencesBeijing 100006China Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaGuangzhou 510060China

Epithelial-mesenchymal transition(EMT)and proliferation play important roles in epithelial cancer formation and progression,but what molecules and how they trigger EMT is largely *** we performed spatial transcriptomic and functional analyses on samples of multistage esophageal squamous-cell carcinoma(ESCC)from mice and humans to decipher these critical *** investigating spatiotemporal gene expression patterns and cell–cell interactions,we demonstrated that the aberrant epithelial cell interaction via EFNB1-EPHB4 triggers EMT and cell cycle mediated by downstream SRC/ERK/AKT *** aberrant epithelial cell interaction occurs within the basal layer at early precancerous lesions,which expands to the whole epithelial layer and strengthens along the cancer development and *** analysis revealed that the aberrant EFNB1-EPHB4 interaction is caused by overexpressedΔNP63 due to TP53 mutation,the culprit in human ESCC *** results shed new light on the role of TP53-TP63/ΔNP63-EFNB1-EPHB4 axis in EMT and cell proliferation in epithelial cancer formation.

关键词： esophageal TP53 squamous

Detection of piRNA-54265 in human serum:evidence and significance

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Cancer Communications 2023年第2期43卷 276-279页

作者： Dongmei Mai Ying Ye Lisha Zhuang Jian Zheng dongxin lin Department of Experimental Research Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdong 510060P.R.China Department of Etiology and Carcinogenesis National Cancer Center/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China

Dear Editor,An increasing number of studies have shown that PIWIinteracting RNAs(piRNAs)are aberrantly expressed in many types of human cancer and involved in regulating the malignant progression,piRNAs would be expected to serve as molecular biomarkers for cancer screening and early *** a previous study,we have identified the presence of piRNA-54265 in human serum[1].Further research has demonstrated that it is a promising and specific blood molecularmarker for colorectal cancer(CRC)[2].In these studies,we have developed a stem-loop primer reverse transcription-quantitative PCR(RT-qPCR)approach to determine the piRNA-54265 levels,which included the reverse transcription of piRNA-54265 to cDNA using a stem-loop primer and the quantitative detection of cDNA by PCR with the primers and probe specific for piR-54265[2].

关键词： cancer serum colorectal

Polymorphism in the Hsa-miR-4274 seed region influences the expression of PEX5 and enhances radiotherapy resistance in colorectal cancer

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Frontiers of Medicine 2024年第5期18卷 921-937页

作者： Qixuan Lu Ningxin Ren Hongxia Chen Shaosen Zhang Ruoqing Yan Mengjie Li linlin Zheng Wen Tan dongxin lin State Key Laboratory of Molecular Oncology Department of Etiology and CarcinogenesisBeijing Key Laboratory for Carcinogenesis and Cancer PreventionNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaGuangzhou 510060China

Identifying biomarkers for predicting radiotherapy efficacy is crucial for optimizing personalized *** previously reported that rs1553867776 in the miR-4274 seed region can predict survival in patients with rectal cancer receiving postoperative chemoradiation ***,to investigate the molecular mechanism of the genetic variation and its impact on the radiosensitivity of colorectal cancer(CRC),in this study,bioinformatics analysis is combined with functional experiments to confirm peroxisomal biogenesis factor 5(PEX5)as a direct target of *** miR-4274 rs1553867776 variant influences the binding of miR-4274 and PEX5 mRNA,which subsequently regulates PEX5 protein *** interaction between PEX5 and Ku70 was verified by co-immunoprecipitation and immunofluorescence.A xenograft tumor model was established to validate the effects of miR-4274 and PEX5 on CRC progression and radiosensitivity in *** overexpression of PEX5 enhances radiosensitivity by preventing Ku70 from entering the nucleus and reducing the repair of ionizing radiation(IR)-induced DNA damage by the Ku70/Ku80 complex in the *** addition,the enhanced expression of PEX5 is associated with increased IR-induced ***,targeting this mechanism might effectively increase the radiosensitivity of *** findings offer novel insights into the mechanism of cancer radioresistance and have important implications for clinical radiotherapy.

关键词： colorectal cancer polymorphism miR-4274 PEX5 radiotherapy resistance

Metformin inhibits pancreatic cancer metastasis caused by SMAD4 deficiency and consequent HNF4G upregulation

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Protein & Cell 2021年第2期12卷 128-144页

作者： Chengcheng Wang Taiping Zhang Quan Liao Menghua Dai Junchao Guo Xinyu Yang Wen Tan dongxin lin Chen Wu Yupei Zhao Department of General Surgery Peking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Department of Etiology and Carcinogenesis National Cancer Center/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Medical UniversityNanjing 211166China Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaGuangzhou 510060China CAMS Oxford Institute(COI) Chinese Academy of Medical SciencesBeijing 100730China

Pancreatic ductal adenocarcinoma(PDAC)has poor prognosis due to limited therapeutic *** study examines the roles of genome-wide association study identified PDAC-associated genes as therapeutic *** have identified HNF4G gene whose silencing most effectively repressed PDAC cell ***4G overexpression is induced by the deficiency of transcriptional factor and tumor suppressor *** HNF4G are correlated with SMAD4 deficiency in PDAC tumor samples and associated with metastasis and poor survival time in xenograft animal model and in patients with PDAC(log-rank P=0.036;HR=1.60,95%CI=1.03–2.47).We have found that Metformin suppresses HNF4G activity via AMPK-mediated phosphorylation-coupled ubiquitination degradation and inhibits in vitro invasion and in vivo metastasis of PDAC cells with SMAD4 ***,Metformin treatment significantly improve clinical outcomes and survival in patients with SMAD4-deficient PDAC(log-rank P=0.022;HR=0.31,95%CI=0.14–0.68)but not in patients with SMAD4-normal *** analysis shows that HNF4G may act in PDAC through the cell-cell junction *** results indicate that SMAD4 deficiency-induced overexpression of HNF4G plays a critical oncogenic role in PDAC progression and metastasis but may form a druggable target for Metformin treatment.

关键词： pancreatic cancer HNF4G SMAD4 deficiency SMAD4-deficient PDAC Metformin

Integrative analysis of gene expression profiles reveals specific signaling pathways associated with pancreatic duct adenocarcinoma

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Cancer Communications 2018年第1期38卷 158-169页

作者： Jun Li Wenle Tan linna Peng Jialiang Zhang Xudong Huang Qionghua Cui Jian Zheng Wen Tan Chen Wu dongxin lin Department of Etiology and Carcinogenesis National Cancer Center/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouGuangdong 510060P.R.China Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Medical UniversityNanjingJiangsu 210009P.R.China

Background:Pancreatic duct adenocarcinoma(PDAC)remains a major health problem because conventional can-cer treatments are relatively ineffective against *** studies have linked many genes to pancreatic cancer,but the available data have not been extensively mined for potential insights into *** study attempted to identify PDAC-associated genes and signaling pathways based on six microarray-based profiles of gene expression in pancre-atic cancer deposited in the gene expression omnibus ***:Pathway network methods were used to analyze core pathways in six publicly available pancreatic cancer gene(GSE71989,GSE15471,GSE16515,GSE32676,GSE41368 and GSE28735)expression *** potentially linked to PDAC were assessed for potential impact on survival time based on data in The Cancer Genome Atlas and International Cancer Genome Consortium databases,and the expression of one candidate gene(CKS2)and its association with survival was examined in 102 patients with PDAC from our *** of CKS2 knockdown were explored in the PDAC cell lines BxPC-3 and ***:The KEGG signaling pathway called“pathway in cancer”may play an important role in pancreatic cancer development and *** genes(BIRC5,CKS2,ITGA3,ITGA6 and RALA)in this pathway were significantly associated with survival time in patients with ***2 was overexpressed in PDAC samples from our hospital,and higher CKS2 expression in these patients was associated with shorter survival ***2 knockdown substantially inhibited PDAC cell proliferation in ***:Analysis integrating existing microarray datasets allowed identification of the“pathway in cancer”as an important signaling pathway in *** integrative approach may be powerful for identifying genes and pathways involved in cancer.

关键词： Pancreatic cancer GEO Pathway network CKS2

A cis-eQTL in NSUN2 promotes esophageal squamous-cell carcinoma progression and radiochemotherapy resistance by mRNA-m^(5)C methylation

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Signal Transduction and Targeted Therapy 2022年第9期7卷 3190-3193页

作者： Xiangjie Niu linna Peng Weiling Liu Chuanwang Miao Xinjie Chen Jiahui Chu Xinyu Yang Wen Tan Chen Wu dongxin lin Department of Etiology and Carcinogenesis National Cancer Center/National Clinical Research Center/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeiingChina CAMS Key Laboratory of Genetics and Genomic Biology Chinese Academy of Medical Sciences and Peking Union Medical CollegeBejingChina Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Medical UniversityNanjingChina

Dear Editor,Esophageal squamous cell carcinoma(ESCC)has poor prognosis because of the difficulty in early detection and low sensitivity of advanced disease to radiochemotherapy.1,2 ESCC presents a high proportion of primary resistance to radiochemotherapy,2which may be due to certain individual genetic *** quantitative trait loci(eQTLs)as proximal and continuous cellular phenotypes have been shown to be helpful to determine how genetic variants may influence phenotype.

关键词： chemotherapy squamous esophageal

CCGD-ESCC： A Comprehensive Database for Genetic Variants Associated with Esophageal Squamous Cell Carcinoma in Chinese Population

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Genomics, Proteomics & Bioinformatics 2018年第4期16卷 262-268页

作者： linna Peng Sijin Cheng Yuan lin Qionghua Cui Yingying Luo Jiahui Chu Mingming Shao Wenyi Fan Yamei Chen Ai lin Yiyi Xi Yanxia Sun Lei Zhang Chao Zhang Wen Tan Ge Gao Chen Wu dongxin lin Department of Etiology and Carcinogenesis National Cancer Center/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China State Key Laboratory of Protein and Plant Gene Research School of Life Sciences Center for Bioinformatics Peking UniversityBeijing 100871China Beijing Advanced Innovation Center for Genomics (ICG) Peking UniversityBeijing 100871China National Engineering Research Center for Beijing Biochip Technology Beijing 102206China School of Life Sciences Peking UniversityBeijing 100871China

Esophageal squamous-cell carcinoma （ESCC） is one of the most lethal malignancies in the world and occurs at particularly higher frequency in China. While several genome-wide association studies （GWAS） of germline variants and whole-genome or whole-exome sequencing studies of somatic mutations in ESCC have been published, there is no comprehensive database publically available for this cancer. Here, we developed the Chinese Cancer Genomic Database-Esophageal Squamous Cell Carcinoma （CCGD-ESCC） database, which contains the associations of 69,593 single nucleotide polymorphisms （SNPs） with ESCC risk in 2022 cases and 2039 controls, survival time of 1006 ESCC patients （survival GWAS） and gene expression （expression quantitative trait loci,eQTL） in 94 ESCC patients. Moreover, this database also provides the associations between8833 somatic mutations and survival time in 675 ESCC patients. Our user-friendly database is a resource useful for biologists and oncologists not only in identifying the associations of genetic variants or somatic mutations with the development and progression of ESCC but also in studying the underlying mechanisms for tumorigenesis of the cancer. CCGD-ESCC is freely accessible at http：//***/ccgd/ESCCdb.

关键词： Esophageal cancer Germline variants Somatic mutations Association databaseChinese population

Expression of cytochrome P4502E1 in human liver: relationship between genotype and phenotype in Chinese

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Science China(Life Sciences) 2001年第4期44卷 356-364页

作者：谭文吴健雄唐槐静林东昕 Department of Etiology and Carcinogenesis Cancer Institute and Hospital Chinese Academy of Medical Sciences Beijing 100021 China

Polymorphic cytochrome P4502E1 (CYP2E1) plays an important role in the metabolic activation of many carcinogens. We have previously shown that the c1/c1 genotype recognized by Rsa I in the 5′-regulatory region of the CYP2E1 may be a susceptibility factor for developing esophageal cancer and lung cancer in Chinese. The present study was to investigate the relationship between the Rsa I genotype and the expression of CYP2E1 in human livers. A total of 50 liver specimens were genotyped for CYP2E1 and assayed for CYP2E1 protein contents and functional activity by using specific antibody in immunoblot and a probe substrate, p-nitrophenol. A considerable interindividual variation in CYP2E1 protein (20-fold) and functional activity (56-fold) was observed among these liver samples. However, when they were categorized according to genotype, the mean content of CYP2E1 protein was significantly higher among individuals with the c1/c1 genotype than that among those having c1/c2 or c2/c2 genotype [124.0±83.9 pmol/mg (n = 28) versus 65.5±38.9 pmol/mg (n = 22), P＜0.01 . The mean activity of CYP2E1 towards p-nitrophenol for the c1/c1 genotype was also higher than that for the variant genotypes (198.4±27.8 pmol/min/mg versus 101.2±18.1 pmol-1·min-1·mg-1, P＜0.01 . Also, the protein levels and functional activity showed a significant correlation (r = 0.68, P＜0.01 . These results demonstrate an association between the Rsa I genotype and the phenotype of CYP2E1 in our samples, and the data are compatible with the assumption that CYP2E1 c1/c1 genotype is a susceptibility factor for certain cancers in Chinese.

关键词： CYP2E1, Rsa I polymorphism, p-nitrophenol, liver microsomes.