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Blockade of NMT1 enzymatic activity inhibits N-myristoylation of VILIP3 protein and suppresses liver cancer progression

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Signal Transduction and Targeted Therapy 2023年第2期8卷 716-729页

作者： Xiang-Peng Tan Yan He Jing Yang Xian Wei You-Long Fan Guo-Geng Zhang Yi-Dong Zhu Zheng-Qiu Li Hua-xin Liao Da-Jiang Qin xin-yuan guan Bin Li The First Affiliated Hospital of Jinan University Jinan UniversityGuangzhouChina Key Laboratory of Biological Targeting Diagnosis Therapy and Rehabilitation of Guangdong Higher Education Institutes and Key Laboratory of Protein Modification and DegradationThe Fifth Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina MOE Key Laboratory of Tumor Molecular Biology and National Engineering Research Center of Genetic Medicine College of Life Science and TechnologyJinan UniversityGuangzhouChina School of Pharmacy Jinan UniversityGuangzhouChina Department of Clinical Oncology The University of Hong KongHong KongChina

Hepatocellular carcinoma(HCC)is one of the most common malignant tumors.Identification of the underlying mechanism of HCC progression and exploration of new therapeutic drugs are urgently needed.Here,a compound library consisting of 419 FDA-approved drugs was taken to screen potential anticancer drugs.A series of functional assays showed that desloratadine,an antiallergic drug,can repress proliferation in HCC cell lines,cell-derived xenograft(CDX),patient-derived organoid(PDO)and patient-derived xenograft(PDX)models.N-myristoyl transferase 1(NMT1)was identified as a target protein of desloratadine by drug affinity responsive target stability(DARTS)and surface plasmon resonance(SPR)assays.Upregulation of NMT1 expression enhanced but NMT1 knockdown suppressed tumor growth in vitro and in vivo.Metabolic labeling and mass spectrometry analyses revealed that Visinin-like protein 3(VILIP3)was a new substrate of NMT1 in protein N-myristoylation modification,and high NMT1 or VILIP3 expression was associated with advanced stages and poor survival in HCC.Mechanistically,desloratadine binds to Asn-246 in NMT1 and inhibits its enzymatic activity,disrupting the NMT1-mediated myristoylation of the VILIP3 protein and subsequent NFκB/Bcl-2 signaling.Conclusively,this study demonstrates that desloratadine may be a novel anticancer drug and that NMT1-mediated myristoylation contributes to HCC progression and is a potential biomarker and therapeutic target in HCC.

关键词： drugs VILI allergic

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High Expression of p300 in Human Breast Cancer Correlates with Tumor Recurrence and Predicts Adverse Prognosis

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Chinese Journal of Cancer Research 2011年第3期23卷 201-207页

作者： Xiang-sheng Xiao Mu-yan Cai Jie-wei Chen xin-yuan guan Hsiang-fu Kung Yi-xin Zeng Dan Xie State Key Laboratory of Oncology in South China Guangzhou 510060China Department of Breast Oncology Guangzhou 510060China Department of Pathology Sun Yat-sen University Cancer CenterGuangzhou 510060China The Chinese University of Hong Kong Hong KongChina

Objective：Transcriptional coactivator p300 has been shown to play a variety of roles in the transcription process and mutation of p300 has been found in certain types of human cancers.However,the expression dynamics of p300 in breast cancer （BC） and its effect on BC patients＇ prognosis are poorly understood.Methods：In the present study,the methods of tissue microarray and immunohistochemistry （IHC） were used to investigate the protein expression of p300 in BCs.Receiver operating characteristic （ROC） curve analysis,Spearman＇s rank correlation,Kaplan-Meier plots and Cox proportional hazards regression model were utilized to analyze the data.Results：Based on the ROC curve analysis,the cutoff value for p300 high expression was defined when the H score for p300 was more than 105.High expression of p300 could be observed in 105/193 （54.4%） of BCs,in 6/25 （24.0%） of non-malignant breast tissues,respectively （P=0.004）.Further correlation analysis showed that high expression of p300 was positively correlated with higher histological grade,advanced clinical stage and tumor recurrence （P0.05）.In univariate survival analysis,a significant association between high expression of p300 and shortened patients＇ survival and poor progression-free survival was found （P0.05）.Importantly,p300 expression was evaluated as an independent prognostic factor in multivariate analysis （P0.05）.Conclusion：Our findings provide a basis for the concept that high expression of p300 in BC may be important in the acquisition of a recurrence phenotype,suggesting that p300 high expression,as examined by IHC,is an independent biomarker for poor prognosis of patients with BC.

关键词： Breast cancer p300 Tumor recurrence Prognosis

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Tumor suppressor genes on frequently deleted chromosome 3p in nasopharyngeal carcinoma

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Chinese Journal of Cancer 2012年第5期31卷 215-222页

作者： Juan Chen Li Fu Li-Yi Zhang Dora L. Kwong Li Yan xin-yuan guan Department of Clinical Oncology The University of Hong Kong Hong Kong P. R. China Cancer Center Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430023 P. R. China State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou Guangdong 510060 P. R. China.

Nasopharyngeal carcinoma (NPC) is among the most common malignancies in southern China.Deletion of genomic DNA,which occurs during the complex pathogenesis process for NPC,represents a pivotal mechanism in the inactivation of tumor suppressor genes (TSGs).In many circumstances,loss of TSGs can be detected as diagnostic and prognostic markers in cancer.The short arm of chromosome 3 (3p) is a frequently deleted chromosomal region in NPC,with 3p21.1-21.2 and 3p25.2-26.1 being the most frequently deleted minimal regions.In recent years,our research group and others have focused on the identification and characterization of novel target TSGs at 3p,such as RASSF1A,BLU,RBMS3,and CHL1,in the development and progression of NPC.In this review,we summarize recent findings of TSGs at 3p and discuss some of these genes in detail.A better understanding of TSGs at 3p will significantly improve our understanding of NPC pathogenesis,diagnosis,and treatment.

关键词： 3号染色体抑癌基因鼻咽癌删除全国人民代表大会基因组DNA 肿瘤抑制基因发病机制

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Genome-wide identification of key regulatory lncRNAs in esophageal cancer metastasis

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Signal Transduction and Targeted Therapy 2021年第3期6卷 621-623页

作者： Wen Wen Xu Can-Can Zheng Qian Zuo Jun-Qi Li Pan Hong Yan-Ru Qin xin-yuan guan Qing-Yu He Hua-xin Liao Bin Li MOE Key Laboratory of Tumor Molecular Biology and guangdong Provincial Key Laboratory of Bioengineering Medicine National Engineering Research Center of Genetic MedicineInstitute of BiomedicineCollege of Life Science and TechnologyJinan UniversityGuangzhouChina MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of guangdong Higher Education Institutes Institute of Life and Health EngineeringCollege of Life Science and TechnologyJinan UniversityGuangzhouChina State Key Laboratory of Esophageal Cancer Prevention and Treatment Department of Clinical OncologyFirst Affiliated HospitalZhengzhou UniversityZhengzhouChina Department of Clinical Oncology Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulamHong Kong SARChina

Dear Editor,Metastasis leads to a poor prognosis of patients with esophageal squamous cell carcinoma(ESCC).1-3 but the study on cancer metastasis has been hampered by a lack of reliable cell and animal models.Systematic identification and functional validation of metastasis-associated long non-coding RNAs(lncRNAs)and microRNAs(miRNAs),as well as-their interactions in ESCC are urgently needed.

关键词： metastasis esophageal cancer

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Cancer stem cell-mediated therapeutic resistance in hepatocellular carcinoma

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Hepatoma Research 2022年第1期8卷 393-414页

作者： Mei-Mei Li Yi-Ti He Jie-Kai Liang xin-yuan guan Ning-Fang Ma Ming Liu guangzhou Municipal and guangdong Provincial Key Laboratory of Protein Modification and Degradation School of Basic Medical SciencesGuangzhou Medical UniversityGuangzhou 511436GuangdongChina The Third Clinical School of guangzhou Medical University Guangzhou Medical UniversityGuangzhou 511436GuangdongChina State Key Laboratory of Oncology in Southern China Collaborative Innovation Center for Cancer MedicineSun Yat-Sen University Cancer CenterGuangzhou 510060GuangdongChina Department of Clinical Oncology State Key Laboratory of Liver ResearchThe University of Hong KongHong KongChina

Hepatocellular carcinoma(HCC)is a highly heterogeneous malignancy.In the clinic,therapeutic resistance is largely attributed to tumor heterogeneity.Growing evidence indicates that cancer stem cells(CSCs)are the major source of tumor heterogeneity.Hence,uncovering the resistance mechanisms associated with CSC properties is essential for developing effective therapeutics.CSCs resemble embryonic stem cells.Embryonic developmentrelated genes and signaling pathways are usually abnormally active and function as oncofetal drivers in HCC.Multiple strategies have been applied to identify oncofetal drivers.The mechanisms of CSC resistance could also provide reliable biomarkers to predict treatment failure.Precisely targeting these specific CSC properties may be effective in preventing or annihilating therapy resistance.This review provides an overview of drug resistance mechanisms associated with CSC traits and summarize therapeutic strategies against drug resistance.

关键词： Hepatocellular carcinoma heterogeneity cancer stem cell drug resistance precision therapy

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Advances in surface markers of liver cancer stem cell

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Hepatoma Research 2019年第7期5卷 29-46页

作者： Jin-Liang Zhang Lan-Qi Gong Qian Yan Ning-Ning Zhou Victor Ho-Fun Lee xin-yuan guan Department of Clinical Oncology Center The University of Hongkong-Shenzhen HospitalShenzhen 518053China Department of Clinical Oncology The University of Hong KongHong KongChina State Key Laboratory for Liver Research The University of Hong KongHong KongChina Department of Medical Oncology Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhou 510060China

Liver cancer stem cells(LCSCs),a small subpopulation that constitutes liver cancer heterogeneity,play a vital role in cancer initiation,invasion,recurrence,metastasis,and resistance to chemo-radiotherapy.It is believed that therapies targeting LCSCs can improve the efficacy of conventional chemotherapy and radiotherapy by completely eliminating tumors while preventing recurrence.Therefore,during last decades,numerous surface markers for LCSCs have been identified and characterized in many subtypes of liver cancer,especially in hepatocellular carcinoma(HCC).These well-recognized surface markers significantly promote the therapeutic efficacy that identifies,targets and destroys LCSCs.Meanwhile,there have been intensive studies that aim to investigate the molecular mechanism of how stemness contributes to liver cancer relapse,recurrence and resistance.However,liver cancer stemness seems to be regulated by a hierarchical organization and crosstalk of a wide variety of signaling pathways.Using individual or few LCSC surface markers may not be able to completely reveal the intrinsic stemness hierarchy.From an integrated perspective,understanding of recent advances in LCSC surface markers remains important and urgent.In this review,we concentrate on demonstrating the indispensable roles of LCSC surface markers in identification and characterization of multiple cancer stages including initiation,invasion,metastasis,resistance and highlighting the cutting-edge therapeutic strategies against cancer stem cells in HCC.

关键词： Liver cancer hepatocellular carcinoma cancer stem cell surface marker

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Comparative genomic hybridization analysis of genetic aberrations associated with development of esophageal squamous cell carcinoma in Henan, China

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World Journal of Gastroenterology 2008年第12期14卷 1828-1835页

作者： Yan-Ru Qin Li-Dong Wang Zong-Min Fan Dora Kwong xin-yuan guan Department of Clinical Oncology The FirstAffiliated Hospital of Zhengzhou University Zhengzhou 450052Henan Province China Laboratory for Cancer Research Experimental Medical Center College of Medicine ZhengzhouUniversity Zhengzhou 450052 Henan Province China Department of Clinical Oncology Queen Mary Hosptital The University of Hong Kong Room 129Professorial Block Pokfulam Road Hong Kong China

AIM: To characterize cytogenetic alterations in esophageal squamous cell carcinoma (ESCC) and its metastasis. METHODS: A total of 37 cases of primary ESCC and 15 pairs of primary ESCC tumors and their matched metastatic lymph nodes cases were enrolled from Linzhou, the high incidence area for ESCC in Henan, northern China. The comparative genomic hybridization (CGH) was applied to determine the chromosomal aberrations on the DNA extracted from the frozen ESCC and metastatic lymph node samples from these patients. RESULTS: CGH showed chromosomal aberrations in all the cases. In 37 cases of primary ESCC, chromosomal profile of DNA copy number was characterized by frequently detected gains at 8q (29/37, 78%), 3q (24/37, 65%), 5p (19/37, 51%); and frequently detected losses at 3p (21/37, 57%), 8p and 9q (14/37, 38%). In 15 pairs of primary ESCC tumors and their matched metastatic lymph node cases, the majority of the chromosomal aberrations in both primary tumor and metastatic lymph node lesions were consistent with the primary ESCC cases, but new candidate regions of interest were also detected. The most significant finding is the gains of chromosome 6p with a minimum high-level amplification region at 6p12-6q12 in 7 metastatic lymph nodes butonly in 2 corresponding primary tumors (P = 0.05) and 20p with a minimum high-level amplification region at 20p12 in 11 metastatic lymph nodes but only in 5 corresponding primary tumors (P < 0.05). Another interesting finding is the loss of chromosome 10p and 10q in 8 and 7 metastatic lymph nodes but only in 2 corresponding primary tumors (P < 0.05). CONCLUSION: Using the CGH technique to detect chromosomal aberrations in both the primary tumor and its metastatic lymph nodes of ESCC, gains of 8q, 3q and 5p and loss of 3p, 8p, 9q and 13q were specifically implicated in ESCC in Linzhou population. Gains of 6p and 20p and loss of 10pq may contribute to the lymph node metastasis of ESCC. These findings suggest that the gains and losses of chromosomal regions may contain ESCC-relate

关键词：食管鳞状细胞癌淋巴节基因杂交

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The genetic and epigenetic alterations in human hepatocellular carcinoma： a recent update

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Protein & Cell 2014年第9期5卷 673-691页

作者： Ming Liu Lingxi Jiang xin-yuan guan Department of Clinical Oncology University of Hong Kong Hong Kong China

Hepatocellular carcinoma （HCC） is one of the most frequent human malignancies worldwide with very poor prognosis. It is generally accepted that the progression of HCC is a long-term process with accumulation of multiple genetic and epigenetic alterations, which further lead to the activation of critical oncogenes or inactivation of tumor suppressor genes. HCC is characterized with multiple cancer hallmarks including their ability to proliferate, anti-poptosis, invade, metastasis, as well as the emerging features such as stem cell properties and energy metabolic switch. The irreversible alterations at genetic level could be detected as early as in the pre-neoplastic stages and accumulate during cancer progression. Thus, they might account for the cancer initiating steps and further malignant transformation. In addition to genetic alterations, epigenetic alterations can affect the cancer transcriptome more extensively. Alterations in DNA methylation, histone modification, miRNAs, RNA editing, and IncRNAs might result in disrupted gene regulation networks and substantially contribute to HCC progression. In this review, the genetic and epigenetic alterations which significantly contribute to the malignant capabilities of HCC will be updated and summarized in detail. Further characterization of those critical molecular events might better elucidate the pathogenesis of HCC and provide novel therapeutic targets for treatment of this deadly disease.

关键词： hepatocellular carcinoma （HCC） cancerhallmarks genetic regulation epigenetic regulation,therapeutic targets HCC progression

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Characterization of CD133+ cancer stem cells in hepatocellular carcinoma

Characterization of CD133+ cancer stem cells in hepatocellul...

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中国病理生理学会第十三届肿瘤、第十四届免疫专业委员会学术会议

作者： xin-yuan guan

Cancer is hierarchically organized and composed of a heterogeneous population of cells,among which researchers have now provided solid evidence of the existence and importance of a cancer stem cell

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Utilization of human excrement in pre-modern China,its theoretical interpretations and ecological significance

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Soil Ecology Letters 2024年第1期6卷 1-5页

作者： xin-Hao Du yuan-Ming Song Ji-An Cai Yong-guan Zhu Institute for the History of Natural Sciences Chinese Academy of SciencesBeijing 100190China Institute for Cultural Heritage and History of Science&Technology University of Science and Technology BeijingBeijing 100083China Faculty of History Nankai UniversityTianjin 300350China Research Center for Eco Environmental Sciences Chinese Academy of SciencesBeijing 100085China

The use of human excrement as fertilizer is a characteristic of traditional Chinese agriculture..The application of excrement from urban residents in agriculture since the Song Dynasty has ensured the cleanliness and hygiene of ancientChinesecities.As early as the Ming Dynasty,the Chinese people defined the principle of fertilizing fields with human excrement from the perspective of materialcirculation.The concept Peri-URban ecosystems(PURE)provides inspiration forurban-rural symbiosis regarding circulareconomy.The use of human excrement in fertilization is a major attribute differentiating the Chinese traditional agriculture from the agriculture in other regions around the world.Despite the fact that the exact record showing that human excrement was used as fertilizer in China emerged in the Western Han Dynasty(B.C.202-A.D.8),such records did not become prevalent until the Southern Song Dynasty(A.D.1127-1279).In the Ming and Qing eras(A.D.1368-1912),human excrement was even considered"top-class fertilizerand servedas themost essential fertilizerin farmland fertilization.The importance of human excrement in the Ming and Qing was mainly reflected by farmers'purchase of human excrement from urban areas.As fertilization practices became increasingly popular during the period,men of letters built a localized theoretical system centering on human excrement.Although the use of human excrement had both positive and negative impacts on public health and the ecological environment,the positive overshadowed the negativeas a whole.Today,it is worth pondering on how the utilization of human excrement as an agricultural resource can be improved so that a material cycle system can be rebuilt to re-connect the urban and rural areas.

关键词： excrement fertilizer theorization urban and rural ecology public health

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