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Acta Pharmaceutica Sinica B 2019年第3期9卷 484-495页

作者： Linlin chang Yan Hu Yingying Fu Tianyi Zhou Jun You Jiamin Du Lin Zheng Ji cao Meidan Ying Xiaoyang Dai Dan Su Qiaojun He Hong Zhu Bo Yang Zhejiang Province Key Laboratory of Anti-cancer Drug Research College of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China Zhejiang cancer Hospital Hangzhou310022China

metastasis-associated drug resistance accounts for high mortality in ovarian cancer and remains to be a major barrier for effective treatment. In this study, SKOV3/T4, a metastatic subpopulation of ovarian cancer SKOV3 cells, was enriched to explore potential interventions against metastaticassociated drug resistance. Quantitative genomic and functional analyses were performed and found that slug was significantly increased in the SKOV3/T4 subpopulation and contributed to the high resistance of SKOV3/T4. Further studies showed that slug activated c-met in a ligand-independent manner due to elevated levels of fibronectin and provoked integrin α V function, which was confirmed by the significant correlation of slug and p-met levels in 121 ovarian cancer patient samples. Intriguingly,c-met inhibitor(s) exhibited greatly enhanced anti-cancer effects in slug-positive ovarian cancer models both in vitro and in vivo. Additionally, IHc analyses revealed that slug levels were highly correlated with reduced survival of ovarian cancer patients. Taken together, this study not only uncovers the critical roles of slug in drug resistance in ovarian cancer but also highlights a promising therapeutic strategy by targeting the noncanonical activation of c-met in slug-positive ovarian cancer patients with poor prognosis.

关键词： Slug c-met Drug resistance Ovarian cancer XL184

c-met immunohistochemical expression in sporadic and inflammatory bowel disease associated lesions

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World Journal of Gastroenterology 2022年第13期28卷 1338-1346页

作者： Grant Halliday Ross J Porter catherine J Black Mark J Arends Shahida Din Department of Pathology Western General HospitalNHS LothianScotland EH42XUUnited Kingdom centre for Inflammation Research Queen’s Medical Research InstituteUniversity of EdinburghEdinburgh EH164TJUnited Kingdom Edinburgh Inflammatory Bowel Disease Unit Western General HospitalNHS LothianEdinburgh EH42XUUnited Kingdom cancer Research UK Edinburgh centre Institute of Cancer&GeneticsWestern General HospitalUniversity of EdinburghEdinburgh EH42XUUnited Kingdom

BAcKGROUND Post-colonoscopy colorectal cancer(cRc)rates for patients with inflammatory bowel disease(IBD)are unacceptably *** colonoscopy,an intravenous fluorescent anti-c-met probe may improve endoscopic detection of ***,c-met expression in IBD lesions is poorly defined,limiting translational *** To comprehensively define c-met expression in sporadic and IBD-associated colorectal *** c-met expression was immunohistochemically assessed in 319 formalin-fixed paraffin-embedded tissue specimens,colonoscopically or surgically retrieved between *** included:30 normal colorectal biopsies,30 hyperplastic polyps(HP),31 sessile serrated lesions(SSL),55 tubular/tubulovillous adenomas with low(TA-LGD,n=32)or high grade dysplasia(TA-HGD,n=23),26 sporadic(s)-cRcs,16 quiescent IBD biopsies,11 active/inflamed IBD biopsies,18 IBDassociated dysplastic lesions(IBD-dys),and 102 *** was scored by two independent observers as:0=absent,1=weak,2=moderate or 3=***-Whitney U and Kruskal-Wallis tests were used to assess *** Positive epithelial cytoplasmic and membranous c-met expression was observed in all tissues,indicating there is ubiquitous expression in the colorectum.c-met expression was weak in normal colonic epithelium compared with each of the sporadic colonic lesions,including TA-LGD(PcRc(Pcifically,in sporadic(non-IBD)lesions,expression was stronger in TA-LGD compared with normal mucosa(PcRc compared with TA-HGD(P=0.004).However,there was no significant difference between TA-LGD and TA-HGD(P=0.852).Further,there was no difference in c-met expression between HP and SSL(P=0.065).In IBD,expression was weaker in quiescent colonic mucosa compared with inflamed colonic mucosa(Pce between inflamed colonic mucosa and IBD-dys(P=0.512)or IBD-cRc(P=0.296).However,expression

关键词： Inflammatory bowel diseases colorectal cancer Surveillance Detection c-met Immunohistochemistry

c-met signaling in the development of tumorigenesis and chemoresistance: Potential applications in pancreatic cancer

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World Journal of Gastroenterology 2014年第26期20卷 8458-8470页

作者： Daniel Delitto Eva Vertes-George Steven J Hughes Kevin E Behrns Jose G Trevino Department of Surgery University of Florida-Gainesville Department of Pathology University of Florida-Gainesville

Pancreatic ductal adenocarcinoma is the 4th leading cause of cancer deaths in the United States. The majority of patients are candidates only for palliative chemotherapy, which has proven largely ineffective in halting tumor progression. One proposed mechanism of chemoresistance involves signaling via the mesenchymal-epithelial transition factor protein (met), a previously established pathway critical to cell proliferation and migration. Here, we review the literature to characterize the role of met in the development of tumorigenesis, metastasis and chemoresistance, highlighting the potential of met as a therapeutic target in pancreatic cancer. In this review, we characterize the role of c-met in the development of tumorigenesis, metastasis and chemoresistance, highlighting the potential of c-met as a therapeutic target in pancreatic cancer.

关键词： Pancreatic adenocarcinoma c-met chemoresistance Receptor tyrosine kinase

MicroRNA-449a suppresses hepatocellular carcinoma cell growth via G1 phase arrest and the HGF/met c-met pathway

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Hepatobiliary & Pancreatic Diseases International 2018年第4期17卷 336-344页

作者： Jun cheng Li-Ming Wu Xue-Song Deng Jian Wu Zhen Lv Hang-Fen Zhao Zhang Yang Yong Ni Department of Hepatobiliary and Pancreatic Surgery the First Affiliated Hospital of Shenzhen UniversityShenzhen Second People's Hospital Department of Hepatobiliary and Pancreatic Surgery the First Affiliated HospitalZhejiang University School of Medicine Key Laboratory of combined Multi-organ Transplantation Ministry of Public Health Institutes of Biomedical Sciences Fudan University School of Life Science Fudan University

Background: Accumulating evidence demonstrates that microRNAs(miRNAs) play essential roles in tumorigenesis and cancer progression of hepatocellular carcinoma(Hcc). Average targets of a miRNA were more than 100. And one miRNA may act in tumor via regulating several targets. The present study aimed to explore more potential targets of miR-449a by proteomics technology and further uncover the role of miR-449a in Hcc ***: Technologies such as i TRAQ-based quantitative proteomic were used to investigate the effect of miR-449a on Hcc. The expression of c-met and miR-449a was detected by q RT-PcR in Hcc ***-and loss-of-function experiments were performed to identify the function and potential target of miR-449a in Hcc ***: In Hcc, miR-449a was significantly downregulated, while c-met was upregulated *** proteomics and luciferase reporter assay identified c-met as a direct target of ***, miR-449a inhibited Hcc growth not only by targeting cDK6 but also by suppressing cmet/Ras/Raf/ERK signaling pathway. Furthermore, the inhibition of c-met expression with a specific siRNA significantly inhibited cells growth and deregulated the ERK pathway in ***: The tumor suppressor miR-449a suppresses Hcc tumorigenesis by repressing the c-met/ERK pathway.

关键词： Hepatocellular carcinoma miR-449a c-met Proteomics Tumorigenesis

Discovery of novel exceptionally potent and orally active c-met PROTAcs for the treatment of tumors with met alterations

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Acta Pharmaceutica Sinica B 2023年第6期13卷 2715-2735页

作者： Pengyun Li changkai Jia Zhiya Fan Xiaotong Hu Wenjuan Zhang Ke Liu Shiyang Sun Haoxin Guo Ning Yang Maoxiang Zhu Xiaomei Zhuang Junhai Xiao Zhibing Zheng Song Li National Engineering Research center for Strategic Drugs Beijing Institute of Pharmacology and Toxicology InstitutionBeijing 100850China State Key Laboratory of Toxicology and Medical countermeasures Beijing Institute of Pharmacology and ToxicologyBeijing 100850China National center for Protein Sciences(Beijing) Beijing Institute of LifeomicsState Key Laboratory of ProteomicsBeijing Proteome Research CenterBeijing 102206China Beijing Key Laboratory for Radiobiology Beijing Institute of Radiation MedicineBeijing 100850China

Various c-mesenchymal-to-epithelial transition(c-met) inhibitors are effective in the treatment of non-small cell lung cancer;however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-met are urgently required. Herein, through rational structure optimization, we obtained novel exceptionally potent and orally active c-met proteolysis targeting chimeras(PROTAcs) namely D10 and D15 based on thalidomide and tepotinib. D10 and D15 inhibited cell growth with low nanomolar Ic_(50) values and achieved picomolar Dc_(50) values and>99% of maximum degradation(D_(max)) in EBc-1 and Hs746T cells. Mechanistically, D10 and D15dramatically induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and ***, intraperitoneal administration of D10 and D15 significantly inhibited tumor growth in the EBc-1 xenograft model and oral administration of D15 induced approximately complete tumor suppression in the Hs746T xenograft model with well-tolerated dose-schedules. Furthermore, D10 and D15 exerted significant anti-tumor effect in cells with c-met^(Y1230H) and c-met^(D1228N) mutations, which are resistant to tepotinib in clinic. These findings demonstrated that D10 and D15 could serve as candidates for the treatment of tumors with met alterations.

关键词： cancer therapy Drug design c-met Proteolysis targeting chimeras(PROTAcs) Drug resistance

The HDAc inhibitor GcJ-490A suppresses c-met expression through IKKα and overcomes gefitinib resistance in non-small cell lung cancer

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cancer Biology & Medicine 2022年第8期19卷 1172-1192页

作者： Ting He Yinglei Gao Yanfen Fang Yangming Zhang Shuwei Zhang Fajun Nan Jian Ding Yi chen Division of Anti-Tumor Pharmacology Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of chinese Academy of Sciences Beijing 100049China State Key Laboratory of Drug Research the National Center for Drug ScreeningShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China

Objective:The novel compound GcJ-490A has been discovered as a pan-histone deacetylase(HDAc)inhibitor that exerts potent inhibitory activity against HDAc1,HDAc3,and *** of the important roles of HDAcs in lung cancer development and the high distribution of GcJ-490A in lung tissue,we explored the anti-tumor potency of GcJ-490A against non-small cell lung cancer(NScLc)in vitro and in vivo in this ***:The in vitro effects of GcJ-490A alone or combined with the EGFR inhibitor gefitinib against NScLc were measured with proliferation,apoptosis,and colony formation *** xenograft models were used to investigate the efficacy of GcJ-490A combined with gefitinib for the treatment of NScLc in *** blot assays,luciferase reporter assays,chromatin immunoprecipitation assays,quantitative real time-PcR,immunohistochemistry,and transcription factor activity assays were used to elucidate possible ***:GcJ-490A effectively inhibited NScLc cell proliferation and induced apoptosis in vitro and in ***,inhibition of HDAc1 and HDAc6 by GcJ-490A increased histone acetylation at the IKKαpromoter and enhanced IKKαtranscription,thus decreasing ***,this c-met downregulation was found to be essential for the synergistic anti-tumor activity of GcJ-490A and ***:These findings highlight the promising potential of HDAc inhibitors in NScLc treatment and provide a rational basis for the application of HDAc inhibitors in combination with EGFR inhibitors in clinical trials.

关键词： HDAc inhibitor c-met IKKα NScLc gefitinib

c-met-targeted chimeric antigen receptor T cells inhibit hepatocellular carcinoma cells in vitro and in vivo

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The Journal of Biomedical Research 2022年第1期36卷 20-31页

作者： Xiaochen Huang Jiaojiao Guo Tao Li Lizhou Jia Xiaojun Tang Jin Zhu Qi Tang Zhenqing Feng National Health commission Key Laboratory of Antibody Techniques Nanjing Medical UniversityNanjingJiangsu 211166China Department of Pathology Nanjing Medical UniversityNanjingJiangsu 211166China Departments of Pathology Jiangsu Cancer Hospital Affiliated to Nanjing Medical UniversityJiangsu Province Institute of CancerNanjingJiangsu 210009China Huadong Medical Institute of Biotechniques NanjingJiangsu 210002China Jiangsu Key Lab of cancer Biomarkers Prevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingJiangsu 211166China.

c-met is a hepatocyte growth factor receptor overexpressed in many tumors such as hepatocellular carcinoma(Hcc).Therefore,c-met may serve as a promising target for Hcc *** T cells to express c-met-specific chimeric antigen receptor(cAR)is an attractive strategy in treating c-met-positive *** study aimed to systematically evaluate the inhibitory effects of 2^(nd)-and 3^(rd)-generation c-met cAR-T cells on hepatocellular carcinoma(Hcc)***,2^(nd)-and 3^(rd)-generation c-met cARs containing an anti-c-met singlechain variable fragment(scFv)as well as the cD28 signaling domain and cD3ζ(c-met-28-3ζ),the cD137 signaling domain and cD3ζ(c-met-137-3ζ),or the cD28 and cD137 signaling domains and cD3ζ(c-met-28-137-3ζ)were constructed,and their abilities to target c-met-positive Hcc cells were evaluated in vitro and in *** c-met cARs were stably expressed on T cell membrane,and c-met cAR-T cells aggregated around c-met-positive Hcc cells and specifically killed them in vitro.c-met-28-137-3ζcAR-T cells secreted more interferon-gamma(IFN-γ)and interleukin 2(IL-2)than c-met-28-3ζcAR-T cells and c-met-137-3ζcAR-T *** with c-met low-expressed cells,c-met cAR-T cells secreted more cytokines when co-cultured with c-met high-expressed ***,c-met-28-137-3ζcAR-T cells eradicated Hcc more effectively in xenograft tumor models compared with the control *** study suggests that 3^(rd)-generation c-met cAR-T cells are more effective in inhibiting c-met-positive Hcc cells than 2^(nd)-generation c-met cAR-T cells,thereby providing a promising therapeutic intervention for c-met-positive Hcc.

关键词： chimeric antigen receptor c-met hepatocellular carcinoma immunotherapy

Prognostic value of c-met in colorectal cancer:A metaanalysis

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World Journal of Gastroenterology 2015年第12期21卷 3706-3710页

作者： Yan Liu Xiao-Feng Yu Jian Zou Zi-Hua Luo Department of Gastroenterology Huadong Hospital Fudan University

AIM: To assess the prognostic value of c-met status in colorectal cancer. metHODS: We conducted a search in Pub Med, Web of Science, and the cochrane Library covering all published papers up to July 2014. Only studies assessing survival in colorectal cancer by c-met status were included. This meta-analysis was performed by using ***: Ultimately, 11 studies were included in this analysis. meta-analysis of the hazard ratios(HR)indicated that patients with high c-met expression have a significantly poorer overall survival(OR)(HR = 1.33, 95%cI: 1.06-1.59) and progression-free survival(PFS)(HR = 1.47, 95%cI: 1.03-1.91). Subgroup analysis showed a significant association between high c-met expression and poorer overall survival in the hazard ratio reported(HR = 1.41, 95%cI: 1.08-1.74).cONcLUSION: The present meta-analysis indicated that high c-met expression was associated with poor prognosis in patients with colorectal cancer.

关键词： colorectal cancer Prognosis c-met metaanalysis Ove

Expression of Ezrin,HGF,c-met in pancreatic cancer and non-cancerous pancreatic tissues of rats

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Hepatobiliary & Pancreatic Diseases International 2010年第6期9卷 639-644页

作者： Tan, Xing-Guo Yang, Zhu-Lin cent S Univ Xiangya Hosp 2 Res Lab Hepatobiliary Dis Changsha 410011 Hunan Peoples R China

BAcKGROUND: Recent studies have confirmed that the expression of Ezrin, hepatocyte growth factor (HGF) and its receptor (c-met) is related to the genesis, progress, invasion and metastasis of some malignant tumors. Researches have also found that the biological function of Ezrin is closely related to HGF/c-met in malignant tumors. However, there is no report on the expression levels of Ezrin, HGF and c-met in rat pancreatic cancer induced by dimethylbenzanthracene (DMBA). This study aimed to detect the expression of Ezrin, HGF and c-met in rat pancreatic cancer and non-cancerous pancreatic tissues, and assess its effect in cancer induction by DMBA. metHODS: Ninety Sprague-Dawley rats were divided into 3 groups randomly: 40 in a pancreatic cancer model group (group A), 40 in a trichostatin A (TSA) intervention group (group B), and 10 in a control group (group c). DMBA was directly implanted into the parenchyma of rat pancreas in group A+group B. The rats of group B were treated with 1 ml of TSA saline solution (1 mu g/ml) via intraperitoneal injection weekly. The carcinogenesis of rats executed within 3-5 months in groups A and B was observed by macrograph and microscopy. Meanwhile, the rats in group c were executed within 5 months. The EnVision (TM) immunohistochemistry for detecting the expression levels of Ezrin, HGF and c-met was used in paraffin-embedded sections of the pancreatic specimens. RESULTS: The incidence of pancreatic cancer in group A was 48.6% and in group B 33.3%. The maximal diameter of tumor mass was significantly larger in group A than that in group B (Pcal changes were observed in the pancreas of group c and other main organs of groups A and B. The positive rates of Ezrin, HGF and c-met were significantly higher in ductal adenocarcinoma than in non-cancerous pancreatic tissues of groups A and B (Pc-met were significantly higher in ductal adenocarcinoma of group A than those in non-

关键词： pancreatic neoplasms animal model Ezrin hepatocyte growth factor c-met

Updates on the hepatocyte growth factor/c-met axis in hepatocellular carcinoma and its therapeutic implications

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World Journal of Gastroenterology 2018年第33期24卷 3695-3708页

作者： Javier A García-Vilas Miguelángel Medina Department of Pediatrics University of AlbertaEdmonton T6G 2S2Canada Departamento de Biología Molecular y Bioquímica Facultad de CienciasAndalucía TechUniversidad de MálagaMálaga 29071Spain Unidad 741 de cIBER“de Enfermedades Raras”(cIBERER) Málaga 29071Spain Institute of Biomedical Research in Málaga Málaga 29071Spain

Hepatocellular carcinoma(Hcc) is the fifth most common cancer and is the second leading cause of cancer death. Since the diagnosis of Hcc is difficult, in many cases patients with Hcc are diagnosed advanced stage of development. Hepatocyte growth factor(HGF)/c-mesenchymal-epithelial transition receptor(c-met) axis is a key signaling pathway in Hcc, either via canonical or non-canonical pathways. Available treatments against Hcc based upon HGF/c-met inhibition can increase patient lifespan, but do not reach the expected therapeutic benefits. In Hcc, c-met monomers can bind other receptor monomers, activating several noncanonical signaling pathways, leading to increased cell proliferation, invasion, motility, and drug resistance. All of these processes are enhanced by the tumor microenvironment, with stromal cells contributing to boost tumor progression through oxidative stress, angiogenesis, lymphangiogenesis, inflammation, and fibrosis. Novel treatments against Hcc are being explored to modulate other targets such as microR NAs, methyltransferases, and acetyltransferases, which are all involved in the regulation of gene expression in cancer. This review compiles basic knowledge regarding signaling pathways in Hcc, and compounds already used or showing potential to be used in clinical trials.

关键词： Hepatocellular carcinoma Hepatocyte growth factor/c-met Tumor microenvironment c-met