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Pathogenesis of RON receptor tyrosine kinase in cancer cells: activation mechanism, functional crosstalk, and signaling addiction

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The Journal of Biomedical Research 2013年第5期27卷 345-356页

作者： ming-hai wang Ruiwen Zhang Yong-Qing Zhou Hang-Ping Yao Cancer Biology Research Center School of Pharmacy Texas Tech University Health Sciences Center Department of Biomedical Sciences School of Pharmacy Texas Tech University Health Sciences Center Department of Pharmaceutical Sciences School of Pharmacy Texas Tech University Health Sciences Center Department of Neurosurgery & Treatment of Infectious Diseases First Affiliated Hospital Zhejiang University School of Medicine Viral Oncogenesis Section in State Key Laboratory for Diagnosis & Treatment of Infectious Diseases First Affiliated Hospital Zhejiang University School of Medicine

The RON receptor tyrosine kinase, a member of the MET proto-oncogene family, is a pathogenic factor im- plicated in tumor malignancy. Specifically, aberrations in RON signaling result in increased cancer cell growth, survival, invasion, angiogenesis, and drug resistance. Biochemical events such as ligand binding, receptor over- expression, generation of structure-defected variants, and point mutations in the kinase domain contribute to RON signaling activation. Recently, functional crosstalk between RON and signaling proteins such as MET and EFGR has emerged as an additional mechanism for RON activation, which is critical for tumorigenic develop- ment. The RON signaling crosstalk acts either as a regulatory feedback loop that strengthens or enhances tumor- igenic phenotype of cancer cells or serves as a signaling compensatory pathway providing a growth/survival ad- vantage for cancer cells to escape targeted therapy. Moreover, viral oncoproteins derived from Friend leukemia or Epstein-Barr viruses interact with RON to drive viral oncogenesis. In cancer cells, RON signaling is integrated into cellular signaling network essential for cancer cell growth and survival. These activities provide the mo- lecular basis of targeting RON for cancer treatment. In this review, we will discuss recent data that uncover the mechanisms of RON activation in cancer cells, review evidence of RON signaling crosstalk relevant to cancer malignancy, and emphasize the significance of the RON signaling addiction by cancer cells for tumor therapy. Understanding aberrant RON signaling will not only provide insight into the mechanisms of tumor pathogenesis, but also lead to the development of novel strategies for molecularly targeted cancer treatment.

关键词： Receptor tyrosine kinase （RON） signaling pathway activation mechanism signaling crosstalk on-cogene addiction tumorigenesis

Pathological significance of abnormal recepteur d'origine nantais and programmed death ligand 1 expression in colorectal cancer

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World Journal of Gastrointestinal Oncology 2020年第11期12卷 1216-1236页

作者： Yi-Zhi Liu Da-Ting Han Dan-Rong Shi Bo Hong Yun Qian Zhi-Gang Wu Shu-Hao Yao Tao-ming Tang ming-hai wang Xiang-ming Xu Hang-Ping Yao Department of Cancer Biology Research State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesNational Clinical Research Center for Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina Department of Pathology The Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina Department of Clinical Laboratory The Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina Department of Stomatology Wenzhou Medical University Renji CollegeWenzhou 325035Zhejiang ProvinceChina Cancer Biology Research Center and Department of Pharmaceutical Sciences School of PharmacyTexas Tech University Health Sciences CenterAmarilloTX 79106United States Department of Cancer Biology Research The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina

BACKGROUND Programmed death ligand 1(PD-L1) immunotherapy remains poorly efficacious in colorectal cancer(CRC). The recepteur d'origine nantais(RON) receptor tyrosine kinase plays an important role in regulating tumor immunity.AIM To identify the patterns of RON and PD-L1 expression and explore their clinical significance in CRC.METHODS Gene expression data from the Gene Expression Omnibus database(GEO;n = 290) and patients at the First Affiliated Hospital, Zhejiang University School of Medicine(FAHZUSM;n = 381) were analyzed to determine the prognostic value of RON and PD-L1 expression within the tumor microenvironment of CRC. HT29 cell line was treated with BMS-777607 to explore the relationship between RON activity and PD-L1 expression. Signaling pathways and protein expression perturbed by RON inhibition were evaluated by cellular immunofluorescence and Western blot.RESULTS In the GEO patient cohort, cut-off values for RON and PD-L1 expression were determined to be 7.70 and 4.3, respectively. Stratification of patients based on these cutoffs demonstrated that high expression of RON and PD-L1 was associated with a poor prognosis. In the FAHZUSM cohort, rates of high expression of RON in tumor cells, high PD-L1 expression in tumor cells and tumor infiltrating monocytes, and both high RON and high PD-L1 expression in the tumor microenvironment were 121(32%), 43(11%), 91(24%), and 51(13.4%), respectively. High expression of RON was significantly correlated with high expression of PD-L1 in the tumor cell compartment(P < 0.001). High expression of RON and that of PD-L1 were independent prognostic factors for poorer overall survival. Concurrent high expression of both RON and PD-L1 in the tumor microenvironment was significantly associated with a poor prognosis. In vitro, BMS-777607 inhibited the phosphorylation of RON, inhibited PD-L1 expression, and attenuated activation of the ERK1/2 and AKT signaling pathways in CRC cells.CONCLUSION RON, PD-L1, and their crosstalk are significant in predicting the prognostic val

关键词： Colorectal cancer Programmed death ligand 1 Prognosis Recepteur d'origine nantais Tumor infiltrating mononuclear cells Tumor microenvironment

Fangji Fuling Decoction Alleviates Sepsis by Blocking MAPK14/FOXO3A Signaling Pathway

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Chinese Journal of Integrative Medicine 2024年第3期30卷 230-242页

作者： wang Yi CHEN ming-qi DAI Lin-feng ZHANG hai-dong wang Xing Department of Critical Care Medicine Changzhou Hospital of Traditional of Chinese Medicine Affiliated to Nanjing University of Chinese MedicineChangzhouJiangsu Province213000China Department of Critical Care Medicine Jiangsu Province Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese MedicineNanjing210029China

Objective:To examine the therapeutic effect of Fangji Fuling Decoction(FFD) on sepsis through network pharmacological analysis combined with in vitro and in vivo experiments.Methods:A sepsis mouse model was constructed through intraperitoneal injection of 20 mg/kg lipopolysaccharide(LPS).RAW264.7 cells were stimulated by 250 ng/m L LPS to establish an in vitro cell model.Network pharmacology analysis identified the key molecular pathway associated with FFD in sepsis.Through ectopic expression and depletion experiments,the effect of FFD on multiple organ damage in septic mice,as well as on cell proliferation and apoptosis in relation to the mitogen-activated protein kinase 14/Forkhead Box O 3A(MAPK14/FOXO3A) signaling pathway,was analyzed.Results:FFD reduced organ damage and inflammation in LPS-induced septic mice and suppressed LPS-induced macrophage apoptosis and inflammation in vitro(P<0.05).Network pharmacology analysis showed that FFD could regulate the MAPK14/FOXO signaling pathway during sepsis.As confirmed by in vitro cell experiments,FFD inhibited the MAPK14 signaling pathway or FOXO3A expression to relieve LPS-induced macrophage apoptosis and inflammation(P<0.05).Furthermore,FFD inhibited the MAPK14/FOXO3A signaling pathway to inhibit LPS-induced macrophage apoptosis in the lung tissue of septic mice(P<0.05).Conclusion:FFD could ameliorate the LPS-induced inflammatory response in septic mice by inhibiting the MAPK14/FOXO3A signaling pathway.

关键词： sepsis Fangji Fuling Decoction mitogen-activated protein kinase 14/Forkhead Box O 3A signaling pathway inflammatory response apoptosis lung injury Chinese medicine

SETDB1-mediated CD147-K71 di-methylation promotes cell apoptosis in non-small cell lung cancer

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Genes & Diseases 2024年第2期11卷 978-992页

作者： ming-Yan Shi Yarong wang Ying Shi Ruofei Tian Xiaohong Chen hai Zhang Ke wang Zhinan Chen Ruo Chen National Translational Science Center for Molecular Medicine & Department of Cell Biology Fourth Military Medical UniversityXi'anShaanxi 710032China

Protein post-translational modifications(PTMs)are at the heart status of cellular signaling events and broadly involved in tumor progression.CD147 is a tumor biomarker with various PTMs,promoting tumor metastasis and metabolism reprogramming.Nevertheless,the relationship between the PTMs of CD147 and apoptosis has not been reported.In our study,we produced a specific anti-CD147-K71 di-methylation(CD147-K71me2)antibody by immunizing with a di-methylated peptide and observed that the level of CD147-K71me2 in non-small cell lung cancer(NSCLC)tissues were lower than that in NSCLC adjacent tissues.SETDB1 was identified as the methyltransferase catalyzing CD147 to generate CD147-K71me2.RNA-seq showed that FOSB was the most significant differentially expressed gene(DEG)between wild-type CD147(CD147-WT)and K71-mutant CD147(CD147-K71R)groups.Subsequently,we found that CD147-K71me2 promoted the expression of FOSB by enhancing the phosphorylation of p38,leading to tumor cell apoptosis.In vivo experiments showed that CD147-K71me2 significantly inhibited tumor progression by promoting cell apoptosis.Taken together,our findings indicate the inhibitory role of CD147-K71me2 in tumor progression from the perspective of post-translational modification,which is distinct from the pro-cancer function of CD147 itself,broadening our perspective on tumor-associated antigen CD147.

关键词： CD147 di-methylation Cell apoptosis FOSB Non-small cell lung cancer SETDB1

Urinary exosomal microRNA-145-5p and microRNA-27a-3p act as noninvasive diagnostic biomarkers for diabetic kidney disease

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World Journal of Diabetes 2024年第1期15卷 92-104页

作者： Lu-Lu Han Sheng-hai wang ming-Yan Yao Hong Zhou Department of Endocrinology The Second Hospital of Hebei Medical UniversityShijiazhuang 050000Hebei ProvinceChina Department of Endocrinology Baoding No.1 Central HospitalBaoding 071000Hebei ProvinceChina Department of Critical Care Medicine The Affiliated Hospital of Hebei UniversityBaoding 071000Hebei ProvinceChina

BACKGROUND Diabetic kidney disease(DKD),characterized by increased urinary microalbumin levels and decreased renal function,is the primary cause of end-stage renal di-sease.Its pathological mechanisms are complicated and multifactorial;Therefore,sensitive and specific biomarkers are needed.Urinary exosome originate from diverse renal cells in nephron segments and partially mirror the pathological changes in the kidney.The microRNAs(miRNAs)in urinary exosome are remark-ably stable and highly tissue-specific for the kidney.METHODS Type 2 diabetic mellitus(T2DM)patients were recruited from the Second Hospital of Hebei Medical University and were divided into two groups:DM,diabetic pa-tients without albuminuria[urinary albumin to creatinine ratio(UACR)hain reaction.The correlation between exosomal miRNAs and the clinical in-dexes was evaluated.The diagnostic values of exosomal miR-145-5p and miR-27a-3p in DKD were determined using receiver operating characteristic(ROC)analysis.Biological functions of miR-145-5p were investigated by performing RESULTS Urinary exosomal expression of miR-145-5p and miR-27a-3p was more upregulated in the DKD group than in the DM group(miR-145-5p:4.54±1.45 vs 1.95±0.93,P<0.001;miR-27a-3p:2.33±0.79 vs 1.71±0.76,P<0.05)and the NC group(miR-145-5p:4.54±1.45 vs 1.55±0.83,P<0.001;miR-27a-3p:2.33±0.79 vs 1.10±0.51,P<0.001).The exosomal miR-145-5p and miR-27a-3p positively correlated with albuminuria and serum creatinine and negatively correlated with the estimated glomerular filtration rate.miR-27a-3p was also closely related to blood glucose,gly-cosylated hemoglobin A1c,and low-density lipoprotein cholesterol.ROC analysis revealed that miR-145-5p had a better area under the curve of 0.88[95%confidence interval(CI):0.784-0.985,P<0.0001]in diagnosing DKD than miR-27a-3p with

关键词： Urinary exosome MicroRNA-145-5p MicroRNA-27a-3p Diabetic kidney disease Diagnostic biomarkers

Developing a diagnostic model for predicting prostate cancer: a retrospective study based on Chinese multicenter clinical data

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Asian Journal of Andrology 2024年第1期26卷 34-40页

作者： Chang-ming wang Lei Yuan Xue-Han Liu Shu-Qiu Chen hai-Feng wang Qi-Fei Dong Bin Zhang ming-Shuo Huang Zhi-Yong Zhang Jun Xiao Tao Tao Department of Urology The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China Department of Radiology The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China Core Facility Center for Medical Sciences The First Affiliated Hospital of USTcDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China Department of Urology Affiliated Zhongda Hospital of Southeast UniversityNanjing 210009China Department of Urology Shanghai East HospitalTongji University School of MedicineShanghai 200120China Department of Urology Shanghai Changhai HospitalSecond Military Medical UniversityShanghai 200000China Department of Urology Affiliated Anhui Provincial Hospital of Anhui Medical UniversityHefei 230001China

The overdiagnosis of prostate cancer(PCa)caused by nonspecific elevation serum prostate-specific antigen(PSA)and the overtreatment of indolent PCa have become a global problem that needs to be solved urgently.We aimed to construct a prediction model and provide a risk stratification system to reduce unnecessary biopsies.In this retrospective study,clinical data of 1807 patients from three Chinese hospitals were used.The final model was built using stepwise logistic regression analysis.The apparent performance of the model was assessed by receiver operating characteristic curves,calibration plots,and decision curve analysis.Finally,a risk stratification system of clinically significant prostate cancer(csPCa)was created,and diagnosis-free survival analyses were performed.Following multivariable screening and evaluation of the diagnostic performances,a final diagnostic model comprised of the PSA density and Prostate Imaging-Reporting and Data System(PI-RADS)score was established.Model validation in the development cohort and two external cohorts showed excellent discrimination and calibration.Finally,we created a risk stratification system using risk thresholds of 0.05 and 0.60 as the cut-off values.The follow-up results indicated that the diagnosis-free survival rate for csPCa at 12 months and 24 months postoperatively was 99.7%and 99.4%,respectively,for patients with a risk threshold below O.05 after the initial negative prostate biopsy,which was significantly better than patients with higher risk.Our diagnostic model and risk stratification system can achieve a personalized risk calculation of csPCa.It provides a standardized tool for Chinese patients and physicians when considering thenecessity of prostatebiopsy.

关键词： nomogram prostate biopsy prostate cancer Prostate Imaging-Reporting and Data System prostate-specific antigen density

Drug repurposing for cancer therapy

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1981-2013页

作者： Ying Xia ming Sun hai Huang Wei-Lin Jin Center for Clinical Laboratories The Affiliated Hospital of Guizhou Medical UniversityGuiyang 550004PR China The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine Guiyang 550001PR China School of Clinical Laboratory Science Guizhou Medical UniversityGuiyang 550004PR China Division of Gastroenterology and Hepatology Department of Medicine andDepartment of OncologySidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreMD 21287USA Institute of Cancer Neuroscience Medical Frontier Innovation Research CenterThe First Hospital of Lanzhou UniversityThe First Clinical Medical College of Lanzhou UniversityLanzhou 730000PR China

Cancer,a complex and multifactorial disease,presents a significant challenge to global health.Despite significant advances in surgical,radiotherapeutic and immunological approaches,which have improved cancer treatment outcomes,drug therapy continues to serve as a key therapeutic strategy.However,the clinical efficacy of drug therapy is often constrained by drug resistance and severe toxic side effects,and thus there remains a critical need to develop novel cancer therapeutics.One promising strategy that has received widespread attention in recent years is drug repurposing:the identification of new applications for existing,clinically approved drugs.Drug repurposing possesses several inherent advantages in the context of cancer treatment since repurposed drugs are typically cost-effective,proven to be safe,and can significantly expedite the drug development process due to their already established safety profiles.In light of this,the present review offers a comprehensive overview of the various methods employed in drug repurposing,specifically focusing on the repurposing of drugs to treat cancer.We describe the antitumor properties of candidate drugs,and discuss in detail how they target both the hallmarks of cancer in tumor cells and the surrounding tumor microenvironment.In addition,we examine the innovative strategy of integrating drug repurposing with nanotechnology to enhance topical drug delivery.We also emphasize the critical role that repurposed drugs can play when used as part of a combination therapy regimen.To conclude,we outline the challenges associated with repurposing drugs and consider the future prospects of these repurposed drugs transitioning into clinical application.

关键词： drugs integrating spite

Sparse Modal Decomposition Method Addressing Underdetermined Vortex-Induced Vibration Reconstruction Problem for Marine Risers

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China Ocean Engineering 2024年第2期38卷 285-296页

作者： DU Zun-feng ZHU hai-ming YU Jian-xing State Key Laboratory of Hydraulic Engineering Intelligent Construction and Operation School of Civil EngineeringTianjin UniversityTianjin 300350China

When investigating the vortex-induced vibration(VIV)of marine risers,extrapolating the dynamic response on the entire length based on limited sensor measurements is a crucial step in both laboratory experiments and fatigue monitoring of real risers.The problem is conventionally solved using the modal decomposition method,based on the principle that the response can be approximated by a weighted sum of limited vibration modes.However,the method is not valid when the problem is underdetermined,i.e.,the number of unknown mode weights is more than the number of known measurements.This study proposed a sparse modal decomposition method based on the compressed sensing theory and the Compressive Sampling Matching Pursuit(Co Sa MP)algorithm,exploiting the sparsity of VIV in the modal space.In the validation study based on high-order VIV experiment data,the proposed method successfully reconstructed the response using only seven acceleration measurements when the conventional methods failed.A primary advantage of the proposed method is that it offers a completely data-driven approach for the underdetermined VIV reconstruction problem,which is more favorable than existing model-dependent solutions for many practical applications such as riser structural health monitoring.

关键词： motion reconstruction vortex-induced vibration(VIV) marine riser modal decomposition method compressed sensing

N-acetylcysteine ameliorates erectile dysfunction in rats with hyperlipidemia by inhibiting oxidative stress and corpus cavernosum smooth muscle cells phenotypic modulation

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Asian Journal of Andrology 2024年第1期26卷 99-106页

作者： Wei Ding Jun-Hong Fan Li-Ren Zhong Nan-Xiong wang Lu-Hao Liu hai-Bo Zhang Li wang ming-Qiang wang Bing-Lin He An-Yang Wei Department of Urology The First Affiliated Hospital of Guizhou University of Traditional Chinese MedicineGuiyang 550002China Department of Urology Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhou 510000China Department of Urology Nanfang HospitalSouthern Medical UniversityGuangzhou 510000China Department of Urology Shenzhen Immigration Inspection General Station HospitalShenzhen 518000China Department of Organ Transplantation The Second Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510000China Department of Endocrinology The First Affiliated Hospital of Guizhou University of Traditional Chinese MedicineGuiyang 550002China

Hyperlipidemia is a major risk factor for erectile dysfunction(ED).Oxidative stress and phenotypic modulation of corpus cavernosum smooth muscle cells(CcSMCs)are the key pathological factors of ED.N-acetylcysteine(NAC)can inhibit oxidative stress;however,whether NAc can alleviate pathological variations in the corpus cavernosum and promote erectile function recovery in hyperlipidemic rats remains unclear.A hyperlipidemia model was established using 27 eight-week-old male Sprague-Dawley(SD)rats fed a high-fat and high-cholesterol diet(hyperlipidemic rats,HR).In addition,9 male SD rats were fed a normal diet to serve as controls(NC).HR rats were divided into three groups:HR,HR+normal saline(NS),and HR+NAC(n=9 for each group;NS or NAc intraperitoneal injections were administered daily for 16 weeks).Subsequently,the lipid profiles,erectile function,oxidative stress,phenotypic modulation markers of ccsMCs,and tissue histology were analyzed.The experimental results revealed that erectile function was significantly impaired in the HR and HR+NS groups,but enhanced in the HR+NAC group.Abnormal lipid levels,over-activated oxidative stress,and multi-organ lesions observed in the HR and HR+NS groups were improved in the HR+NAC group.Moreover,the HR group showed significant phenotypic modulation of CCSMCs,which was also inhibited by NAC treatment.This report focuses on the therapeutic effect of NAc in restoring erectile function using a hyperlipidemic rat model by preventing CcSMC phenotypic modulationand attenuating oxidativestress.

关键词： erectile dysfunction hyperlipidemia N-acetylcysteine oxidative stress henotypic modulation