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Baicalin Antagonizes Prostate cancer stemness via Inhibiting Notch1/NF-κB Signaling Pathway

中国结合医学杂志:英文版 2023年第10期29卷 914-923页

作者： WU Ming-hui WU Kun ZHU Yuan-bing LI Da-chuan YANG Huan ZENG Hong Department of Urology Hubei University of Traditional Chinese MedicineWuhan430065China Department of Urology Chongqing Jiangjin District Hospital of Chinese MedicineChongqing402260China

Objective To investigate the molecular mechanisms underlying the effect of baicalin on prostate cancer(PCa)progression both in vivo and in *** The in situ PCa stem cells(PCSCs)-injected xenograft tumor models were established in BALB/c nude *** volume and weight were respectively checked after baicalin(100 mg/kg)***-eosin(HE)staining was used to observe the growth arrest and cell *** expression levels of acetaldehyde dehydrogenase 1(ALDH1),CD44,CD133 and Notch1 were determined by reverse transcription-polymerase chain *** expression levels of ALDH1,CD44,CD133,Notch1,nuclear factorκB(NF-κB)P65 and NF-κB p-P65 were detected by Western *** and subcellular location of ALDH1,CD44,CD133,Notch1 and NF-κB p65 were detected by immunofluorescence *** vitro,cell cycle distribution and cell apoptosis of PC3 PCSCs was assessed by flow cytometry after baicalin(125µmol/L)*** migration and invasion abilities of PCSCs were assessed using Transwell *** electron microscopy scanning was utilized to observe the structure and autophagosome formation of baicalin-treated *** addition,PCSCs were infected with lentiviruses expressing human *** Compared with the control group,the tumor volume and weight were notably reduced in mice treated with 100 mg/kg baicalin(P<0.05 or P<0.01).Histopathological analysis showed that baicalin treatment significantly inhibited cell proliferation and promoted cell ***,baicalin treatment reduced mRNA and protein expression levels of CD44,CD133,ALDH1,and Notch1 as well as the protein expression of NF-κB p-P65 in the xenograft tumor(P<0.01).In vitro,the cell proliferation of PCSCs was significantly attenuated after treatment with 125µmol/L baicalin for 72 h(P<0.01).The cell migration and invasion rates were decreased following treatment with baicalin for 48 and 72 h(P<0.01).Baicalin notably induced cell apoptosis and seriously

关键词： baicalin prostate cancer cancer stemness Notch1/nuclear factorκB signaling

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Jiedu Recipe,a compound Chinese herbal medicine,inhibits cancer stemness in hepatocellular carcinoma via Wnt/β-catenin pathway under hypoxia

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结合医学学报:英文版 2023年第5期21卷 474-486页

作者： Bing-jie Guo Yi Ruan Ya-jing Wang Chu-lan Xiao Zhi-peng Zhong Bin-bin Cheng Juan Du Bai Li Wei Gu Zi-fei Yin School of Traditional Chinese Medicine Naval Medical UniversityShanghai 200433China Department of Gastroenterology Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghai 200433China PLA Naval Medical Center Shanghai 200052China Department of Traditional Chinese Medicine the 920th Hospital of Joint Logistics Support ForceKunming 650000Yunan ProvinceChina Department of Rehabilitation Changhai HospitalNaval Medical UniversityShanghai 200433China

Objective Jiedu Recipe(JR),a Chinese herbal remedy,has been shown to prolong overall survival time and decrease recurrence and metastasis rates in patients with hepatocellular carcinoma(HCC).This work investigated the mechanism of JR in HCC *** The chemical constituents of JR were detected using liquid chromatography-mass *** potential anti-HCC mechanism of JR was screened using network pharmacology and messenger ribonucleic acid(mRNA)microarray chip assay,followed by experimental validation in human HCC cells(SMMC-7721 and Huh7)in vitro and a nude mouse subcutaneous transplantation model of HCC in *** cell characteristics of proliferation,migration and invasion under hypoxic setting were investigated using thiazolyl blue tetrazolium bromide,wound healing and Transwell assays,***-i^(TM)Hypoxia Reagent was added to reveal hypoxic *** cell sphere formation assay was used to detect the ***-mesenchymal transition(EMT)markers like E-cadherin,vimentin andα-smooth muscle actin,and pluripotent transcription factors including nanog homeobox,octamer-binding transcription factor 4,and sex-determining region Y box protein 2 were analyzed using Western blotting and real-time polymerase chain *** blot was performed to ascertain the anti-HCC effect of JR under hypoxia involving the Wnt/β-catenin *** According to network pharmacology and mRNA microarray chip analysis,JR may potentially act on hypoxia and inhibit the Wnt/β-catenin *** vitro and in vivo experiments showed that JR significantly decreased hypoxia,and suppressed HCC cell features of proliferation,migration and invasion;furthermore,the hypoxia-induced increases in EMT and stemness marker expression in HCC cells were inhibited by *** based on the co-administration of JR and an agonist(LiCl)or inhibitor(IWR-1-endo)verified that JR suppressed HCC cancer stem-like properties under hypoxia by blocking the Wnt/β-ca

关键词： Jiedu Recipe Chinese medicine Hepatocellular carcinoma Hypoxia cancer stemness Wnt/β-cateninpathway

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PLEK2 promotes cancer stemness and tumorigenesis of head and neck squamous cell carcinoma via the c-Myc-mediated positive feedback loop

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cancer Communications 2022年第10期42卷 987-1007页

作者： Xinyuan Zhao Dalong Shu Wenjuan Sun Shanshan Si Wei Ran Bing Guo Li Cui Department of Endodontics Stomatological HospitalSouthern Medical UniversityGuangzhouGuangdong 510280P.R.China Department of Oral and Maxillofacial Surgery The First Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdong 510080P.R.China Department of Stomatology The Third Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdong 510630P.R.China Department of Oral Emergency Stomatological HospitalSouthern Medical UniversityGuangzhouGuangdong 510280P.R.China Department of Dentistry The First Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdong 510080P.R.China Department of Oral and Maxillofacial Surgery Stomatological HospitalSouthern Medical UniversityGuangzhouGuangdong 510280P.R.China Division of Oral Biology and Medicine School of DentistryUniversity of CaliforniaLos AngelesLos AngelesCalifornia 90095United States

Background:Head and neck squamous cell carcinoma(HNSCC)is one of the most frequent malignancies worldwide and is characterized by unfavorable prognosis,high lymph node metastasis and early ***,the molecular events regulating HNSCC tumorigenesis remain poorly ***,uncovering the underlying mechanisms is urgently needed to identify novel and promising therapeutic targets for *** this study,we aimed to explore the role of pleckstrin-2(PLEK2)in regulating HNSCC ***:The expression pattern of PLEK2 and its clinical significance in HNSCC were determined by analyzing publicly assessable datasets and our own independent HNSCC *** vitro and in vivo experiments,including cell proliferation,colony formation,Matrigel invasion,tumor sphere formation,ALDEFLUOR,Western blotting assays and xenograft mouse models,were used to investigate the role of PLEK2 in regulating the malignant behaviors of HNSCC *** underlying molecular mechanisms for the tumor-promoting role of PLEK2 were elucidated using co-immunoprecipitation,cycloheximide chase analysis,ubiquitination assays,chromatin immunoprecipitation-quantitative polymerase chain reaction,luciferase reporter assays and rescue ***:The expression levels of PLEK2 mRNA and protein were significantly increased in HNSCC tissues,and PLEK2 overexpression was strongly associated with poor overall survival and therapeutic ***,PLEK2 was important for maintaining the proliferation,invasion,epithelial-mesenchymal transition,cancer stemness and tumorigenesis of HNSCC cells and could alter the cellular metabolism of the cancer ***,PLEK2 interacted with c-Myc and reduced the association of F-box and WD repeat domain containing 7(FBXW7)with c-Myc,thereby avoiding ubiquitination and subsequent proteasome-mediated degradation of ***,the c-Myc signaling activated by PLEK2 was important for sustaining the aggressive malignant

关键词： c-Myc cancer stemness FBXW7 HNSCC PLEK2 positive feedback loop tumorigenesis ubiquitination-mediated degradation

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Physical exercise suppresses hepatocellular carcinoma progression by alleviating hypoxia and attenuating cancer stemness through the Akt/GSK-3β/β-catenin pathway

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Journal of Integrative Medicine 2023年第2期21卷 184-193页

作者： Chu-lan Xiao Zhi-peng Zhong Can Lü Bing-jie Guo Jiao-jiao Chen Tong Zhao Zi-fei Yin Bai Li Department of Rehabilitation Changhai HospitalNaval Medical UniversityShanghai 200433China Department of Traditional Chinese Medicine The 920th Hospital of Joint Logistics Support ForceKunming 650000Yunnan ProvinceChina Second Team Graduate SchoolNaval Medical UniversityShanghai 200433China College of Integrated Traditional Chinese and Western Medicine Nanjing University of Traditional Chinese MedicineNanjing 210023Jiangsu ProvinceChina Department of Military Traditional Chinese Medicine Faculty of Traditional Chinese MedicineNaval Medical UniversityShanghai 200433China

Objective:Physical exercise,a common non-drug intervention,is an important strategy in cancer treatment,including hepatocellular carcinoma(HCC).However,the mechanism remains largely *** to the importance of hypoxia and cancer stemness in the development of HCC,the present study investigated whether the anti-HCC effect of physical exercise is related to its suppression on hypoxia and cancer ***:A physical exercise intervention of swimming(30 min/d,5 d/week,for 4 weeks)was administered to BALB/c nude mice bearing subcutaneous human HCC *** anti-HCC effect of swimming was assessed in vivo by tumor weight monitoring,hematoxylin and eosin(HE)staining,and immunohistochemistry(IHC)detection of proliferating cell nuclear antigen(PCNA)and *** expression of stemness transcription factors,including Nanog homeobox(NANOG),octamer-binding transcription factor 4(OCT-4),v-Myc avian myelocytomatosis viral oncogene homolog(C-MYC)and hypoxia-inducible factor-1a(HIF-1a),was detected using real-time reverse transcription polymerase chain reaction.A hypoxia probe was used to explore the intratumoral hypoxia *** blot was used to detect the expression of HIF-1a and proteins related to protein kinase B(Akt)/glycogen synthase kinase-3β(GSK-3β)/β-catenin signaling *** IHC analysis of platelet endothelial cell adhesion molecule-1(CD31),and the immunofluorescence co-location of CD31 and desmin were used to analyze tumor blood ***-7721 cells were treated with nude mice *** inhibition effect on cancer stemness in vitro was detected using suspension sphere experiments and the expression of stemness transcription *** hypoxia status was inferred by measuring the protein and mRNA levels of ***,the expression of proteins related to Akt/GSK-3β/β-catenin signaling pathway was ***:Swimming significantly reduced the body weight and tumor weight in nude mice bearing HCC *** staining and IHC results show

关键词： Physical exercise Swimming Hepatocellular carcinoma Liver cancer Blood perfusion Hypoxia cancer stemness Akt/GSK-3β/β-catenin

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EMT-associated microRNAs and their roles in cancer stemness and drug resistance

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cancer Communications 2021年第3期41卷 199-217页

作者： Guangtao Pan Yuhan Liu Luorui Shang Fangyuan Zhou Shenglan Yang Department of Traditional Chinese Medicine Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430022P.R.China

Epithelial-to-mesenchymal transition(EMT)is implicated in a wide array of malignant behaviors of cancers,including proliferation,invasion,and *** notably,previou studies have indicated that both cancer stem-like properties and drug resistance were associated with ***,microRNAs(miRNAs)play a pivotal role in the regulation of EMT phenotype,as a result,some miRNAs impact cancer stemness and drug ***,understanding the relationship between EMT-associated miRNAs and cancer stemness/drug resistance is beneficial to both basic research and clinical *** this review,we preliminarily looked into the various roles that the EMT-associated miRNAs play in the stem-like nature of malignant ***,we reviewed the interaction between EMT-associated miRNAs and the drugresistant complex signaling pathways of multiple cancers including lung cancer,gastric cancer,gynecologic cancer,breast cancer,liver cancer,colorectal cancer,pancreatic cancer,esophageal cancer,and nasopharyngeal *** finally discussed the relationship between EMT,cancer stemness,and drug resistance,as well as looked forward to the potential applications of miRNA therapy for malignant tumors.

关键词： cancer epithelial-to-mesenchymal transition microRNA cancer stem cell cancer stemness drug resistance

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QAP21 reduces stemness and mobility of metastatic breast cancer cells involving D1DR activation

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Journal of Chinese Pharmaceutical Sciences 2021年第4期30卷 289-305页

作者： Ling Yong Ye Yao Mengyi Han Xiaoxue Yan Qingyu Yao Yuchen Guo Junsheng Xue Guoshu Chen Tianyan Zhou Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System Department of PharmaceuticsSchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China Chemical Basic Laboratory School of Chemistry and Chemical EngineeringGuangzhou UniversityGuangzhou 510006China

Breast cancer is the second leading cause of cancer death in women mainly due to metastasis,which is closely related to cancer *** has shown that cancer stem-like cells(CSCs),which are responsible for cancer stemness,can be decreased by activating dopamine D1 receptor(D1 DR).In the present study,we aimed to explore the pharmacological effects as well as the underlying mechanisms of QAP21,a newly synthesized compound that can be orally administered,in metastatic breast cancer *** results showed that QAP21 dose-dependently inhibited the ability of colony formation in 4 T1 and MDA-MB-231 *** mobility,including cell migration and invasion,was also remarkably ***,QAP21 significantly inhibited mammosphere formation and decreased CSC proportion,indicating reduced cancer *** further verified that the nuclear factor-kappa B(NF-κB)/Akt/epithelial-mesenchymal transition(EMT)pathway was markedly impacted by QAP21 ***,QAP21 up-regulated the expressions of D1 DR and its second messengers,including cAMP and cGMP,which can be increased when D1 DR is *** 23390,a specific D1 DR antagonist,partially or completely reversed the above-mentioned effects of QAP21,indicating that D1 DR activation might be involved in the underlying mechanism of *** summary,QAP21 effectively reduced breast cancer stemness and cell mobility,indicating its potential use for metastatic breast cancer therapy.

关键词： Metastatic breast cancer Dopamine D1 receptor cancer stemness Cell mobility QAP21

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Systematic screening reveals synergistic interactions that overcome MAPK inhibitor resistance in cancer cells

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cancer Biology & Medicine 2022年第2期19卷 229-252页

作者： Yu Yu Minzhen Tao Libin Xu Lei Cao Baoyu Le Na An Jilin Dong Yajie Xu Baoxing Yang Wei Li Bing Liu Qiong Wu Yinying Lu Zhen Xie Xiaohua Lian Department of Cell Biology Basic Medical CollegeArmy Medical University(Third Military Medical University)Chongqing 400038China MOE Key Laboratory of Bioinformatics and Bioinformatics Division Center for Synthetic and System BiologyDepartment of AutomationBeijing National Research Center for Information Science and TechnologyTsinghua UniversityBeijing 100084China National cancer Center/National Clinical Research Center for cancer/cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Department of Thoracic Surgery Peking Union Medical College HospitalChinese Academy of Medical SciencesBeijing 100730China Beijing Syngentech Co. LtdBeijing 102206China School of Life Sciences Tsinghua UniversityBeijing 100084China The Comprehensive Liver cancer Center The 5th Medical Center of PLA General HospitalBeijing 100039China

Objective:Effective adjuvant therapeutic strategies are urgently needed to overcome MAPK inhibitor(MAPKi)resistance,which is one of the most common forms of resistance that has emerged in many types of ***,we aimed to systematically identify the genetic interactions underlying MAPKi resistance,and to further investigate the mechanisms that produce the genetic interactions that generate synergistic MAPKi ***:We conducted a comprehensive pair-wise sgRNA-based high-throughput screening assay to identify synergistic interactions that sensitized cancer cells to MAPKi,and validated 3 genetic combinations through competitive growth,cell viability,and spheroid formation *** next conducted Kaplan-Meier survival analysis based on The cancer Genome Atlas database and conducted immunohistochemistry to determine the clinical relevance of these synergistic *** also investigated the MAPKi resistance mechanisms of these validated synergistic combinations by using co-immunoprecipitation,Western blot,qRTPCR,and immunofluorescence ***:We constructed a systematic interaction network of MAPKi resistance and identified 3 novel synergistic combinations that effectively targeted MAPKi resistance(ITGB3+IGF1R,ITGB3+JNK,and HDGF+LGR5).We next analyzed their clinical relevance and the mechanisms by which they sensitized cancer cells to MAPKi ***,we discovered a novel protein complex,HDGF-LGR5,that adaptively responded to MAPKi to enhance cancer cell stemness,which was up-or downregulated by the inhibitors of ITGB3+JNK or ITGB3+***:Pair-wise sgRNA library screening provided systematic insights into elucidating MAPKi resistance in cancer ***3-+IGF1R-targeting drugs(cilengitide+linsitinib)could be used as an effective therapy for suppressing the adaptive formation of the HDGF-LGR5 protein complex,which enhanced cancer stemness during MAPKi stress.

关键词： Pair-wise sgRNA library genetic interactions MAPKi resistance combinatorial therapy cancer stemness

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Roles of conventional and complementary therapies in recurrent hepatocellular carcinoma

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World Journal of Gastrointestinal Oncology 2023年第1期15卷 19-35页

作者： Hsiang-Chun Lai Hung-Jen Lin Long-Bin Jeng Sheng-Teng Huang Graduate Institute of Chinese Medicine School of Chinese MedicineCollege of Chinese MedicineChina Medical UniversityTaichung 40447Taiwan Department of Chinese Medicine China Medical University HospitalTaichung 40447Taiwan Organ Transplantation Center China Medical University HospitalTaichung 40447Taiwan School of Chinese Medicine China Medical UniversityTaichung 40447Taiwan cancer Research Center for Traditional Chinese Medicine Department of Medical ResearchChina Medical University HospitalTaichung 40447Taiwan An-Nan Hospital China Medical UniversityTainan 709204Taiwan

Hepatocellular carcinoma(HCC)is the fifth most common type of cancer and the fourth leading cause of cancer-related deaths in the *** has a reported recurrence rate of 70%-80%after 5 years of *** tumor recurrence is the most critical factor associated with HCC *** salvage therapies for recurrent HCC include re-hepatectomy or liver transplantation,transcatheter arterial chemoembolization,Y-90,target therapy,and immunotherapy;however,these conventional treatment modalities have yet to achieve consistently favorable ***,previous studies have demonstrated that conventional therapies in combination with traditional Chinese medicine(TCM),acupuncture,moxibustion or dietary supplements could notably benefit patients with HCC recurrence by strengthening and augmenting the overall management ***,systemic reviews related to the interactions between complementary therapies and conventional therapy in recurrent HCC are *** this review,we discuss the molecular mechanisms underlying the functions of complementary therapies for recurrent HCC,which include augmenting the local control to improve the congestion status of primary tumors and reducing multicentric tumor occurrence via inducing autophagy,apoptosis or cell cycle *** and its derivatives may play important roles in helping to control HCC recurrence by inhibiting epithelial-mesenchymal transition,migration,invasion,and metastasis,inhibiting cancer stem cells,and ameliorating drug resistance.

关键词： Recurrence Hepatocellular carcinoma Complementary therapy Traditional Chinese medicine cancer stemness Drug resistance

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Carrier-free nanodrugs for stemness inhibition-enhanced photodynamic therapy

聚集体(英文)

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聚集体(英文) 2023年第3期4卷 84-93页

作者： Yuwei Liu Kaiqi Long Tianyi Wang Weirong Kang Weiping Wang State Key Laboratory of Pharmaceutical Biotechnology The University of Hong KongHong KongChina Department of Pharmacology and Pharmacy Li Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina Laboratory of Molecular Engineering and Nanomedicine Dr.Li Dak-Sum Research CentreThe University of Hong KongHong KongChina

cancer stem cell(CSC)has been considered a key driver of tumor growth,recurrence,and metastasis due to its self-renewal and tumor initiation capacities called *** is also responsible for the high resistance of CSC to current therapeutic strategies,including photodynamic therapy(PDT)and *** this study,a carrier-free nanodrug(designated as MKCe6 nanoparticle[NP])selfassembled by photosensitizer chlorin e6(Ce6)and stemness inhibitor MK-0752 was prepared for effective tumor *** inhibition caused by MK-0752 could sensitize CSCs to *** from the high drug-loading capacity and efficient cellular internalization,MKCe6 NPs exhibited good performance in PDT and stemness *** this way,effective tumor growth repression and tumorigenesis inhibition by MKCe6 NPs were observed both in vitro and in *** self-delivery nanodrug for stemness inhibition-enhanced photodynamic therapy may provide new insights for clinical cancer therapy.

关键词： cancer stemness nanomedicine Notch pathway photodynamic therapy self-assembly

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CAFs shape myeloid-derived suppressor cells to promote stemness of intrahepatic cholangiocarcinoma via 5-lipoxygenase

CAFs shape myeloid-derived suppressor cells to promote stemn...

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第十四届全国免疫学学术大会

作者： Yuli Lin Qian Cai Yu Chen Tiancong Shi Weiren Liu Li Mao Bo Deng Zhen Ying Yuan Gao Haoyang Luo Xuguang Yang Xiaowu Huang Yinghong Shi Rui He Fudan University Key Laboratory of Carcinogenesis and cancer Invasion of Ministry of Education Department of Liver SurgeryLiver Cancer Institute Zhongshan Hospital Shanghai Ninth People's Hospital School of Medicine Shanghai Jiaotong University Department of Oncology Cancer Institute Longhua Hospital Shanghai University of Traditional Chinese Medicine

Background: and Aims: We previously demonstrated that cancer-associated fibroblasts(CAFs) promote tumor growth via recruiting of myeloid-derived suppressor cells(MDSCs). 5-lipoxygenase(5-LO) is highly expressed in myeloid cells and critical for synthesizing leukotriene B4(LTB4), which is involved in tumor progression via activating its receptor Leukotriene B4 receptor type 2(BLT2). In this study, we investigated the potential role of CAFs in regulating MDSC function to enhance cancer stemness, the driving force of the cancer aggressiveness and chemotherapy refractoriness, in highly desmoplastic intrahepatic cholangiocarcinoma(ICC).Approach and Results: RNA-sequencing analysis revealed enriched metabolic pathways but decreased inflammatory pathways in cancer MDSCs compared with blood MDSCs from ICC patients. Co-injection of ICC patient-derived CAFs promoted cancer stemness in an orthotopic ICC model, which was blunted by MDSC depletion. Conditioned media(CM) from CAF-educated MDSCs drastically promoted tumorsphere formation efficiency and stemness marker gene expression in ICC cells. CAF-CM stimulation increased expression and activity of 5-LO in MDSCs while 5-LO inhibitor impaired the stemness-enhancing capacity of MDSCs in vitro and in vivo. Furthermore, CAFs were identified as the major source for IL-6 and IL-33, which mediated hyperactivated 5-LO metabolism in MDSCs. Furthermore, IL-6 and IL-33 mainly expressed by CAFs mediated hyperactivated 5-LO metabolism in *** identify the LTB4-BLT2 axis as the critical downstream metabolite signaling of 5-LO in promoting cancer stemness, as treatment with LTB4 that were elevated in CAF-educated MDSCs or blockade of BLT2 that was preferentially expressed in stem-like ICC cells significantly reduced stemness-enhancing effects of CAF-educated MDSCs. Finally, BLT2 blockade augmented chemotherapeutic efficacy in ICC patient derived-xenograft(PDX) ***: Our study reveals a previously unrecognized role for CAFs

关键词： cancer-associated fibroblasts myeloid-derived suppressor cells cancer stemness leukotriene intrahepatic cholangiocarcinoma

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