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CK2αcauses stemness and chemotherapy resistance in liver cancer through the hedgehog signaling pathway

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Hepatobiliary & Pancreatic Diseases International 2023年第4期22卷 383-391页

作者： Di Wu Yuan-Qin Yin Yan Li Ling Zhang You-Hong Jiang Zhe Wang Department of Tumor Biotherapy and Cancer Research the First Affiliated Hospital of China Medical UniversityShenyang 110001China Department of Pathology Shengjing Hospital of China Medical UniversityShenyang 110004China

Background:Liver cancer is one of the major causes of cancer-related deaths *** cell stem-ness and chemotherapy resistance contribute to the high *** evidence indicates that the alpha subunit of protein kinase 2(CK2α)is involved in several human cancers,its function in liver cancer remains *** the present study,we aimed to elucidate the role of CK2αin liver ***:We examined the role of CK2αregulation in stemness and chemotherapy resistance capacity of liver cancer *** assays,tumor sphere formation assays,RT-PCR,flow cytometry,Western blotting assay,clonogenicity assay,matrigel invasion assay and bioinformatics were conducted in this ***:CK2αexpression in the liver cancer tissues was notably upregulated compared with that in the corresponding non-tumorous *** overexpression of CK2αpromoted tumor sphere formation,increased the percentage of CD133(+)and side population cells,caused the resistance of liver cancer cells to 5-FU treatment,increased the expression levels of NANOG,OCT4,SOX2,Gli1 and Ptch1,and enhanced the ability of CD133(+)cell clone formation and ***,the downregulation of CK2αhad the opposite ***2αsilencing inhibited the hedgehog pathway by reducing the expression of Gli1 and ***,CK2αregulation on liver cancer cell stemness and chemotherapy resistance was found to be involved in the hedgehog signaling ***:Our study may bring some new insights into the occurrence of liver ***,these findings suggest that targeting CK2αmay be a novel therapeutic strategy for patients with liver cancer.

关键词： CK2α Liver cancer hedgehog signaling pathway Stemness Chemotherapy resistance

Genetic variants in the hedgehog signaling pathway genes are associated with gastric cancer risk in a Chinese Han population

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The Journal of Biomedical Research 2022年第1期36卷 32-41页

作者： Yujuan Zhang Kai Lu Xu Wu Hanting Liu Junyi Xin Xiaowei Wang Weida Gong Qinghong Zhao Meilin Wang Haiyan Chu Mulong Du Guoquan Tao Zhengdong Zhang Department of Environmental Genomics Jiangsu Key Laboratory of Cancer BiomarkersPrevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingJiangsu 211166China Department of Genetic Toxicology the Key Laboratory of Modern Toxicology of Ministry of EducationCenter for Global HealthSchool of Public HealthNanjing Medical UniversityNanjingJiangsu 211166China Department of General Surgery the Affiliated Huai'an No.1 People's Hospital of Nanjing Medical UniversityHuai'anJiangsu 223300China Department of General Surgery Yixing People's HospitalYixingJiangsu 214200China Department of General Surgery the Second Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu 210011China Department of Environmental Genomics Center for Global HealthSchool of Public HealthNanjing Medical UniversityNanjingJiangsu 211166China Department of Biostatistics Center for Global HealthSchool of Public HealthNanjing Medical UniversityNanjing 211166China.

The hedgehog signaling pathway participates in the occurrence and progression of cancers including gastric *** conducted this study to evaluate whether genetic variants in the hedgehog signaling pathway genes would affect gastric cancer ***-marker Analysis of GenoMic Annotation(MAGMA)was used to investigate the aggregated genetic effects of single nucleotide polymorphisms(SNPs)assigned to candidate *** relationship between SNPs and gastric cancer risk was estimated by multivariate logistic regression *** expression was calculated using databases obtained from The Cancer Genome Atlas(TCGA)and The Gene Expression Omnibus(GEO).Kaplan‐Meier plotter was used to evaluate the association between gene expression with gastric cancer *** Immune Estimation Resource 2.0(TIMER 2.0)was applied to determine the correlation between selected gene expression and the immune cell infiltration *** identified that the G allele of rs2990912 in KIF27 was associated with higher gastric cancer risk,especially in the young and male *** expression of KIF27 in gastric cancer tissues was higher than that in normal tissues,leading to poor survival in gastric cancer ***,KIF27 expression was related to immune cell infiltration and positively correlated with PD-L1 *** findings highlight the key role of genetic variation in the hedgehog signaling pathway genes in gastric cancer susceptibility,which may provide important insights into the diagnosis,prognosis,and treatment of gastric cancer.

关键词： gastric cancer hedgehog signaling pathway genetic susceptibility molecular epidemiology

Inhibitory action of berberine on colorectal cancer HCT116 cells by regulation of hedgehog signaling pathway

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中国药理学与毒理学杂志 2021年第10期35卷 771-772页

作者： SUN Qiang CHEN Li ZENG Sha LIU Mao-lun REN Shan ZHAO Hui YANG Han MING Tian-qi LU Jin-jian XU Hai-bo State Key Laboratory of Southwestern Chinese Medicine Resources Department of PharmacologyChengdu University of Traditional Chinese MedicineChengdu 611137China Institute of Chinese Medical Sciences University of MacaoMacaoChina

OBJECTIVE To investigate the inhibition and mechanism of berberine on human colorectal cancer HCT116 cells through canonical hedgehog signaling *** The effect of berberine on cell morphology was observed by *** colorimetric assay,cell scratch experiment,colony formation assay and Hoechest/PI staining were utilized to detect the activities of berberine on cell viability,cell migration and cell *** cytometry was applied to examine the cell *** effects of berberine on caspase-3 and caspase-9 were detected by caspase activity detection *** expressions of hedgehog signaling pathway-related proteins SHH,GLI1,PTCH1,SMO,SUFU,apoptosis-related proteins Bax and Bcl-2 as well as cell cycle-related proteins cyclin D1 were detected by Western ***,quantitative real time RT-PCR was employed to assess the mRNA expression levels of hedgehog signaling pathway-related genes SHH,GLI1,PTCH1,SMO,SUFU,apoptosis-related genes Bax and Bcl-2 as well as cell cycle-related genes cyclin *** Berberine sharply altered the morphology of human colorectal cancer HCT116 cells,demonstrated by that migration ability of HCT116 cells was reduced significantly and the nuclei were densely *** could induce apoptosis in a dose-dependent *** activities of caspase-3 and caspase-9 were increased *** expression levels of hedgehog signaling pathway-related protein SUFU and apoptosis-related protein Bax were augmented *** expression levels of hedgehog signaling pathway-related proteins SHH,GLI1,PTCH1,SMO,apoptosis-related protein Bcl-2 as well as cell cycle-related genes cyclin D1 were markedly ***,the mRNA expression levels of hedgehog signaling pathway-related gene SUFU and apoptosis-related gene Bax were augmented *** mRNA expression levels of hedgehog signaling pathway-related genes SHH,GLI1,PTCH1,SMO,apoptosis-related gene Bcl-2 as well as cell cycle-related gene c

关键词： berberine hedgehog signaling pathway colorectal cancer cell proliferation cell apoptosis

Suppression of cell growth and migration by blocking hedgehog signaling pathway in gastric cancer cells

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Suppression of cell growth and migration by blocking hedgeho...

Inhibition of self-renewal and differentiation of HT-29 cells-derived cancer stem-like cells by scutellarin via hedgehog signaling pathway

细胞—生命的基础——中国细胞生物学学会2013年全国学术大会·武汉

作者： Runwei Yan Xiang Peng Xiaogang Yuan Qingtian Luo Yong Li Xuan Huang Nonghua Lv Shiwen Luo Department of Gastroenterology The First Affiliated Hospital of Nanchang UniversityKey Laboratory of Digestive Diseases of Jiangxi Province Center for Experimental Medicine The First Affiliated Hospital of Nanchang University

Background Previous studies suggest hedgehog signaling is essential for gastric cancer,but the precise function of hedgehog signaling in gastric cancer is still *** aim of this study is to clarify the role of hedgehog signaling in gastric tumorigenesis. Methods The expressions of hedgehog signaling key components in clinical samples of gastric

关键词： hedgehog signaling pathway gastric cancer Glil cDNA microarray analysis

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中国药理学与毒理学杂志 2019年第9期33卷 687-687页

作者： LEI Nan XIONG Si-hui TAN Li HE Man ZHANG Meng SUN Qiang ZENG Sha CHEN Li XU Hai-bo Department of Pharmacology School of PharmacyChengdu University of Traditional Chinese Medicine

OBJECTIVE To investigate the inhibitory effect of scutellarin on the self-renewal and differentiation of HT-29 cells-derived cancer stem-like cells(HT-29CSC)in vitro and in vivo,and to explore its *** The effect of scutellarin on the growth of HT-29CSC was determined by 3D Culture *** effect of scutellarin on growth and transformation of HT-29CSC was probed by soft agar colony formation *** effect of scutellarin on the differentiation of HT-29CSC was determined by serum induction differentiation assay in *** effects of scutellarin on the expressions of marker gene Lgr5,target gene c-Myc,proliferation gene CK20 and Nanog gene were measured by quantitative real-time *** the effect of scutellarin on the expression of c-Myc,Gli1,and Lgr5 protein by Western blotting.A subcutaneous xenograft model of colon cancer in nude mice was established and administered by intraperitoneal *** change of body weight and tumor size of nude mice were observed every two ***⁃gate the effects of scutellarin on the growth of xenograft tumors in nude *** expression of CD133,Lgr5,Gli1,Ptch1,c-Myc,Ki67,CK20,Nanog gene in tumors were measured by quantitative real-time *** expression of c-Myc,Gli1,Lgr5,CD133,Ki67 protein were measured by Western *** Scutellarin can inhibit the growth of HT-29CSC in 3D *** with the solvent control group,scutellarin can significantly inhibit the growth and transformation and differentiation of HT-29CSC in vitro(P<0.01).The expression levels of marker genes Lgr5,target gene c-Myc,proliferation gene CK20 and Nanog in HT-29CSC were down-regulated by *** can reduce the expression of c-Myc,Gli1,and Lgr5 protein in *** can inhibit the growth of colon cancer xenografts,lower CD133,Lgr5,Gli1,Ptch1,c-Myc,Ki67,CK20,and Nanog mRNA level of xenograft tumors,reduce the expression of c-Myc,Gli1,Lgr5,CD133,and Ki67 protein of xenograft tumor

关键词： scutellarin colon cancer cancer stem cell differentiation xenografted tumor hedgehog signaling pathway

Research Progress of PTCH1 Gene in Lung Cancer

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Journal of Biosciences and Medicines 2024年第5期12卷 1-9页

作者： Chaoyue Liang Changfeng Wang Health Science Center Yangtze University Jingzhou China Department of Respiratory and Critical Care Medicine Huanggang Central Hospital of Yangtze University Huanggang China Department of Critical Medicine Brain Hospital of Guangxi Zhuang Autonomous Region Liuzhou China

Background: The PTCH1 gene, also known as Patched 1, is located on the long arm of human chromosome 9 (9q22.3). It encodes the PTCH1 protein, which is a critical transmembrane receptor within the hedgehog signaling pathway (Hh), playing a pivotal role in cellular communication and developmental processes. Recent studies have highlighted the significance of mutations in PTCH1 in the pathogenesis of lung cancer, positioning it as a crucial molecule for investigation in oncology. Purpose: This review aims to elucidate the role of the PTCH1 and the hedgehog pathway in the initiation, progression, and potential treatment of lung cancer, thereby providing a theoretical foundation for personalized and precise therapeutic strategies. Method: To ensure a comprehensive review, this study systematically searched for literature related to the PTCH1, lung cancer, and the hedgehog pathway across multiple databases including PubMed, Web of Science, and CNKI (China National Knowledge Infrastructure). The search strategy involved using specific keywords and advanced filtering options to include the most relevant and recent studies. Initial screening excluded irrelevant articles, followed by a detailed evaluation of the selected studies based on their scientific quality and relevance. Results: This review indicated that specific mutations in the PTCH1 gene are closely associated with the onset and progression of lung cancer. These mutations impede normal hedgehog signaling, leading to unregulated cell proliferation and tumor growth. Targeting PTCH1, including vismodegib, have shown efficacy in clinical cases, particularly in SCCL with specific PTCH1 mutations, leading to complete remissions. Furthermore, the interaction between PTCH1 and microRNA-212 suggests potential therapeutic approaches by targeting miRNA to regulate PTCH1 expression. In addition, the investigation of traditional Chinese medicines such as Ginsenosides and Cordyceps sinensis extracts has shown their potential to

关键词： PTCH1 hedgehog signaling pathway Lung Cancer

Development of hedgehog pathway inhibitors by epigenetically targeting GLI through BET bromodomain for the treatment of medulloblastoma

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Acta Pharmaceutica Sinica B 2021年第2期11卷 488-504页

作者： Xiaohua Liu Yu Zhang Yalei Li Juan Wang Huaqian Ding Wenjing Huang Chunyong Ding Hongchun Liu Wenfu Tan Ao Zhang CAS Key Laboratory of Receptor Research Shanghai Institute of Materia Medica(SIMM)Chinese Academy of SciencesShanghai 201203China Department of Pharmacology School of PharmacyFudan UniversityShanghai 201203China State Key Laboratory of Drug Research Shanghai Institute of Materia Medica(SIMM)Chinese Academy of SciencesShanghai 201203China School of Pharmacy Shanghai Jiao Tong UniversityShanghai 200240China School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Esophageal Cancer Prevention and Treatment Ministry of Education of ChinaZhengzhou UniversityZhengzhou 450001China

Medulloblastoma(MB)is a common yet highly heterogeneous childhood malignant brain tumor,however,clinically effective molecular targeted therapy is *** of hedgehog(HH)signaling by epigenetically targeting the transcriptional factors GLI through bromodomain-containing protein 4(BRD4)has recently spurred new interest as potential treatment of HH-driven *** screening of current clinical BRD4 inhibitors for their inhibitory potency against glioma-associated oncogene homolog(GLI)protein,the BRD4 inhibitor 2 was selected as the lead for further structural optimization,which led to the identification of compounds 25 and 35 as the high potency HH *** profiling showed that both compounds suppressed HH signaling by interacting with the transcriptional factor GLI,and were equally potent against the clinical resistant mutants and the wild type of smoothened(SMO)receptor with IC50 values around 1 nmol/*** the resistant MB allograft mice,compound 25 was well tolerated and markedly suppressed tumor growth at both 5 mg/kg(TGI=83.3%)and 10 mg/kg(TGI=87.6%)*** further modification is needed to improve the pharmacokinetic(PK)parameters,compound 25 represents an efficacious lead compound of GLI inhibitors,possessing optimal safety and tolerance to fight against HH-driven MB.

关键词： Medulloblastoma hedgehog signaling pathway Drug resistance GLI BRD4

Novel molecular targets in hepatocellular carcinoma

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World Journal of Clinical Oncology 2020年第8期11卷 589-605页

作者： Ariel Ka-Man Chow Simon Wing-Lung Yau Lui Ng School of Nursing and Health Studies The Open University of Hong KongHong KongChina Department of Surgery Li Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina

Globally,hepatocellular carcinoma(HCC)is a leading cause of cancer and cancerrelated *** therapeutic efficacy of locoregional and systemic treatment in patients with advanced HCC remains low,which results in a poor *** development of sorafenib for the treatment of HCC has resulted in a new era of molecular targeted therapy for this ***,the median overall survival was reported to be barely higher in the sorafenib treatment group than in the control ***,in this review we describe the importance of developing more effective targeted therapies for the management of advanced *** investigations of molecular signaling pathways in several cancers have provided some insights into developing molecular therapies that target critical members of these signaling *** involved in the hedgehog and Notch signaling pathways,Polo-like kinase 1,arginine,histone deacetylases and Glypican-3 can be potential targets in the treatment of *** has limited therapeutic efficacy due to the development of inhibitory feedback mechanisms and induction of ***,emphasis is now on the development of personalized and combination molecular targeted therapies that can serve as ideal therapeutic strategies for improved management of HCC.

关键词： Hepatocellular carcinoma Prognosis Arginine deprivation Cancer stem cells Glypican-3 hedgehog signaling pathway Histone deacetylases Personalized medicine Molecular targeted therapy Notch signaling pathway Polo-like kinase 1 Tumourassociated antigens

The role of microRNAs during the genesis of medulloblastomas induced by the hedgehog pathway

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The Journal of Biomedical Research 2011年第1期25卷 42-48页

作者： Steven Y Cheng Department of Developmental Genetics and Center for Regenerative Medicine Nanjing Medical University

Constitutive hedgehog （Hh） signaling is associated with the genesis of medulloblastomas （MB）. The objective of this study is to identify special microRNAs （miRNAs） regulated by the Hh pathway, and to clarify the role of miRNAs during the genesis of MB induced by sustained Hh activation. In the primary screening, we used stemloop RT-PCR to test the expression of 90 different miRNAs in the wildtype （WT） and Ptc-/- MEF cell lines. In the secondary screening, the miRNAs screened from the first screening were validated in the Sufu-/- MEF cell lines. We then verified the expression of miRNAs both in the normal cerebellar tissues and the MB induced by activated Hh pathway, and examined the expression of the other 21 miRNA members of the miR-154 cluster in the MB and normal cerebellum. In the first screening, 13 miRNAs showed significant differential expression in WT and Ptc-/- MEF cell lines, while 10 of them had significant difference in the Sufu-/- MEF cell line. Compared to the normal mouse cerebellum, only 2 miRNAs in 15 miRNAs were differentially expressed between the MB and normal cerebellar tissues. Among 21 members of the miR-154 cluster, 6 miRNAs were downregulated in the MB. Our study demonstrated that miR-154 may be regulated by the Hh pathway, and the activation of the Hh pathway led to the downregulation of the miR-154 cluster, resulting in the genesis of MB.

关键词： hedgehog signaling pathway microRNAs miR-154 cluster medulloblastomas