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Schachtschneider KM, Redlon LN, Lokken RP, Huang YH, Guzman G, Schook LB, Gaba RC. Epigenetic regulation of individual components of combined hepatocellular-cholangiocarcinoma. PLoS One 2025; 20:e0324145. [PMID: 40424447 PMCID: PMC12112136 DOI: 10.1371/journal.pone.0324145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 04/21/2025] [Indexed: 05/29/2025] Open
Abstract
Combined hepatocellular carcinoma-cholangiocarcinoma (HCC-CCA) is a rare liver tumor comprising histologic features of both HCC and CCA. Due to its heterogeneous nature, treatment of combined HCC-CCA is a significant clinical challenge and prognosis remains poor. Therefore, further understanding of the tumor biology underlying the individual subtypes of this mixed tumor is required to improve treatment stratification and optimize treatment strategies. This study sought to identify altered epigenetic regulation and gene expression patterns in the individual components of combined HCC-CCA. Formalin fixed paraffin embedded (FFPE) tumor specimens from 9 patients diagnosed with combined HCC-CCA were utilized in this study. Hematoxylin and eosin (H&E) staining was performed for each sample, and regions representative of the individual HCC and CCA components were delineated. Adjacent unstained slides were cut and dissected to separate HCC and CCA components. DNA and RNA extraction was performed for each sample for DNA methylation (n = 7 HCC and 7 CCA) and gene expression (n = 7 HCC and 8 CCA) profiling via reduced representation bisulfite sequencing (RRBS) and RNA-seq, respectively. Samples did not cluster by tumor type when comparing genome-wide DNA methylation or gene expression patterns. Of the 5 patients with DNA methylation data available for both subtypes, 4 clustered by patient as opposed to cancer subtype, suggesting similar epigenetic regulatory patterns arising from development in the same microenvironment and genetic background. Differential analysis resulted in the identification of 57 differentially expressed genes (DEGs) and 808 differentially methylated regions (DMRs) between the HCC and CCA subtypes. Genes associated with DMRs were associated with Wnt signaling, voltage-gated channels, metal binding, and cellular regulation. Finally, increased expression of several genes previously implicated in tumor aggressiveness, prognosis, and treatment responses were identified. These results highlight the potential importance of accounting for underlying HCC and CCA tumor biology when determining the optimal course of treatment for this deadly disease.
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Affiliation(s)
- Kyle M. Schachtschneider
- Department of Radiology, University of Illinois at Chicago, Chicago, Illinois, United States of America
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois, United States of America
- National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
| | - Luke N. Redlon
- College of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Ryan Peter Lokken
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, United States of America
| | - Yu-Hui Huang
- Department of Radiology, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Grace Guzman
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Lawrence B. Schook
- Department of Radiology, University of Illinois at Chicago, Chicago, Illinois, United States of America
- National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America
| | - Ron C. Gaba
- Department of Radiology, University of Illinois at Chicago, Chicago, Illinois, United States of America
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Hammouz RY, Baryła I, Styczeń-Binkowska E, Bednarek AK. Twenty-five years of WWOX insight in cancer: a treasure trove of knowledge. Funct Integr Genomics 2025; 25:100. [PMID: 40327201 PMCID: PMC12055895 DOI: 10.1007/s10142-025-01601-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 04/01/2025] [Accepted: 04/12/2025] [Indexed: 05/07/2025]
Abstract
More than two decades ago, MD Anderson Cancer group discovered, characterised, and identified the WW domain-containing oxidoreductase (WWOX) as a genes of interest mapping to the chromosomal region 16q23.3-24.2. This was pioneering research since WWOX is a critical tumour suppressor gene implicated in various cancers, involving interactions with numerous signalling pathways and molecular mechanisms. Notably, it inhibits the Wnt/β-catenin pathway, which is often activated in tumours. This inhibition helps prevent tumour formation by regulating cell proliferation and promoting apoptosis. Restoration of WWOX expression in cancer cell lines has been shown to reduce tumour growth and increased sensitivity to treatments. In addition to its role in tumour suppression, WWOX has been found to interact with proteins involved in critical signalling pathways such as TGF-β. Recent advancements allowed to reveal its interactions with key proteins and microRNAs that regulate cellular adhesion, invasion, and motility. Proteomic studies have shown that WWOX directly interacts with signalling molecules like Dishevelled and SMAD3, further underscoring its role in antagonizing metastasis. Challenges remain in translating this knowledge into clinical applications. For instance, the mechanisms underlying WWOX loss in tumours and its role across diverse cancer types require further investigation. Overall, WWOX serves as a vital player in maintaining cellular stability and preventing cancer progression through its multifaceted functions. Here, we include an updated molecular function of WWOX in cancers to possibly contribute to the potential use of WWOX expression as a biomarker regarding prognosis and response to the treatment. CLINICAL TRIAL NUMBER: Not applicable.
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Affiliation(s)
- Raneem Y Hammouz
- Department of Molecular Carcinogenesis, Medical University of Lodz, Żeligowskiego 7/9, Lodz, 90-752, Poland
| | - Izabela Baryła
- Department of Molecular Carcinogenesis, Medical University of Lodz, Żeligowskiego 7/9, Lodz, 90-752, Poland
| | - Ewa Styczeń-Binkowska
- Department of Molecular Carcinogenesis, Medical University of Lodz, Żeligowskiego 7/9, Lodz, 90-752, Poland
| | - Andrzej K Bednarek
- Department of Molecular Carcinogenesis, Medical University of Lodz, Żeligowskiego 7/9, Lodz, 90-752, Poland.
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Saadh MJ, Ghnim ZS, Mahdi MS, Mandaliya V, Ballal S, Bareja L, Chaudhary K, Sharma R, Gupta S, Taher WM, Alwan M, Jawad MJ, Hamad AK. The emerging role of kinesin superfamily proteins in Wnt/β-catenin signaling: Implications for cancer. Pathol Res Pract 2025; 269:155904. [PMID: 40073645 DOI: 10.1016/j.prp.2025.155904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 02/27/2025] [Accepted: 03/06/2025] [Indexed: 03/14/2025]
Abstract
Cellular processes such as proliferation, differentiation, and tissue homeostasis are significantly influenced by the Wnt/β-catenin signaling pathway. Dysregulation of this pathway has been implicated in the development of various types of cancer. This study focuses on the emerging role of kinesin superfamily proteins (KIFs) in modulating cancer signaling. KIFs, a group of motor proteins, have attracted attention for their dual roles in intracellular transport: facilitating the cellular entry of Wnt ligands and contributing to the assembly of the β-catenin destruction complex. The study explores the interactions between KIFs and the Wnt/β-catenin pathway, identifying specific KIFs that interact with key components of the signaling cascade and examining their roles in cancer progression. Furthermore, it evaluates therapeutic strategies targeting KIFs to suppress aberrant Wnt activity in cancer and investigates how KIF-mediated transport spatially and temporally regulates Wnt signaling. The insights provided could guide future research into the role of KIFs in cancer biology and their involvement in oncogenic signaling pathways.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan.
| | | | | | - Viralkumar Mandaliya
- Marwadi University Research Center, Department of Microbiology, Faculty of Science Marwadi University, Rajkot, Gujarat 360003, India
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Lakshay Bareja
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab 140401, India
| | - Kamlesh Chaudhary
- Department of Neurology, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India
| | - Rsk Sharma
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh 531162, India
| | - Sofia Gupta
- Department of Applied Sciences, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab 140307, India
| | - Waam Mohammed Taher
- College of Nursing, National University of Science and Technology, Dhi Qar, Iraq
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Tang Y, Yuan F, Cao M, Ren Y, Li Y, Yang G, Zhong Z, Liang H, Xiong Z, He Z, Lin N, Deng M, Yao Z. CircRNA-mTOR Promotes Hepatocellular Carcinoma Progression and Lenvatinib Resistance Through the PSIP1/c-Myc Axis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2410591. [PMID: 40231634 PMCID: PMC12120768 DOI: 10.1002/advs.202410591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 11/26/2024] [Indexed: 04/16/2025]
Abstract
Circular RNAs (circRNAs) are crucial regulators of targeted drug resistance in hepatocellular carcinoma (HCC). However, the specific mechanisms underlying resistance that significantly hampers the effectiveness of HCC treatments remain unclear. Here, it is found that circRNA-mTOR is highly expressed in HCC and strongly correlated with patient prognosis. Furthermore, circRNA-mTOR enhances the stemness of HCC cells, thereby promoting the progression of HCC and contributing to lenvatinib resistance. Mechanistically, circRNA-mTOR promotes the nuclear translocation of the RNA-binding protein (RBP) PC4 and SRSF1 interacting protein 1 (PSIP1) through specific binding. The enhancement of HCC cell stemness by circRNA-mTOR occurs via the PSIP1/c-Myc signaling pathway, ultimately driving HCC progression and lenvatinib resistance. This study highlights the important role of circRNA-mTOR in HCC progression and the maintenance of lenvatinib resistance and underscores its potential as a biomarker for the diagnosis and prognosis of HCC. In conclusion, this study provides an experimental foundation for targeted drug therapy in HCC and offers novel insights, perspectives, and methodologies for understanding the development and occurrence of this disease. These findings are significant for the development of new diagnostic and therapeutic markers for HCC, with the ultimate goal of reducing drug resistance.
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Affiliation(s)
- Yongchang Tang
- Department of Hepatobiliary SurgeryThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
- Department of General SurgeryQilu HospitalShandong UniversityJinan250012China
| | - Feng Yuan
- Department of Hepatobiliary SurgeryThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
- Department of Hepatobiliary SurgeryThe First Affiliated HospitalGuangzhou Medical UniversityGuangzhou510120China
| | - Mingbo Cao
- Department of Hepatobiliary SurgeryThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
| | - Yupeng Ren
- Department of Hepatobiliary SurgeryThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
| | - Yuxuan Li
- Department of Hepatobiliary SurgeryThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
| | - Gaoyuan Yang
- Department of Hepatobiliary SurgeryThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
| | - Zhaozhong Zhong
- Department of Hepatobiliary SurgeryThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
- Department of Kidney TransplantationThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
| | - Hao Liang
- Department of Hepatobiliary and Pancreatic SurgeryThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
| | - Zhiyong Xiong
- Department of Hepatobiliary and Pancreatic SurgeryThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
| | - Zhiwei He
- Department of Hepatobiliary SurgeryThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
| | - Nan Lin
- Department of Hepatobiliary SurgeryThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
| | - Meihai Deng
- Department of Hepatobiliary SurgeryThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
| | - Zhicheng Yao
- Department of Hepatobiliary and Pancreatic SurgeryThe Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
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Zhou Z, Gu Y, Yi Z, Wang J, Xiong Z, Guo H, Du Y, Zhu X, He L, Ren W, Tian Y, Wang Y, Fan Z. SNORA74A Drives Self-Renewal of Liver Cancer Stem Cells and Hepatocarcinogenesis Through Activation of Notch3 Signaling. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2504054. [PMID: 40270470 DOI: 10.1002/advs.202504054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Indexed: 04/25/2025]
Abstract
Liver cancer stem cells (CSCs) account for tumor initiation, heterogeneity and therapy resistance. However, the role of small nucleolar RNAs (snoRNAs) in the regulation of liver CSCs remains largely unclear. Here, this work identifies a conserved H/ACA box snoRNA SNORA74A which is highly expressed in liver CSCs. SNORA74A deletion impaired the self-renewal of liver CSCs and suppressed hepatocarcinogenesis. Mechanistically, highly expressed SNORA74A in liver CSCs bound DCAF13 to prevent K48 linked ubiquitination of E2F2 for degradation. E2F2 induced NOTCH3 transcription to initiate Notch3 signaling activation, leading to self-renewal of liver CSCs and hepatocarcinogenesis. Moreover, expression levels of SNORA74A and NOTCH3 are positively related with severity and poor prognosis of hepatocellular carcinoma (HCC) patients. Of note, antisense oligonucleotides (ASOs) against SNORA74A showed effective efficacy for HCC tumors, suggesting SNORA74A might be a potential therapeutic target for HCC therapy by eliminating liver CSCs.
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Affiliation(s)
- Ziheng Zhou
- State Key Laboratory of RNA Science and Engineering, State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yang Gu
- State Key Laboratory of RNA Science and Engineering, State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Zhibin Yi
- State Key Laboratory of RNA Science and Engineering, State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jianyi Wang
- State Key Laboratory of RNA Science and Engineering, State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhen Xiong
- State Key Laboratory of RNA Science and Engineering, State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Hui Guo
- State Key Laboratory of RNA Science and Engineering, State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Ying Du
- State Key Laboratory of RNA Science and Engineering, State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Xiaoxiao Zhu
- State Key Laboratory of RNA Science and Engineering, State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Lei He
- Department of Hepatobiliary Surgery, PLA General Hospital, Beijing, 100853, China
| | - Weizheng Ren
- Department of Hepatobiliary Surgery, PLA General Hospital, Beijing, 100853, China
| | - Yong Tian
- State Key Laboratory of RNA Science and Engineering, State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yanying Wang
- Ministry of Education Key Laboratory of Cell Proliferation and Regulation Biology, Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing, 100875, China
| | - Zusen Fan
- State Key Laboratory of RNA Science and Engineering, State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
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6
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Wang Y, Gao H, Li X, Li D, Huang F, Sun Y, Liu X, Yang J, Sun F. PRC1 as an independent adverse prognostic factor in Wilms tumor via integrated bioinformatics and experimental validation. Sci Rep 2025; 15:13282. [PMID: 40247060 PMCID: PMC12006549 DOI: 10.1038/s41598-025-98030-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 04/09/2025] [Indexed: 04/19/2025] Open
Abstract
Wilms Tumor (WT), a prevalent pediatric renal malignancy, exhibits marked heterogeneity and variable clinical outcomes. Epithelial-mesenchymal transition (EMT), a biological process enabling epithelial cells to acquire mesenchymal traits associated with enhanced migratory and invasive capacities, plays a crucial role in cancer progression. Protein Regulator of Cytokinesis 1 (PRC1) is a critical protein in cell division, whose overexpression is linked to poor prognosis in various cancers. This study investigates the role of PRC1 as a key prognostic factor in WT and explore the mechanism through comprehensive bioinformatic and experimental approaches. Through bulk RNA-seq data from the TARGET database, we identified PRC1 as significantly up-regulated in WT and associated with poor overall survival. Functional enrichment analyses (GO, KEGG, GSEA) demonstrated PRC1's involvement in cell division, chromatin dynamics, and activation of oncogenic pathways including Wnt/β-catenin, PI3K/AKT/mTOR, and Hedgehog signaling. Immunological analysis showed that elevated PRC1 expression correlates with diminished immune cell activity, particularly in NK cells, suggesting potential immune evasion mechanisms. Single-cell RNA-seq analysis (GSE200256) confirmed PRC1's elevated expression in anaplastic Wilms tumor (AWT) compared to favorable Wilms tumor (FWT), and highlighted its involvement in intercellular communication and metastasis via the EMT process. Genomic analyses identified copy number variations (CNVs) and downregulated PRC1-targeting microRNAs as drivers of its overexpression. In vitro, PRC1 knockdown in WIT-49 cells significantly impaired migratory capacity, invasive potential, EMT progression, and glycolytic metabolism. These findings collectively position PRC1 as a promising therapeutic target and prognostic biomarker in WT.
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Affiliation(s)
- Yanping Wang
- Department of Pediatric Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Hongjie Gao
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China
| | - Xuetian Li
- Department of Pediatric Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Ding Li
- Department of Pediatric Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Fan Huang
- Department of Pediatric Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Yuqiang Sun
- Department of Pediatric Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Xingjian Liu
- Department of Pediatric Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Junli Yang
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China.
| | - Fengyin Sun
- Department of Pediatric Surgery, Qilu Hospital of Shandong University, Jinan, China.
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7
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Xu Y, Xu J, Xu K, Zhang C, Wang F, Zhang R, Zhu P. PRC1 promotes ovarian cancer progression by binding to RPL4 and increasing MDM2-mediated p53 ubiquitination. Exp Cell Res 2025; 447:114509. [PMID: 40089132 DOI: 10.1016/j.yexcr.2025.114509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 02/26/2025] [Accepted: 03/06/2025] [Indexed: 03/17/2025]
Abstract
Ovarian cancer (OC) is one of the most fatal gynecological carcinomas, causing significant detriment to women's health. Protein regulator of cytokinesis 1 (PRC1) is a microtubule-associated protein that is found to be highly expressed in many different cancers. Despite this, the exact way in which PRC1 stimulates the growth of OC has yet to be completely understood. Our research demonstrated that PRC1 expression was increased in OC, which was closely related to poor prognosis. Moreover, PRC1 exhibited noteworthy efficacy in enhancing the proliferation and migration capacities of OC cells, as well as affecting the cell cycle in OC cells. Silencing PRC1 significantly suppressed OC growth in vivo. Mechanically, PRC1 could interact with RPL4, which caused a decrease in RPL4/MDM2 complex formation, resulting in the enhanced ubiquitination of p53 and a reduction of p53 proteins. These findings revealed that PRC1 was involved in the RPL4-MDM2-p53 pathway thus playing a tumorigenic role on OC.
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Affiliation(s)
- Yinyin Xu
- The Third Affiliated Hospital, Southern Medical University, Guangzhou, China; Department of Obstetrics and Gynecology, Shanghai Fengxian District Central Hospital, Shanghai, China
| | - Jiaxing Xu
- The Third Affiliated Hospital, Southern Medical University, Guangzhou, China; Department of Obstetrics and Gynecology, Shanghai Fengxian District Central Hospital, Shanghai, China
| | - Kai Xu
- Department of Gynecological Oncology, Zhongshan Hospital, Fudan University School of Medicine, Shanghai, China
| | - Cancan Zhang
- Department of Obstetrics and Gynecology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fengmian Wang
- Department of Obstetrics and Gynecology, Shanghai Fengxian District Central Hospital, Shanghai, China
| | - Rong Zhang
- The Third Affiliated Hospital, Southern Medical University, Guangzhou, China; Department of Obstetrics and Gynecology, Shanghai Fengxian District Central Hospital, Shanghai, China; Department of Gynecological Oncology, Shanghai Geriatric Medical Center, Shanghai, China.
| | - Pengfeng Zhu
- Department of Gynecological Oncology, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, China.
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Zheng W, Zhou C, Xue Z, Qiao L, Wang J, Lu F. Integrative analysis of a novel signature incorporating metabolism and stemness-related genes for risk stratification and assessing clinical outcomes and therapeutic responses in lung adenocarcinoma. BMC Cancer 2025; 25:591. [PMID: 40170009 PMCID: PMC11963273 DOI: 10.1186/s12885-025-13984-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 03/20/2025] [Indexed: 04/03/2025] Open
Abstract
BACKGROUND Metabolism and stemness-related genes (msRGs) are critical in the development and progression of lung adenocarcinoma (LUAD). Nevertheless, reliable prognostic risk signatures derived from msRGs have yet to be established. METHODS In this study, we downloaded and analyzed RNA-sequencing and clinical data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. We employed univariate and multivariate Cox regression analyses, along with least absolute shrinkage and selection operator (LASSO) regression analysis, to identify msRGs that are linked to the prognosis of LUAD and to develop the prognostic risk signature. The prognostic value was evaluated using Kaplan-Meier analysis and log-rank tests. We generated receiver operating characteristic (ROC) curves to evaluate the predictive capability of the prognostic signature. To estimate the relative proportions of infiltrating immune cells, we utilized the CIBERSORT algorithm and the MCPCOUNTER method. The prediction of the half-maximal inhibitory concentration (IC50) for commonly used chemotherapy drugs was conducted through ridge regression employing the "pRRophetic" R package. The validation of our analytical findings was performed through both in vivo and in vitro studies. RESULTS A novel five-gene prognostic risk signature consisting of S100P, GPX2, PRC1, ARNTL2, and RGS20 was developed based on the msRGs. A risk score derived from this gene signature was utilized to stratify LUAD patients into high- and low-risk groups, with the former exhibiting significantly poorer overall survival (OS). A nomogram was constructed incorporating the risk score and other clinical characteristics, showcasing strong capabilities in estimating the OS rates for LUAD patients. Furthermore, we observed notable differences in the infiltration of various immune cell subtypes, as well as in responses to immunotherapy and chemotherapy, between the low-risk and high-risk groups. Results from gene set enrichment analysis (GSEA) and in vitro studies indicated that the prognostic signature gene ARNTL2 influenced the prognosis of LUAD patients, primarily through the activation of the PI3K/AKT/mTOR signaling pathway. CONCLUSIONS Utilizing this gene signature for risk stratification could help with clinical treatment management and improve the prognosis of LUAD patients.
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Affiliation(s)
- Wanrong Zheng
- Department of Medical Oncology, Huaihe Hospital of Henan University, Kaifeng, China
| | - Chuchu Zhou
- Department of Immunology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Zixin Xue
- Department of Immunology, School of Basic Medical Sciences, Henan University, Kaifeng, China
- Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Ling Qiao
- Department of Immunology, School of Basic Medical Sciences, Henan University, Kaifeng, China
| | - Jianjun Wang
- Department of Medical Oncology, Huaihe Hospital of Henan University, Kaifeng, China
| | - Feng Lu
- Department of Immunology, School of Basic Medical Sciences, Henan University, Kaifeng, China.
- Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China.
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9
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Saadh MJ, Ahmed HH, Kareem RA, Chandra M, Monsi M, Walia C, Prasad GVS, Taher WM, Alwan M, Jawad MJ, Hamad AK. From Motor Proteins to Oncogenic Factors: The Evolving Role of Kinesin Superfamily Proteins in Breast Cancer Development. Mol Biotechnol 2025:10.1007/s12033-025-01428-2. [PMID: 40146390 DOI: 10.1007/s12033-025-01428-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 02/24/2025] [Indexed: 03/28/2025]
Abstract
The kinesin family of proteins (KIFs), known for their role as motor proteins, is integral to transporting cargo within cells along microtubule tracks, which is crucial for processes, such as cell division, differentiation, and intracellular communication. Increasing evidence shows that specific KIFs are overexpressed in breast cancer, a change linked to higher tumor aggression and poorer outcomes in patients. KIFs contribute to the cancerous characteristics of breast tumor cells through several mechanisms, including disruptions in spindle assembly during cell division, altered cell motility, and accelerated proliferation. This review summarizes current insights into KIFs' functions in breast cancer pathology and assesses their viability as therapeutic targets. By unraveling the complex involvement of KIFs, the article aims to open pathways for new therapeutic approaches in breast cancer and to promote further study into the cellular pathways that these proteins regulate.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan.
| | | | | | - Muktesh Chandra
- Department of Microbiology, Faculty of Science, Marwadi University Research Center, Marwadi University, Rajkot, Gujarat, 360003, India
| | - Mekha Monsi
- Department of Pharmacy Practice, NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, 302131, India
| | - Chakshu Walia
- Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab, 140307, India
| | - G V Siva Prasad
- Department of Basic Sciences and Humanities, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, 531162, India
| | - Waam Mohammed Taher
- College of Nursing, National University of Science and Technology, Nasiriyah, Dhi Qar, Iraq
| | - Mariem Alwan
- Pharmacy College, Al-Farahidi University, Baghdad, Iraq
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10
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Li B, Pan Y, Wu J, Miao C, Wang Z. Large-scale genomic-wide CRISPR screening revealed PRC1 as a tumor essential candidate in clear cell renal cell carcinoma. Int J Med Sci 2025; 22:1658-1671. [PMID: 40093809 PMCID: PMC11905274 DOI: 10.7150/ijms.107691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 02/06/2025] [Indexed: 03/19/2025] Open
Abstract
Background: Clear cell renal cell carcinoma (ccRCC) is a prevalent and aggressive subtype of kidney cancer, often associated with metastasis and recurrence. Identifying key genes involved in ccRCC progression is critical for improving treatment strategies and patient outcomes. Methods: We performed a large-scale genome-wide CRISPR screening to identify genes crucial to ccRCC progression using the DepMap database. For discovery and validation, we integrated multi-omics data from The Cancer Genome Atlas (TCGA), GEO, and the NJMU-ccRCC clinical cohort. Bioinformatics analyses, including differential expression, pathway enrichment, and protein-protein interaction network analysis, were conducted to elucidate the biological functions. To validate our findings, we employed immunohistochemistry, qRT-PCR, and various cellular assays to investigate the role of PRC1 in ccRCC. Results: CRISPR screening identified PRC1 as a key gene significantly overexpressed in ccRCC tissues from the DepMap database. Elevated PRC1 expression was associated with poor overall survival, disease-specific survival, and progression-free interval. Silencing PRC1 in ccRCC cell lines inhibited cell proliferation, migration, and colony formation. Functional enrichment analyses revealed that PRC1 is involved in essential processes such as cell cycle regulation, mitosis, and cytokinesis. Additionally, PRC1 expression was correlated with the activation of the Wnt/β-catenin pathway, suggesting that PRC1 plays a pivotal role in tumor progression. Conclusion: PRC1 emerges as a promising biomarker and therapeutic target for ccRCC. Elevated PRC1 expression is associated with poor prognosis, and its inhibition suppresses ccRCC cell proliferation and migration. Our findings underscore the crucial role of PRC1 in ccRCC progression and highlight the need for further investigation into its molecular mechanisms and therapeutic potential.
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Affiliation(s)
| | | | - Jiajin Wu
- Department of Urology, First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, Jiangsu Province 210029, China
| | - Chenkui Miao
- Department of Urology, First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, Jiangsu Province 210029, China
| | - Zengjun Wang
- Department of Urology, First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, Jiangsu Province 210029, China
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11
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Jiang H, Jin X, Gu H, Li B, Li Z, Sun Y. SPC25 upregulates CCND1 to promote the progression of esophageal squamous cell carcinoma by inhibiting MDM2-mediated E2F1 ubiquitination. Transl Oncol 2025; 53:102300. [PMID: 39919356 PMCID: PMC11849203 DOI: 10.1016/j.tranon.2025.102300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 01/24/2025] [Accepted: 01/28/2025] [Indexed: 02/09/2025] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is highly malignant worldwide. Despite significant advances in the treatment of ESCC, the prognosis remains unfavourable, necessitating research into its mechanisms and treatments. Spindle component 25 (SPC25) can ensure the fidelity of mitotic progression and the accurate segregation of chromosomes, thus plays an important role in the development of malignant tumors, but its role in ESCC is yet to be determined. In this study, the expression of SPC25 was assessed by IHC in 88 primary ESCC samples, with its expression being correlated with advanced clinical features. The function of SPC25 in the proliferation, migration and tumorigenicity of ESCC cells was verified in vitro and in vivo. Mechanistically, SPC25 facilitated tumorigenesis through promoting CCND1 expression. As the transcription factor for CCND1, E2F1 is stabilized by SPC25 through binding the ubiquitin ligase MDM2, resulting in enhanced E2F1 expression, which in turn promotes the expression of CCND1. In addition, overexpression of CCND1 counteracted the effects of SPC25 silencing. Collectively, we demonstrated that the aberrant expression of SPC25 inhibited E2F1 ubiquitination and promoted CCND1 expression, thus accelerating the progression of ESCC. These findings propose novel insights into the role of SPC25 in ESCC and provide potential therapeutic strategies for targeting SPC25 in ESCC patients.
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Affiliation(s)
- Haoyao Jiang
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, PR China
| | - Xiangfeng Jin
- Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, PR China
| | - Haiyong Gu
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, PR China
| | - Bin Li
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, PR China
| | - Zhigang Li
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, PR China.
| | - Yifeng Sun
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, PR China.
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Peled A, Abraham M, Wald H, Hay O, Hagbi S, Gamaev L, Monin J, Borthakur G, Ayoub E, Andreeff M, Rosenfeld R, Eizenberg O, Aharon A. BKT300: A Novel Anti-Leukemic Small Molecule Targeting the Protein Regulator of Cytokinesis 1 (PRC1) Pathway. RESEARCH SQUARE 2025:rs.3.rs-6017610. [PMID: 40034437 PMCID: PMC11875301 DOI: 10.21203/rs.3.rs-6017610/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Protein regulator of cytokinesis 1 (PRC1) is frequently overexpressed in various cancers and is associated with poor prognosis. BKT300 is a small molecule shown to selectively inhibit leukemic cell migration and survival by targeting the PRC1 pathways. The current work aimed to examine the role of PRC1 in acute myeloid leukemia (AML) and to assess the impact of BKT300, a small molecule PRC1 inhibitor, on AML cell viability and tumor growth in mouse xenograft AML models. BKT300 directly bound PRC1, resulting in disrupted actin and microtubule formation, G2/M cell cycle arrest, mitotic catastrophe and apoptosis via the caspase-3 pathway in AML cells. BKT300 inhibited PRC1 dephosphorylation at T481, downregulated CDC25C and upregulated p21, effectively halting the cell cycle and inhibiting leukemic cell proliferation while sparing normal cells. PRC1 was found to be overexpressed in AML patients and cell lines, with high levels associated with reduced overall patient survival. In addition, PRC1 expression levels correlated with BKT300 efficacy. BKT300 treatment led to 98% of tumor growth inhibition and 89.4% of tumor regression in mouse xenograft AML models, without notable impacts on normal hematopoiesis or biochemistry, even at high doses. As a first-in-class targeted therapy, BKT300 presents a promising new treatment option for advanced AML.
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13
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Wu Z, Li C, Zhang S, Sun L, Hu J, Qiu B, Liu S, Hong Y, Chen T, Wang K, Yin X, Yan J. High interstitial fluid pressure enhances USP1-dependent KIF11 protein stability to promote hepatocellular carcinoma progression. J Transl Med 2025; 23:66. [PMID: 39810156 PMCID: PMC11730827 DOI: 10.1186/s12967-025-06124-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 01/08/2025] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND HCC is characterized by a high interstitial fluid pressure (HIFP) environment, which appears to support cancer cell survival. However, the mechanisms behind this phenomenon are not fully understood. METHODS This study investigates the role of kinesin family member 11 (KIF11) in HCC under HIFP conditions, using both in vivo and in vitro models. In vitro experiments replicated the HIFP environment to observe changes in HCC cell behavior and protein expression, while in vivo studies involved mice portal hypertension to create an orthotopic liver cancer model, allowing for the evaluation of tumor progression. Additionally, clinical samples from HCC patients were analyzed for consistency with the experimental findings. RESULTS Results demonstrated that the HIFP environment significantly increased the proliferation, invasion, and metastasis in HCC cells. Omics analysis and subsequent molecular validation revealed that KIF11 protein levels were markedly upregulated under HIFP, despite no significant change in mRNA levels. Further investigation showed that this upregulation was linked to a reduction in KIF11's ubiquitin-mediated degradation, suggesting that the HIFP environment stabilizes KIF11 expression by inhibiting its degradation pathway. Co-immunoprecipitation and proteomic analysis identified ubiquitin-specific peptidase 1 (USP1) as a crucial factor in this process, deubiquitinating KIF11 at the K77 site, thus stabilizing its protein levels. Clinical analysis confirmed that both USP1 and KIF11 were significantly overexpressed in HCC patients with portal hypertension, with a strong correlation between the two. Inhibition of USP1 using ML323 significantly reduced KIF11 protein levels and suppressed tumor progression in the mouse model. CONCLUSION These findings suggest that the HIFP environment fosters HCC progression through USP1-mediated stabilization of KIF11, highlighting USP1 as a potential therapeutic target, especially in patients with portal hypertension.
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Affiliation(s)
- Zhengyi Wu
- Department of General Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1, Minde Road, Nanchang, 330006, Jiangxi, China
- Jiangxi Provincial Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, No.1, Minde Road, Nanchang, 330006, Jiangxi, China
| | - Chao Li
- Department of General Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1, Minde Road, Nanchang, 330006, Jiangxi, China
- Jiangxi Provincial Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, No.1, Minde Road, Nanchang, 330006, Jiangxi, China
| | - Shouhua Zhang
- Department of General Surgery, Jiangxi Provincial Children's Hospital, The Affiliated Children's Hospital of Nanchang Medical College, 122 Yangming Road, Nanchang, 330006, Jiangxi, China
| | - Liang Sun
- Department of General Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1, Minde Road, Nanchang, 330006, Jiangxi, China
| | - Junwen Hu
- Department of General Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1, Minde Road, Nanchang, 330006, Jiangxi, China
| | - Bingbing Qiu
- Department of General Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1, Minde Road, Nanchang, 330006, Jiangxi, China
| | - Shuiqiu Liu
- Department of General Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1, Minde Road, Nanchang, 330006, Jiangxi, China
| | - Yiran Hong
- Department of General Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1, Minde Road, Nanchang, 330006, Jiangxi, China
| | - Tianxiang Chen
- Department of General Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1, Minde Road, Nanchang, 330006, Jiangxi, China
| | - Kai Wang
- Department of General Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1, Minde Road, Nanchang, 330006, Jiangxi, China.
| | - Xiangbao Yin
- Department of General Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1, Minde Road, Nanchang, 330006, Jiangxi, China.
| | - Jinlong Yan
- Department of General Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No.1, Minde Road, Nanchang, 330006, Jiangxi, China.
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Huang LH, Wu SC, Liu YW, Liu HT, Chien PC, Lin HP, Wu CJ, Hsieh TM, Hsieh CH. Identification of Crucial Cancer Stem Cell Genes Linked to Immune Cell Infiltration and Survival in Hepatocellular Carcinoma. Int J Mol Sci 2024; 25:11969. [PMID: 39596041 PMCID: PMC11593742 DOI: 10.3390/ijms252211969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 11/01/2024] [Accepted: 11/01/2024] [Indexed: 11/28/2024] Open
Abstract
Hepatocellular carcinoma is characterized by high recurrence rates and poor prognosis. Cancer stem cells contribute to tumor heterogeneity, treatment resistance, and recurrence. This study aims to identify key genes associated with stemness and immune cell infiltration in HCC. We analyzed RNA sequencing data from The Cancer Genome Atlas to calculate mRNA expression-based stemness index in HCC. A weighted gene co-expression network analysis was performed to identify stemness-related gene modules. A single-sample gene set enrichment analysis was used to evaluate immune cell infiltration. Key genes were validated using RT-qPCR. The mRNAsi was significantly higher in HCC tissues compared to adjacent normal tissues and correlated with poor overall survival. WGCNA and subsequent analyses identified 10 key genes, including minichromosome maintenance complex component 2, cell division cycle 6, forkhead box M1, NIMA-related kinase 2, Holliday junction recognition protein, DNA topoisomerase II alpha, denticleless E3 ubiquitin protein ligase homolog, maternal embryonic leucine zipper kinase, protein regulator of cytokinesis 1, and kinesin family member C1, associated with stemness and low immune cell infiltration. These genes were significantly upregulated in HCC tissues. A functional enrichment analysis revealed their involvement in cell cycle regulation. This study identified 10 key genes related to stemness and immune cell infiltration in HCC. These genes, primarily involved in cell cycle regulation, may serve as potential targets for developing more effective treatments to reduce HCC recurrence and improve patient outcomes.
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Affiliation(s)
- Lien-Hung Huang
- Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; (L.-H.H.); (P.-C.C.); (H.-P.L.); (C.-J.W.)
| | - Shao-Chun Wu
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan;
| | - Yueh-Wei Liu
- Department of General Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan;
| | - Hang-Tsung Liu
- Department of Trauma Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan;
| | - Peng-Chen Chien
- Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; (L.-H.H.); (P.-C.C.); (H.-P.L.); (C.-J.W.)
| | - Hui-Ping Lin
- Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; (L.-H.H.); (P.-C.C.); (H.-P.L.); (C.-J.W.)
| | - Chia-Jung Wu
- Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; (L.-H.H.); (P.-C.C.); (H.-P.L.); (C.-J.W.)
| | - Ting-Min Hsieh
- Department of Trauma Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan;
| | - Ching-Hua Hsieh
- Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; (L.-H.H.); (P.-C.C.); (H.-P.L.); (C.-J.W.)
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15
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Lee H, Bae AN, Yang H, Lee JH, Park JH. Modulation of PRC1 Promotes Anticancer Effects in Pancreatic Cancer. Cancers (Basel) 2024; 16:3310. [PMID: 39409930 PMCID: PMC11475828 DOI: 10.3390/cancers16193310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 09/11/2024] [Accepted: 09/25/2024] [Indexed: 10/20/2024] Open
Abstract
Background: Pancreatic cancer, while relatively uncommon, is extrapolated to become the second leading cause of cancer-related deaths worldwide. Despite identifying well-known markers like the KRAS gene, the exact regulation of pancreatic cancer progression remains elusive. Methods: Clinical value of PRC1 was analyzed using bioinformatics database. The role of PRC1 was further evaluated through cell-based assays, including viability, wound healing, and sensitivity with the drug. Results: We demonstrate that PRC1 was significantly overexpressed in pancreatic cancer compared to pancreases without cancer, as revealed through human databases and cell lines analysis. Furthermore, high PRC1 expression had a negative correlation with CD4+ T cells, which are crucial for the immune response against cancers. Additionally, PRC1 showed a positive correlation with established pancreatic cancer markers. Silencing PRC1 expression using siRNA significantly inhibited cancer cell proliferation and viability and increased chemotherapeutic drug sensitivity. Conclusions: These findings suggest that targeting PRC1 in pancreatic cancer may enhance immune cell infiltration and inhibit cancer cell proliferation, offering a promising avenue for developing anticancer therapies.
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Affiliation(s)
| | | | | | | | - Jong Ho Park
- Department of Anatomy, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea
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16
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Zhu Y, Li Z, Wu Z, Zhuo T, Dai L, Liang G, Peng H, Lu H, Wang Y. MIS18A upregulation promotes cell viability, migration and tumor immune evasion in lung adenocarcinoma. Oncol Lett 2024; 28:376. [PMID: 38910901 PMCID: PMC11190817 DOI: 10.3892/ol.2024.14509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Accepted: 05/13/2024] [Indexed: 06/25/2024] Open
Abstract
Lung adenocarcinoma (LUAD) presents a significant global health challenge owing to its poor prognosis and high mortality rates. Despite its involvement in the initiation and progression of a number of cancer types, the understanding of the precise impact of MIS18 kinetochore protein A (MIS18A) on LUAD remains incomplete. In the present study, the role of MIS18A in LUAD was investigated by analyzing the genomic and clinical data from multiple public datasets. The expression of MIS18A was validated using reverse transcription-quantitative polymerase chain reaction, and in vitro experiments involving small interfering RNA-induced downregulation of MIS18A in lung cancer cells were conducted to further explore its impact. These findings revealed that elevated MIS18A expression in LUAD was associated with advanced clinical features and poor prognosis. Functional analysis also revealed the role of MIS18A in regulating the cell cycle and immune-related pathways. Moreover, MIS18A altered the immune microenvironment in LUAD, influencing its response to immunotherapy and drug sensitivity. The results of the in vitro experiments indicated that suppression of MIS18A expression reduced the proliferative and migratory capacities of LUAD cells. In summary, MIS18A possesses potential as a biomarker and may serve as a possible therapeutic target for LUAD, with significant implications for tumor progression by influencing both cell cycle dynamics and immune infiltration.
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Affiliation(s)
- Yongjie Zhu
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Zihao Li
- Department of Thoracic Surgery, Liuzhou People's Hospital Affiliated to Guangxi Medical University, Liuzhou, Guangxi Zhuang Autonomous Region 545026, P.R. China
| | - Zuotao Wu
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Ting Zhuo
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Lei Dai
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Guanbiao Liang
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Huajian Peng
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Honglin Lu
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yongyong Wang
- Department of Cardio-Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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17
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Zhuang R, Liu H. Mechanism of regulation of KIF23 on endometrial cancer cell growth and apoptosis. Discov Oncol 2024; 15:83. [PMID: 38514510 PMCID: PMC10957832 DOI: 10.1007/s12672-024-00937-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 03/14/2024] [Indexed: 03/23/2024] Open
Abstract
OBJECTIVE The global incidence of endometrial cancer, a malignant tumor in females, is on the rise. It is one of the most common gynecological cancers. Early-stage endometrial cancers can often be treated successfully with uterine extirpation. However, those diagnosed at a later stage have a poor prognosis and encounter treatment challenges. Therefore, additional research is necessary to develop primary prevention strategies for high-risk women and improve survival rates among patients with endometrial cancer. Hence, gene therapy targeting KIF23 shows promise as an advanced strategy for the treatment of endometrial cancer. METHODS Immunohistochemistry, Western blotting, and PCR were used to examine the expression of KIF23 and its associated pathway factors in endometrial cancer tissue (specifically Ishikawa and SNGM cells, respectively). We investigated the functional roles of KIF23 using CCK-8, colony-forming proliferation assays, Transwell migration assays, and xenotransplantation in mice. RESULTS Immunohistochemistry analysis showed variations in the expression levels of KIF23 between endometrial cancer tissue and normal endometrium tissue. KIF23 downregulated BAX and caspase-3 protein expression while upregulating BCL-2 protein expression. Additionally, knocking out KIF23 inhibits endometrial cancer cell proliferation and migration while promoting cell death. Mechanistically, our study provides evidence that KIF23 promotes endometrial cancer cell proliferation by activating the ERK and AKT/PI3K pathways, while simultaneously inhibiting programmed cell death in endometrial cancer. CONCLUSION Our study provides evidence to support the inhibition of endometrial cancer by KIF23 knockdown. This offers valuable insights for future research on potential therapeutic strategies for this type of cancer.
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Affiliation(s)
- Ruiying Zhuang
- Jinzhou Medical University, Jinzhou, Liaoning Province, China
| | - Haiyan Liu
- The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning Province, China.
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Zhao K, Li X, Feng Y, Wang J, Yao W. The role of kinesin family members in hepatobiliary carcinomas: from bench to bedside. Biomark Res 2024; 12:30. [PMID: 38433242 PMCID: PMC10910842 DOI: 10.1186/s40364-024-00559-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 01/03/2024] [Indexed: 03/05/2024] Open
Abstract
As a major component of the digestive system malignancies, tumors originating from the hepatic and biliary ducts seriously endanger public health. The kinesins (KIFs) are molecular motors that enable the microtubule-dependent intracellular trafficking necessary for mitosis and meiosis. Normally, the stability of KIFs is essential to maintain cell proliferation and genetic homeostasis. However, aberrant KIFs activity may destroy this dynamic stability, leading to uncontrolled cell division and tumor initiation. In this work, we have made an integral summarization of the specific roles of KIFs in hepatocellular and biliary duct carcinogenesis, referring to aberrant signal transduction and the potential for prognostic evaluation. Additionally, current clinical applications of KIFs-targeted inhibitors have also been discussed, including their efficacy advantages, relationship with drug sensitivity or resistance, the feasibility of combination chemotherapy or other targeted agents, as well as the corresponding clinical trials. In conclusion, the abnormally activated KIFs participate in the regulation of tumor progression via a diverse range of mechanisms and are closely associated with tumor prognosis. Meanwhile, KIFs-aimed inhibitors also carry out a promising tumor-targeted therapeutic strategy that deserves to be further investigated in hepatobiliary carcinoma (HBC).
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Affiliation(s)
- Kai Zhao
- Department of Biliary and Pancreatic Surgery, Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China
| | - Xiangyu Li
- Department of Thoracic Surgery Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China
| | - Yunxiang Feng
- Department of Biliary and Pancreatic Surgery, Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China
| | - Jianming Wang
- Department of Biliary and Pancreatic Surgery, Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China.
- Affiliated Tianyou Hospital, Wuhan University of Science & Technology, 430064, Wuhan, China.
| | - Wei Yao
- Department of Oncology Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China.
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19
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Wei JB, Zeng XC, Ji KR, Zhang LY, Chen XM. Identification of Key Genes and Related Drugs of Adrenocortical Carcinoma by Integrated Bioinformatics Analysis. Horm Metab Res 2023. [PMID: 38109896 DOI: 10.1055/a-2209-0771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2023]
Abstract
Adrenocortical carcinoma (ACC) is a malignant carcinoma with an extremely poor prognosis, and its pathogenesis remains to be understood to date, necessitating further investigation. This study aims to discover biomarkers and potential therapeutic agents for ACC through bioinformatics, enhancing clinical diagnosis and treatment strategies. Differentially expressed genes (DEGs) between ACC and normal adrenal cortex were screened out from the GSE19750 and GSE90713 datasets available in the GEO database. An online Venn diagram tool was utilized to identify the common DEGs between the two datasets. The identified DEGs were subjected to functional assessment, pathway enrichment, and identification of hub genes by performing the protein-protein interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The differences in the expressions of hub genes between ACC and normal adrenal cortex were validated at the GEPIA2 website, and the association of these genes with the overall patient survival was also assessed. Finally, on the QuartataWeb website, drugs related to the identified hub genes were determined. A total of 114 DEGs, 10 hub genes, and 69 known drugs that could interact with these genes were identified. The GO and KEGG analyses revealed a close association of the identified DEGs with cellular signal transduction. The 10 hub genes identified were overexpressed in ACC, in addition to being significantly associated with adverse prognosis in ACC. Three genes and the associated known drugs were identified as potential targets for ACC treatment.
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Affiliation(s)
- Jian-Bin Wei
- The Third Clinical Medical College, Fujian Medical University, Fuzhou, China
| | - Xiao-Chun Zeng
- The Third Clinical Medical College, Fujian Medical University, Fuzhou, China
| | - Kui-Rong Ji
- Department of Endocrinology, Zhongshan Hospital Xiamen University, Xiamen, China
| | - Ling-Yi Zhang
- Department of Endocrinology, Zhongshan Hospital Xiamen University, Xiamen, China
| | - Xiao-Min Chen
- Department of Endocrinology, Zhongshan Hospital Xiamen University, Xiamen, China
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20
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Wang Y, Yao N, Sun J. Upregulation of miR-194-5p or silencing of PRC1 enhances radiotherapy sensitivity in esophageal squamous carcinoma cells. Heliyon 2023; 9:e22282. [PMID: 38046164 PMCID: PMC10686870 DOI: 10.1016/j.heliyon.2023.e22282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 11/08/2023] [Accepted: 11/08/2023] [Indexed: 12/05/2023] Open
Abstract
Background To investigate the possible molecular mechanism of miR-194-5p/PRC1/Wnt/β-catenin signaling axis that regulates the invasive metastatic ability and radiotherapy sensitivity of esophageal squamous cell carcinoma (ESCC) cells. Methods ESCC-related differentially expressed miRNAs were identified by microarray analysis, followed by the identification of a putative target. The targeting relationship between miR-194-5p and PRC1 was assayed. A series of mimic and shRNA were transfected into ESCC cells to find out the mechanism of miR-194-5p in ESCC by regulating PRC1 through Wnt/β-catenin signaling pathway and their effect on cell proliferation, migration, invasion, and radiosensitivity as well as xenograft tumor growth and metastasis in nude mice. Results We demonstrated low miR-194-5p expression and high PRC1 expression in ESCC tissues and cells. PRC1 was confirmed as a putative target for miR-194-5p. High miR-194-5p or silenced PRC1 enhanced ESCC cell radiosensitivity but reduced proliferation, invasion, and migration via PRC1 through modulation of the Wnt/β-catenin signaling pathway. Animal experiments also validated that overexpression of miR-194-5p suppressed tumorigenesis and in vivo metastasis in nude mice.Conclusion: miR-194-5p can inhibit the Wnt/β-catenin signaling pathway through down-regulation of the PRC1 gene, thereby enhancing the sensitivity of ESCC cells to radiotherapy and attenuating the invasion and metastasis ability of ESCC cells.
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Affiliation(s)
- Yan Wang
- Department of Radiotherapy, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, PR China
| | - Ninghua Yao
- Department of Radiotherapy, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, PR China
| | - Jie Sun
- Department of Radiotherapy, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, PR China
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21
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Li Q, Sun M, Meng Y, Feng M, Wang M, Chang C, Dong H, Bu F, Xu C, Liu J, Ling Q, Qiao Y, Chen J. Kinesin family member 18B activates mTORC1 signaling via actin gamma 1 to promote the recurrence of human hepatocellular carcinoma. Oncogenesis 2023; 12:54. [PMID: 37957153 PMCID: PMC10643429 DOI: 10.1038/s41389-023-00499-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 10/08/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023] Open
Abstract
The mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway is frequently reported to be hyperactivated in hepatocellular carcinoma (HCC) and contributes to HCC recurrence. However, the underlying regulatory mechanisms of mTORC1 signaling in HCC are not fully understood. In the present study, we found that the expression of kinesin family member 18B (KIF18B) was positively correlated with mTORC1 signaling in HCC, and the upregulation of KIF18B and p-mTOR was associated with a poor prognosis and HCC recurrence. Utilizing in vitro and in vivo assays, we showed that KIF18B promoted HCC cell proliferation and migration through activating mTORC1 signaling. Mechanistically, we identified Actin gamma 1 (γ-Actin) as a binding partner of KIF18B. KIF18B and γ-Actin synergistically modulated lysosome positioning, promoted mTORC1 translocation to lysosome membrane, and prohibited p70 S6K from entering lysosomes for degradation, which finally led to the enhancement of mTORC1 signaling transduction. Moreover, we found that KIF18B was a direct target of Forkhead box M1, which explains the potential mechanism of KIF18B overexpression in HCC. Our study highlights the potential of KIF18B as a therapeutic target for the treatment of HCC.
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Affiliation(s)
- Qian Li
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China
| | - Mengqing Sun
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China
| | - Yao Meng
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China
| | - Mengqing Feng
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China
| | - Menglan Wang
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China
| | - Cunjie Chang
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China
| | - Heng Dong
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China
| | - Fangtian Bu
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China
| | - Chao Xu
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China
| | - Jing Liu
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China
| | - Qi Ling
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, P. R. China.
| | - Yiting Qiao
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China.
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, P. R. China.
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, 250000, P. R. China.
| | - Jianxiang Chen
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, P. R. China.
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, P. R. China.
- Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Centre, Singapore, 169610, Singapore.
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Koo Y, Han W, Keum BR, Lutz L, Yun SH, Kim GH, Han JK. RNF2 regulates Wnt/ß-catenin signaling via TCF7L1 destabilization. Sci Rep 2023; 13:19750. [PMID: 37957244 PMCID: PMC10643375 DOI: 10.1038/s41598-023-47111-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 11/09/2023] [Indexed: 11/15/2023] Open
Abstract
The Wnt signaling pathway is a crucial regulator of various biological processes, such as development and cancer. The downstream transcription factors in this pathway play a vital role in determining the threshold for signaling induction and the length of the response, which vary depending on the biological context. Among the four transcription factors involved in canonical Wnt/ß-catenin signaling, TCF7L1 is known to possess an inhibitory function; however, the underlying regulatory mechanism remains unclear. In this study, we identified the E3 ligase, RNF2, as a novel positive regulator of the Wnt pathway. Here, we demonstrate that RNF2 promotes the degradation of TCF7L1 through its ubiquitination upon activation of Wnt signaling. Loss-of-function studies have shown that RNF2 consistently destabilizes nuclear TCF7L1 and is required for proper Wnt target gene transcription in response to Wnt activation. Furthermore, our results revealed that RNF2 controls the threshold, persistence, and termination of Wnt signaling by regulating TCF7L1. Overall, our study sheds light on the previously unknown degradation mechanism of TCF7L1 by a specific E3 ligase, RNF2, and provides new insights into the variability in cellular responses to Wnt activation.
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Affiliation(s)
- Youngmu Koo
- Department of Life Sciences, Pohang University of Science and Technology, 77 Cheongam-Ro, Nam-Gu, Pohang, Gyeongbuk, 37673, Republic of Korea
| | - Wonhee Han
- F. M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Byeong-Rak Keum
- Department of Life Sciences, Pohang University of Science and Technology, 77 Cheongam-Ro, Nam-Gu, Pohang, Gyeongbuk, 37673, Republic of Korea
| | - Leila Lutz
- Department of Life Sciences, Pohang University of Science and Technology, 77 Cheongam-Ro, Nam-Gu, Pohang, Gyeongbuk, 37673, Republic of Korea
| | - Sung Ho Yun
- Center for Research Equipment, Korea Basic Science Institute, Cheongju, 28119, Republic of Korea
| | - Gun-Hwa Kim
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju, 28119, Republic of Korea
| | - Jin-Kwan Han
- Department of Life Sciences, Pohang University of Science and Technology, 77 Cheongam-Ro, Nam-Gu, Pohang, Gyeongbuk, 37673, Republic of Korea.
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23
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Li S, Motiño O, Lambertucci F, Martins I, Sun L, Kroemer G. Protein regulator of cytokinesis 1: a potential oncogenic driver. Mol Cancer 2023; 22:128. [PMID: 37563591 PMCID: PMC10413716 DOI: 10.1186/s12943-023-01802-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 06/05/2023] [Indexed: 08/12/2023] Open
Abstract
Protein regulator of cytokinesis 1 (PRC1) is involved in cytokinesis. Growing evidence suggests the association of PRC1 with multiple cancers. Here, we unveil that, in 28 cancer types, PRC1 is higher expressed in tumor tissues than in non-malignant tissues. Overexpression of PRC1 indicates unfavorable prognostic value, especially in ACC, LGG, KIRP, LICH, LUAD, MESO, PAAD, SARC and UCEC, while methylation of the PRC1 gene at sites associated with its inactivation has a favorable prognostic value in ACC, KIRP, LUAD, MESO, KIRP and LGG. Differentially expressed genes (DEGs) associated with high (> median) PRC1 expression contribute to key signaling pathways related with cell cycle, DNA damage and repair, EMT, cell migration, invasion and cell proliferation in most cancer types. More specifically, the DEGs involved in RAS/RAF/MAPK, PI3K/AKT, WNT, NOTCH, TGF-β, integrin, EMT process, focal adhesion, RHO GTPase-related pathway or microtubule cytoskeleton regulation are upregulated when PRC1 expression is above median, as confirmed for most cancers. Most importantly, high expression of PRC1 appears to be associated with an overabundance of poor-prognosis TH2 cells. Furthermore, positive correlations of PRC1 and some immune checkpoint genes (CD274, CTLA4, HAVCR2, LAG3, PDCD1, PDCD1LG2, TIGIT, and CD86) were observed in several cancers, especially BLCA, BRCA, KIRC, LUAD, LIHC, PRAD and THCA. These findings plead in favor of further studies validating the diagnostic and prognostic impact of PRC1 as well as the elaboration of pharmacological strategies for targeting PRC1.
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Affiliation(s)
- Sijing Li
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France
- Faculté de Médecine, Université de Paris Saclay, Kremlin Bicêtre, France
| | - Omar Motiño
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France
| | - Flavia Lambertucci
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France
| | - Isabelle Martins
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France
| | - Li Sun
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Paris, France.
- Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France.
- Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, Paris, HP, France.
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24
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Bakrania A, To J, Zheng G, Bhat M. Targeting Wnt-β-Catenin Signaling Pathway for Hepatocellular Carcinoma Nanomedicine. GASTRO HEP ADVANCES 2023; 2:948-963. [PMID: 39130774 PMCID: PMC11307499 DOI: 10.1016/j.gastha.2023.07.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 07/17/2023] [Indexed: 08/13/2024]
Abstract
Hepatocellular carcinoma (HCC) represents a high-fatality cancer with a 5-year survival of 22%. The Wnt/β-catenin signaling pathway presents as one of the most upregulated pathways in HCC. However, it has so far not been targetable in the clinical setting. Therefore, studying new targets of this signaling cascade from a therapeutic aspect could enable reversal, delay, or prevention of hepatocarcinogenesis. Although enormous advancement has been achieved in HCC research and its therapeutic management, since HCC often occurs in the context of other liver diseases such as cirrhosis leading to liver dysfunction and/or impaired drug metabolism, the current therapies face the challenge of safely and effectively delivering drugs to the HCC tumor site. In this review, we discuss how a targeted nano drug delivery system could help minimize the off-target toxicities of conventional HCC therapies as well as enhance treatment efficacy. We also put forward the current challenges in HCC nanomedicine along with some potential therapeutic targets from the Wnt/β-catenin signaling pathway that could be used for HCC therapy. Overall, this review will provide an insight to the current advances, limitations and how HCC nanomedicine could change the landscape of some of the undruggable targets in the Wnt/β-catenin pathway.
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Affiliation(s)
- Anita Bakrania
- Toronto General Hospital Research Institute, Toronto, Ontario, Canada
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Jeffrey To
- Toronto General Hospital Research Institute, Toronto, Ontario, Canada
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Gang Zheng
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Mamatha Bhat
- Toronto General Hospital Research Institute, Toronto, Ontario, Canada
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
- Division of Gastroenterology, Department of Medicine, University Health Network and University of Toronto, Toronto, Ontario, Canada
- Department of Medical Sciences, University Health Network, Toronto, Ontario, Canada
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25
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Lin I, Wei A, Awamleh Z, Singh M, Ning A, Herrera A, REACH Biobank and Registry, Russell BE, Weksberg R, Arboleda VA. Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and noncanonical Wnt signaling dysregulation. JCI Insight 2023; 8:e167744. [PMID: 37053013 PMCID: PMC10322691 DOI: 10.1172/jci.insight.167744] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 04/07/2023] [Indexed: 04/14/2023] Open
Abstract
ASXL1 (additional sex combs-like 1) plays key roles in epigenetic regulation of early developmental gene expression. De novo protein-truncating mutations in ASXL1 cause Bohring-Opitz syndrome (BOS; OMIM #605039), a rare neurodevelopmental condition characterized by severe intellectual disabilities, distinctive facial features, hypertrichosis, increased risk of Wilms tumor, and variable congenital anomalies, including heart defects and severe skeletal defects giving rise to a typical BOS posture. These BOS-causing ASXL1 variants are also high-prevalence somatic driver mutations in acute myeloid leukemia. We used primary cells from individuals with BOS (n = 18) and controls (n = 49) to dissect gene regulatory changes caused by ASXL1 mutations using comprehensive multiomics assays for chromatin accessibility (ATAC-seq), DNA methylation, histone methylation binding, and transcriptome in peripheral blood and skin fibroblasts. Our data show that regardless of cell type, ASXL1 mutations drive strong cross-tissue effects that disrupt multiple layers of the epigenome. The data showed a broad activation of canonical Wnt signaling at the transcriptional and protein levels and upregulation of VANGL2, which encodes a planar cell polarity pathway protein that acts through noncanonical Wnt signaling to direct tissue patterning and cell migration. This multiomics approach identifies the core impact of ASXL1 mutations and therapeutic targets for BOS and myeloid leukemias.
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Affiliation(s)
- Isabella Lin
- Department of Human Genetics
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
- Department of Computational Medicine, UCLA, Los Angeles, California, USA
| | - Angela Wei
- Department of Human Genetics
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
- Department of Computational Medicine, UCLA, Los Angeles, California, USA
- Interdepartmental BioInformatics Program, UCLA, Los Angeles, California, USA
| | - Zain Awamleh
- Department of Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Meghna Singh
- Department of Human Genetics
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
- Department of Computational Medicine, UCLA, Los Angeles, California, USA
| | - Aileen Ning
- Department of Human Genetics
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
- Department of Computational Medicine, UCLA, Los Angeles, California, USA
| | - Analeyla Herrera
- Department of Human Genetics
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
- Department of Computational Medicine, UCLA, Los Angeles, California, USA
| | | | - Bianca E. Russell
- Division of Genetics, Department of Pediatrics, UCLA, Los Angeles, California, USA
| | - Rosanna Weksberg
- Department of Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
- Division of Clinical & Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada
- Institute of Medical Sciences and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Valerie A. Arboleda
- Department of Human Genetics
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
- Department of Computational Medicine, UCLA, Los Angeles, California, USA
- Interdepartmental BioInformatics Program, UCLA, Los Angeles, California, USA
- Molecular Biology Institute, UCLA, Los Angeles, California, USA
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA
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26
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Shi XJ, Yao CG, Li HL, Wei YH, Hu KH. Chromosome hyperploidy induced by chronic hepatitis B virus infection and its targeted therapeutic strategy. Shijie Huaren Xiaohua Zazhi 2023; 31:299-306. [DOI: 10.11569/wcjd.v31.i8.299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/28/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection induces chromosomal hyperploidy (including aneuploidy and polyploidy) and chromosomal instability in hepatocytes, which is one of the main causes of primary hepatocellular carcinoma (HCC). Although hepatocytes can regulate polyploidization of chromosomes under normal conditions, it is difficult to regulate hyperploidization caused by HBV infection and thus carcinogenesis. Studies have shown that HBV can cause dysregulation of many signal pathways such as PLK1/PRC1, and induce chromosome hyperploidy and malignant transformation of hepatocytes. Herein we review the mechanism of HBV infection-induced chromosomal hyperploidy of hepatocytes to cuase hepatocarcinogenesis and the advances in research of drugs targeting chromosomal hyperploidy.
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27
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Xu H, Liu J, Zhang Y, Zhou Y, Zhang L, Kang J, Ning C, He Z, Song S. KIF23, under regulation by androgen receptor, contributes to nasopharyngeal carcinoma deterioration by activating the Wnt/β-catenin signaling pathway. Funct Integr Genomics 2023; 23:116. [PMID: 37010644 DOI: 10.1007/s10142-023-01044-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 03/22/2023] [Accepted: 03/27/2023] [Indexed: 04/04/2023]
Abstract
Our study aimed to explore the potential mechanisms of KIF23 regulating function in the progression of nasopharyngeal carcinoma and pinpoint novel therapeutic targets for the clinical treatment of nasopharyngeal carcinoma patients. Firstly, the mRNA and protein level of KIF23 in nasopharyngeal carcinoma was measured using quantitative real-time PCR and western blot. Then, the influence of KIF23 on tumor metastasis and growth in nasopharyngeal carcinoma was determined through the in vivo and in vitro experiments. Lastly, the regulatory mechanisms of KIF23 in nasopharyngeal carcinoma were illustrated in the chromatin immunoprecipitation assay. KIF23 was first found to be overexpressed in nasopharyngeal carcinoma samples, and its expression was associated with poor prognosis. Then, the nasopharyngeal carcinoma cell's proliferation, migration, and invasion potential could be improved by inducing KIF23 expression both in vivo and in vitro. Furthermore, androgen receptor (AR) was found to bind to the KIF23 promoter region directly and enhance KIF23 transcription. At last, KIF23 could accelerate nasopharyngeal carcinoma deterioration via activating the Wnt/β-catenin signaling pathway. AR/KIF23/Wnt/β-catenin pathway promotes nasopharyngeal carcinoma deterioration. Our findings could serve as a new therapeutic strategy for nasopharyngeal carcinoma in the clinical practice.
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Affiliation(s)
- Hongbo Xu
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
- Anhui Province Key Laboratory of Translational Cancer Research Affiliated to Bengbu Medical College, Bengbu, Anhui, China
| | - Jingjing Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
| | - Yajun Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
| | - Yan Zhou
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
| | - Lei Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
| | - Jia Kang
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
| | - Can Ning
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China
| | - Zelai He
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China.
- Anhui Province Key Laboratory of Translational Cancer Research Affiliated to Bengbu Medical College, Bengbu, Anhui, China.
| | - Shilong Song
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, No.287, Changhuai Road, Longzihu District, Bengbu, 233004, Anhui, China.
- Anhui Province Key Laboratory of Translational Cancer Research Affiliated to Bengbu Medical College, Bengbu, Anhui, China.
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28
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Hanselmann S, Gertzmann D, Shin WJ, Ade CP, Gaubatz S. Expression of the cytokinesis regulator PRC1 results in p53-pathway activation in A549 cells but does not directly regulate gene expression in the nucleus. Cell Cycle 2023; 22:419-432. [PMID: 36135961 PMCID: PMC9879178 DOI: 10.1080/15384101.2022.2122258] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 08/05/2022] [Accepted: 09/05/2022] [Indexed: 01/29/2023] Open
Abstract
Protein regulator of cytokinesis 1 (PRC1) is a microtubule-binding protein with essential roles in mitosis and cytokinesis. PRC1 is frequently overexpressed in cancer cells where it could contribute to chromosomal instability. Due to its nuclear localization in interphase, it has been speculated that PRC1 has additional functions that are involved in its pro-tumorigenic functions. In this study we investigated the potential nuclear functions of PRC1 in a lung cancer cell line. Genome wide expression profiling by RNA sequencing revealed that the expression of PRC1 results in activation of the p53 pathway and inhibition of the pro-proliferative E2F-dependent gene expression. A mutant of PRC1 that is unable to enter into the nucleus regulated the same gene sets as wildtype PRC1, suggesting that PRC1 has no nuclear-exclusive functions in A549 cells. Instead, induction of p53 by PRC1 correlates with multinucleation and depends on the localization of PRC1 to the midbody, suggesting that the induction of p53 is a consequence of overexpressed PRC1 to interfere with the normal function of PRC1 during cytokinesis. Activation of p53 by PRC1 results in cellular senescence but not in apoptosis. In conclusion, while PRC1 is frequently overexpressed in many cancers, the p53 pathways may initially protect cancer cells from the negative effects of PRC1 overexpression on cytokinesis. Because depletion of PRC1 also results in p53-pathway activation and senescence, levels of PRC1 need to be tightly regulated to allow unperturbed proliferation. Targeting the expression or function of PRC1 could create a therapeutic vulnerability for the treatment of cancer.
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Affiliation(s)
- Steffen Hanselmann
- Theodor Boveri Institute, Biocenter, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany
| | - Dörthe Gertzmann
- Theodor Boveri Institute, Biocenter, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany
| | - Woo Jin Shin
- Theodor Boveri Institute, Biocenter, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany
| | - Carsten P. Ade
- Theodor Boveri Institute, Biocenter, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany
| | - Stefan Gaubatz
- Theodor Boveri Institute, Biocenter, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany
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Shi J, Hao S, Liu X, Li Y, Zheng X. Feiyiliu Mixture sensitizes EGFR Del19/T790M/C797S mutant non-small cell lung cancer to osimertinib by attenuating the PRC1/Wnt/EGFR pathway. Front Pharmacol 2023; 14:1093017. [PMID: 36744262 PMCID: PMC9892466 DOI: 10.3389/fphar.2023.1093017] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 01/10/2023] [Indexed: 01/20/2023] Open
Abstract
Introduction: Osimertinib is a potent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the treatment of patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, the emergence of acquired resistance due to the EGFR-Del19/T790M/C797S mutation limits the clinical application of osimertinib. Feiyiliu Mixture (FYLM), a clinical experience formula of Chinese medicine, was used to treat lung cancer with good clinical efficacy. In this study, we aimed to investigate the mechanism by which Feiyiliu Mixture delays osimertinib resistance in EGFR-mutant cell lines and EGFR-mutant cell tumor-bearing mice. Methods: The osimertinib-resistant cell models were established in mouse Lewis lung carcinoma (LLC) cells transfected with EGFR-Del19/T790M/C797S mutant lentivirus. In cell experiments, after 48 h of treatment with Feiyiliu Mixture-containing serum, MTT assay was used to detect the relative cell viability, and western blotting was used to detect EGFR protein phosphorylation expression. In animal experiments, C57BL/6J mice were subcutaneously injected with Lewis lung carcinoma cells stably expressing EGFR-Del19/T790M/C797S mutations to construct a xenograft model. After 2 weeks of Feiyiliu Mixture and/or osimertinib treatment, the expression of proliferation-related, apoptosis-related and PRC1/Wnt/EGFR pathway markers was detected by real-time qPCR, western blotting and immunohistochemistry. Results: The results showed that when combined with osimertinib, Feiyiliu Mixture synergistically reduces proliferation and increases apoptosis to improve drug resistance. In vitro, Feiyiliu Mixture-containing serum reduced the EGFR phosphorylation. In vivo, Feiyiliu Mixture downregulated the expression of cyclin B1 and Bcl-2 while upregulating the level of cleaved Caspase-3 protein, indicating that Feiyiliu Mixture promotes apoptosis. Furthermore, Feiyiliu Mixture reduced the expression of p-EGFR, p-Akt, PRC1 and Wnt pathway-related proteins such as β-catenin, c-Myc and c-Jun. Conclusion: The present study identified that Feiyiliu Mixture inhibited PRC1/Wnt/EGFR pathway activation, reduced proliferation, and promoted apoptosis, thereby increasing the sensitivity of EGFR-mutant non-small cell lung cancer to osimertinib. Our study provided a new idea for Chinese medicine to play a role in enhancing efficacy and reducing toxicity in the treatment of non-small cell lung cancer.
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Affiliation(s)
- Jingjing Shi
- College of First Clinical Medical, Shandong University of Traditional Chinese Medicine, Jinan, China
- Qingdao Hospital of Traditional Chinese Medicine (Qingdao Hiser Hospital), Qingdao, China
| | - Shaoyu Hao
- Department of Thoracic Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Xiantao Liu
- Department of Respiratory Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yingying Li
- College of First Clinical Medical, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xin Zheng
- Qingdao Hospital of Traditional Chinese Medicine (Qingdao Hiser Hospital), Qingdao, China
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Jiayu F, Jiang Y, Zhou X, Zhou M, Pan J, Ke Y, Zhen J, Huang D, Jiang W. Comprehensive analysis of prognostic value, relationship to cell cycle, immune infiltration and m6A modification of ZSCAN20 in hepatocellular carcinoma. Aging (Albany NY) 2022; 14:9550-9578. [PMID: 36462500 PMCID: PMC9792207 DOI: 10.18632/aging.204312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 09/17/2022] [Indexed: 12/05/2022]
Abstract
Hepatocellular carcinoma (HCC) is a common tumor across the globe with a high mortality rate. ZSCAN20 is a ZNF transcription factor, a key determinant of gene expression. Nonetheless, the mechanism of ZSCAN20 as a potential clinical biomarker and therapeutic target for HCC is not understood. Here, TIMER, TCGA, ICGC databases and immunohistochemical (IHC) and Western Blot found ZSCAN20 mRNA and protein levels were upregulated. Additionally, Kaplan-Meier Plotter, GEPIA and TCGA databases showed high ZSCAN20 expression was related to the short survival time of HCC patients. Multivariate Cox analysis exposed that ZSCAN20 can act as an independent prognostic factor. We observed methylation level of ZSCAN20 was associated with the clinicopathological characteristics and prognosis of HCC patients through UALCAN. Furthermore, enrichment examination exposed functional association between ZSCAN20 and cell cycle, immune infiltration. Functional experiments showed that interference with ZSCAN20 significantly reduced the invasion, migration and proliferation abilities of HCC cells. An immune infiltration analysis showed that ZSCAN20 was associated with immune cells, particularly T cells. The expression of ZSCAN20 was correlated with poor prognosis in the Regulatory T-cell. And Real-Time RT-PCR analysis found interference with ZSCAN20 significantly reduced the expression of some chemokines. Finally, the TCGA and ICGC data analysis suggested that the ZSCAN20 expression was greatly related to m6A modifier related genes. In conclusion, ZSCAN20 can serve as a prognostic biomarker for HCC and provide clues about cell cycle, immune infiltration, and m6A modification.
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Affiliation(s)
- Fang Jiayu
- Second Affiliated Hospital of Nanchang University, Nanchang, China
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Yike Jiang
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Xuanrui Zhou
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Minqin Zhou
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Jingying Pan
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Yun Ke
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Jing Zhen
- Second College of Clinical Medicine, Nanchang University, Nanchang, China
| | - Da Huang
- Department of Thyroid Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Weifan Jiang
- Department of Urology, Second Affiliated Hospital of Nanchang University, Nanchang, China
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Wu J, Li L, Zhong H, Zhang HH, Li J, Zhang HB, Zhao YQ, Xu B, Song QB. Bioinformatic and Experimental Analyses Reveal That KIF4A Is a Biomarker of Therapeutic Sensitivity and Predicts Prognosis in Cervical Cancer Patients. Curr Med Sci 2022; 42:1273-1284. [PMID: 36260268 DOI: 10.1007/s11596-022-2636-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 03/21/2022] [Indexed: 02/07/2023]
Abstract
OBJECTIVE This study aims to investigate the expression, prognostic value, and function of kinesin superfamily 4A (KIF4A) in cervical cancer. METHODS Cervical cancer cell lines (Hela and SiHa) and TCGA data were used for experimental and bioinformatic analyses. Overall survival (OS) and progression free survival (PFS) were compared between patients with high or low KIF4A expression. Copy number variation (CNV) and somatic mutations of patients were visualized and GISTIC 2.0 was used to identify significantly altered sites. The function of KIF4A was also explored based on transcriptome analysis and validated by experimental methods. Chemotherapeutic and immunotherapeutic benefits were inferred using multiple reference databases and algorithms. RESULTS Patients with high KIF4A expression had better OS and PFS. KIF4A could inhibit proliferation and migration and induce G1 arrest of cervical cancer cells. Higher CNV load was observed in patients with low KIF4A expression, while the group with low KIF4A expression displayed more significantly altered sites. A total of 13 genes were found to mutate more in the low KIF4A expression group, including NOTCH1 and PUM1. The analysis revealed that low KIF4A expression may indicate an immune escape phenotype, and patients in this group may benefit more from immunotherapy. With respect to chemotherapy, cisplatin and gemcitabine may respond better in patients with high KIF4A expression, while 5-fluorouracil etc. may be responded better in patients with low KIF4A expression CONCLUSION: KIF4A is a tumor suppressor gene in cervical cancer, and it can be used as a prognostic and therapeutic biomarker in cervical cancer.
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Affiliation(s)
- Jie Wu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430030, China
| | - Lan Li
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430030, China
| | - Hao Zhong
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430030, China
| | - Hao-Han Zhang
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430030, China
| | - Jing Li
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430030, China
| | - Hui-Bo Zhang
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430030, China.,Department of Bioinformatics, Wissenschaftszentrum Weihenstephan, Technical University of Munich, Freising, 85354, Germany
| | - Ya-Qi Zhao
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430030, China
| | - Bin Xu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430030, China.
| | - Qi-Bin Song
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430030, China.
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Li Z, Yang HY, Zhang XL, Zhang X, Huang YZ, Dai XY, Shi L, Zhou GR, Wei JF, Ding Q. Kinesin family member 23, regulated by FOXM1, promotes triple negative breast cancer progression via activating Wnt/β-catenin pathway. J Exp Clin Cancer Res 2022; 41:168. [PMID: 35524313 PMCID: PMC9077852 DOI: 10.1186/s13046-022-02373-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 04/25/2022] [Indexed: 11/13/2022] Open
Abstract
Background Triple negative breast cancer (TNBC) is highly malignant and has a worse prognosis, compared with other subtypes of breast cancer due to the absence of therapeutic targets. KIF23 plays a crucial role in the tumorigenesis and cancer progression. However, the role of KIF23 in development of TNBC and the underlying mechanism remain unknown. The study aimed to elucidate the biological function and regulatory mechanism of KIF23 in TNBC. Methods Quantitative real-time PCR and Western blot were used to determine the KIF23 expression in breast cancer tissues and cell lines. Then, functional experiments in vitro and in vivo were performed to investigate the effects of KIF23 on tumor growth and metastasis in TNBC. Chromatin immunoprecipitation assay was conducted to illustrate the potential regulatory mechanisms of KIF23 in TNBC. Results We found that KIF23 was significantly up-regulated and associated with poor prognosis in TNBC. KIF23 could promote TNBC proliferation, migration and invasion in vitro and in vivo. KIF23 could activate Wnt/β-catenin pathway and promote EMT progression in TNBC. In addition, FOXM1, upregulated by WDR5 via H3K4me3 modification, directly bound to the promoter of KIF23 gene to promote its transcription and accelerated TNBC progression via Wnt/β-catenin pathway. Both of small inhibitor of FOXM1 and WDR5 could inhibit TNBC progression. Conclusions Our findings elucidate WDR5/FOXM1/KIF23/Wnt/β-catenin axis is associated with TNBC progression and may provide a novel and promising therapeutic target for TNBC treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02373-7.
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Song R, Huang J, Yang C, Li Y, Zhan G, Xiang B. ESPL1 is Elevated in Hepatocellular Carcinoma and Predicts Prognosis. Int J Gen Med 2022; 15:8381-8398. [PMID: 36465268 PMCID: PMC9717693 DOI: 10.2147/ijgm.s381188] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 11/21/2022] [Indexed: 03/27/2025] Open
Abstract
PURPOSE The extra spindle pole bodies-like 1 (ESPL1) gene is associated with malignant biological behaviors in several tumors. Nevertheless, the correlation between hepatocellular carcinoma (HCC) and ESPL1 has not been determined. The present study analyzed the molecular function and prognostic value of ESPL1 in HCC. PATIENTS AND METHODS Samples from 121 HCCs and 119 adjacent normal tissue specimens were subjected to next-generation sequencing. Clinicopathological and genetic data of HCC patients in The Cancer Genome Atlas (TCGA) were also collected. ESPL1 expression was assessed in 20 pairs of HCC and normal liver specimens by qRT-PCR and immunohistochemistry (IHC). The prognostic value of ESPL1 expression was determined by Cox univariate and multivariate regression analyses. ESPL1-related co-expressed genes were evaluated by weighted gene co-expression network analysis (WGCNA). Processes and pathways involving ESPL1 in HCC were determined by Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The prognostic values of hub genes were determined by joint effect survival analysis. RESULTS RNA-Seq, RT-qPCR and IHC showed that ESPL1 expression was significantly higher in HCC than in normal liver tissues. Increased ESPL1 expression, greater tumor size and advanced BCLC stage were independently prognostic of poorer overall survival; and increased ESPL1 and advanced BCLC stage were independently prognostic of poorer recurrence-free survival. WGCNA showed that the top 10 co-expressed genes associated with ESPL1 were GTSE1, KIF18B, BUB1B, GINS1, PRC1, KIF23, KIF18A, TOP2A, NEK2 and FANCD2. Enrichment analysis indicated that ESPL1 and its co-expressed genes might be involved in the cell cycle and cell division of HCC. Joint effect survival analysis showed that the mortality rate was approximately 3.37 times higher in HCC patients with high than low expression of ESPL1, GTSE1, BUB1B, PRC1, KIF23, and TOP2A. CONCLUSION ESPL1 might be associated with cell cycle and might be an effective prognostic indicator in patients with HCC.
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Affiliation(s)
- Rui Song
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumors, Ministry of Education, Nanning, People’s Republic of China
| | - Juntao Huang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumors, Ministry of Education, Nanning, People’s Republic of China
| | - Chenglei Yang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumors, Ministry of Education, Nanning, People’s Republic of China
| | - Yuankuan Li
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumors, Ministry of Education, Nanning, People’s Republic of China
| | - Guohua Zhan
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumors, Ministry of Education, Nanning, People’s Republic of China
| | - Bangde Xiang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumors, Ministry of Education, Nanning, People’s Republic of China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, People’s Republic of China
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Ye J, Lin Y, Gao X, Lu L, Huang X, Huang S, Bai T, Wu G, Luo X, Li Y, Liang R. Prognosis-Related Molecular Subtypes and Immune Features Associated with Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14225721. [PMID: 36428813 PMCID: PMC9688639 DOI: 10.3390/cancers14225721] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 10/29/2022] [Accepted: 11/01/2022] [Indexed: 11/23/2022] Open
Abstract
Bioinformatics tools were used to identify prognosis-related molecular subtypes and biomarkers of hepatocellular carcinoma (HCC). Differential expression analysis of four datasets identified 3330 overlapping differentially expressed genes (DEGs) in the same direction in all four datasets. Those genes were involved in the cell cycle, FOXO signaling pathway, as well as complement and coagulation cascades. Based on non-negative matrix decomposition, two molecular subtypes of HCC with different prognoses were identified, with subtype C2 showing better overall survival than subtype C1. Cox regression and Kaplan-Meier analysis showed that 217 of the overlapping DEGs were closely associated with HCC prognosis. The subset of those genes showing an area under the curve >0.80 was used to construct random survival forest and least absolute shrinkage and selection operator models, which identified seven feature genes (SORBS2, DHRS1, SLC16A2, RCL1, IGFALS, GNA14, and FANCI) that may be involved in HCC occurrence and prognosis. Based on the feature genes, risk score and recurrence models were constructed, while a univariate Cox model identified FANCI as a key gene involved mainly in the cell cycle, DNA replication, and mismatch repair. Further analysis showed that FANCI had two mutation sites and that its gene may undergo methylation. Single-sample gene set enrichment analysis showed that Th2 and T helper cells are significantly upregulated in HCC patients compared to controls. Our results identify FANCI as a potential prognostic biomarker for HCC.
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Affiliation(s)
- Jiazhou Ye
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Yan Lin
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Xing Gao
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Lu Lu
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Xi Huang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Shilin Huang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Tao Bai
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Guobin Wu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Xiaoling Luo
- Department of Experimental Research, Guangxi Medical University Cancer Hospital, Nanning 530021, China
| | - Yongqiang Li
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
- Correspondence: (Y.L.); (R.L.); Tel./Fax: +86-771-5335155 (Y.L. & R.L.)
| | - Rong Liang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning 530021, China
- Correspondence: (Y.L.); (R.L.); Tel./Fax: +86-771-5335155 (Y.L. & R.L.)
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Tong Q, Yi M, Kong P, Xu L, Huang W, Niu Y, Gan X, Zhan H, Tian R, Yan D. TRIM36 inhibits tumorigenesis through the Wnt/β-catenin pathway and promotes caspase-dependent apoptosis in hepatocellular carcinoma. Cancer Cell Int 2022; 22:278. [PMID: 36068629 PMCID: PMC9450375 DOI: 10.1186/s12935-022-02692-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 08/22/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and has an extremely poor prognosis. We aimed to determine the latent relationships between TRIM36 regulation of apoptosis and the Wnt/β-catenin pathway in HCC. METHODS Immunohistochemistry and western blotting were used to characterize the aberrant expression of TRIM36 in HCC and adjacent tissues. Clinical information was analyzed using Kaplan-Meier and Cox methods. RNA-seq of potential targets was conducted to detect the regulation of TRIM36. Apoptosis assays and cellular proliferation, invasion and migration were conducted in a loss- and gain-of-function manner in cultured cells to determine the biological functions of TRIM36. A rescue experiment was conducted to confirm the role of Wnt/β-catenin signaling in TRIM36 regulation. Finally, in vivo experiments were conducted using cell line-derived xenografts in nude mice to validate the central role of TRIM36 in HCC. RESULTS TRIM36 expression was significantly downregulated in HCC tissues compared to adjacent non-tumor tissues. TRIM36 repressed the proliferation, migration, and invasion of Huh7 and HCCLM3 cells, whereas it stimulated apoptosis. Wnt/β-catenin signaling was inhibited by TRIM36, and rescue experiments highlighted its importance in HCC proliferation, migration, and invasion. In vivo experiments further confirmed the effects of sh-TRIM36 on HCC tumorigenesis, inhibition of apoptosis, and promotion of Wnt/β-catenin signaling. CONCLUSION Our study is the first to indicate that TRIM36 acts as a tumor suppressor in HCC. TRIM36 activates apoptosis and inhibits cellular proliferation, invasion, and migration via the Wnt/β-catenin pathway, which may serve as an important biomarker and promising therapeutic target for HCC.
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Affiliation(s)
- Qing Tong
- Department of Hepatopancreatobiliary Surgery, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, 830011, Xinjiang, China
- The Third Affiliated, Teaching Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Mingyu Yi
- The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Panpan Kong
- Department of Hepatopancreatobiliary Surgery, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, 830011, Xinjiang, China
| | - Lin Xu
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Wukui Huang
- The Third Affiliated, Teaching Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Yue Niu
- The Third Affiliated, Teaching Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Xiaojing Gan
- The Third Affiliated, Teaching Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Huan Zhan
- The Third Affiliated, Teaching Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Rui Tian
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Dong Yan
- Department of Hepatopancreatobiliary Surgery, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, 830011, Xinjiang, China.
- The Third Affiliated, Teaching Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
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Ruiz-Manriquez LM, Carrasco-Morales O, Sanchez Z EA, Osorio-Perez SM, Estrada-Meza C, Pathak S, Banerjee A, Bandyopadhyay A, Duttaroy AK, Paul S. MicroRNA-mediated regulation of key signaling pathways in hepatocellular carcinoma: A mechanistic insight. Front Genet 2022; 13:910733. [PMID: 36118880 PMCID: PMC9478853 DOI: 10.3389/fgene.2022.910733] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 08/10/2022] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. The molecular pathogenesis of HCC varies due to the different etiologies and genotoxic insults. The development of HCC is characterized by complex interactions between several etiological factors that result in genetic and epigenetic changes in proto-onco and/or tumor suppressor genes. MicroRNAs (miRNAs) are short non-coding RNAs that also can act as oncomiRs or tumor suppressors regulating the expression of cancer-associated genes post-transcriptionally. Studies revealed that several microRNAs are directly or indirectly involved in cellular signaling, and dysregulation of those miRNAs in the body fluids or tissues potentially affects key signaling pathways resulting in carcinogenesis. Therefore, in this mini-review, we discussed recent progress in microRNA-mediated regulation of crucial signaling networks during HCC development, concentrating on the most relevant ones such as PI3K/Akt/mTOR, Hippo-YAP/TAZ, and Wnt/β-catenin, which might open new avenues in HCC management.
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Affiliation(s)
| | | | - E. Adrian Sanchez Z
- Tecnologico de Monterrey, School of Engineering and Sciences, Queretaro, Mexico
| | | | | | - Surajit Pathak
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Chennai, India
| | - Antara Banerjee
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Chennai, India
| | - Anindya Bandyopadhyay
- International Rice Research Institute, Manila, Philippines
- Reliance Industries Ltd., Navi Mumbai, India
| | - Asim K. Duttaroy
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Sujay Paul
- Tecnologico de Monterrey, School of Engineering and Sciences, Queretaro, Mexico
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Protein Regulator of Cytokinesis 1 (PRC1) Upregulation Promotes Immune Suppression in Liver Hepatocellular Carcinoma. J Immunol Res 2022; 2022:7073472. [PMID: 35983074 PMCID: PMC9381293 DOI: 10.1155/2022/7073472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 04/23/2022] [Accepted: 05/30/2022] [Indexed: 11/30/2022] Open
Abstract
Liver hepatocellular carcinoma (LIHC) is a malignant cancer with widespread prevalence. The suppressive immune environment causes largely refractory to current treatment. The protein regulator of cytokinesis 1 (PRC1) is an essential gene for cytokinesis and is involved in cancer pathogenesis. However, the functions of PRC1 have been barely clarified, especially in LIHC. Here, we investigated the expression, prognostic value, and functions of PRC1 in LIHC. Pan-cancer analysis revealed the overexpression of PRC1 in the Cancer Genome Atlas (TCGA) database. Four LIHC datasets from the Gene Expression Omnibus (GEO) database confirmed the PRC1 overexpression in LIHC. The mRNA and protein levels of PRC1 in LIHC cells were higher than in normal liver cells. The overexpression of PRC1 predicted progressed clinical stage and poor prognosis of LIHC. We further investigated the functions of PRC1 by performing the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, and Gene Set Enrichment Analysis (GSEA) of its coexpressing genes. High PRC1 expression was associated with increased genome instability of LIHC. Moreover, PRC1 was positively correlated with the infiltration of suppressive immune cells like T regulatory cells (Tregs) and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and was negatively correlated with the effector immune cells' infiltration, including B cells and CD8+ T cells. In addition, PRC1 was positively correlated with the expression of tumor immune checkpoint molecules. Taken together, PRC1 overexpression contributes to the genome instability and the suppressive immune microenvironment of LIHC. Thus, PRC1 has the potential to be a prognostic marker and therapeutic target of LIHC.
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Li X, Li J, Xu L, Wei W, Cheng A, Zhang L, Zhang M, Wu G, Cai C. CDK16 promotes the progression and metastasis of triple-negative breast cancer by phosphorylating PRC1. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:149. [PMID: 35449080 PMCID: PMC9027050 DOI: 10.1186/s13046-022-02362-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 04/09/2022] [Indexed: 12/12/2022]
Abstract
Background Cyclin-dependent kinase 16 (CDK16) is an atypical PCTAIRE kinase, and its activity is dependent on the Cyclin Y (CCNY) family. Ccnys have been reported to regulate mammary stem cell activity and mammary gland development, and CCNY has been recognized as an oncoprotein in various cancers, including breast cancer. However, it remains unclear whether CDK16 has a role in breast cancer and whether it can be used as a therapeutic target for breast cancer. Methods Publicly available breast cancer datasets analyses and Kaplan-Meier survival analyses were performed to reveal the expression and clinical relevance of atypical CDKs in breast cancer. CDK16 protein expression was further examined by immunohistochemical and immunoblot analyses of clinical samples. Cell proliferation was measured by colony formation and MTT analyses. Cell cycle and apoptosis were examined by fluorescence-activated cell sorting (FACS) analysis. Wound-healing and trans-well invasion assays were conducted to test cell migration ability. The functions of CDK16 on tumorigenesis and metastasis were evaluated by cell line-derived xenograft, patient-derived organoid/xenograft, lung metastasis and systemic metastasis mouse models. Transcriptomic analysis was performed to reveal the potential molecular mechanisms involved in the function of CDK16. Pharmacological inhibition of CDK16 was achieved by the small molecular inhibitor rebastinib to further assess the anti-tumor utility of targeting CDK16. Results CDK16 is highly expressed in breast cancer, particularly in triple-negative breast cancer (TNBC). The elevated CDK16 expression is correlated with poor outcomes in breast cancer patients. CDK16 can improve the proliferation and migration ability of TNBC cells in vitro, and promote tumor growth and metastasis of TNBC in vivo. Both genetic knockdown and pharmacological inhibition of CDK16 significantly suppress the tumor progression of TNBC. Mechanistically, CDK16 exerts its function by phosphorylating protein regulator of cytokinesis 1 (PRC1) to regulate spindle formation during mitosis. Conclusion CDK16 plays a critical role in TNBC and is a novel promising therapeutic target for TNBC. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02362-w.
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Affiliation(s)
- Xiao Li
- Department of Thyroid and Breast Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Jinpeng Li
- Department of Thyroid and Breast Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Liming Xu
- Department of Thyroid and Breast Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Wei Wei
- Department of Thyroid and Breast Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Anyi Cheng
- Department of Thyroid and Breast Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Lingxian Zhang
- Department of Thyroid and Breast Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Mengna Zhang
- Department of Thyroid and Breast Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Gaosong Wu
- Department of Thyroid and Breast Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
| | - Cheguo Cai
- Department of Thyroid and Breast Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China.
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Yao M, Yang JL, Wang DF, Wang L, Chen Y, Yao DF. Encouraging specific biomarkers-based therapeutic strategies for hepatocellular carcinoma. World J Clin Cases 2022; 10:3321-3333. [PMID: 35611205 PMCID: PMC9048543 DOI: 10.12998/wjcc.v10.i11.3321] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/10/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
The prevention, early discovery and effective treatment of patients with hepatocellular carcinoma (HCC) remain a global medical challenge. At present, HCC is still mainly treated by surgery, supplemented by vascular embolization, radio frequency, radiotherapy, chemotherapy and biotherapy. The application of multikinase inhibitor sorafenib, chimeric antigen receptor T cells, or PD-1/PD-L1 inhibitors can prolong the median survival of HCC patients. However, the treatment efficacy is still unsatisfactory due to HCC metastasis and postoperative recurrence. During the process of hepatocyte malignant transformation, HCC tissues can express and secrete many types of specific biomarkers, or oncogenic antigen molecules into blood, for example, alpha-fetoprotein, glypican-3, Wnt3a (one of the key signaling molecules in the Wnt/β-catenin pathway), insulin-like growth factor (IGF)-II or IGF-I receptor, vascular endothelial growth factor, secretory clusterin and so on. In addition, combining immunotherapy with non-coding RNAs might improve anti-cancer efficacy. These biomarkers not only contribute to HCC diagnosis or prognosis, but may also become molecular targets for HCC therapy under developing or clinical trials. This article reviews the progress in emerging biomarkers in basic research or clinical trials for HCC immunotherapy.
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Affiliation(s)
- Min Yao
- Research Center of Clinical Medicine & Department of Immunology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Jun-Ling Yang
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - De-Feng Wang
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Li Wang
- Department of Medical Informatics, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Ying Chen
- Department of Oncology, Affiliated Second Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Deng-Fu Yao
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
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Du Y, Han Y, Wang X, Wang H, Qu Y, Guo K, Ma W, Fu L. Identification of Immune-Related Breast Cancer Chemotherapy Resistance Genes via Bioinformatics Approaches. Front Oncol 2022; 12:772723. [PMID: 35387129 PMCID: PMC8978268 DOI: 10.3389/fonc.2022.772723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 02/25/2022] [Indexed: 11/13/2022] Open
Abstract
Chemotherapy resistance in breast cancer is an important factor affecting the prognosis of breast cancer patients. We computationally analyzed the differences in gene expression before and after chemotherapy in breast cancer patients, drug-sensitive groups, and drug-resistant groups. Through functional enrichment analysis, immune microenvironment analysis, and other computational analysis methods, we identified PRC1, GGTLC1, and IRS1 as genes that may mediate breast cancer chemoresistance through the immune pathway. After validation of certain other clinical datasets and in vitro cellular assays, we found that the above three genes influenced drug resistance in breast cancer patients and were closely related to the tumor immune microenvironment. Our finding that chemoresistance in breast cancer could be influenced by the mediation of tumor immunity expanded our knowledge of how to address this problem and could guide future research involving chemoresistance.
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Affiliation(s)
- Yabing Du
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yikai Han
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xin Wang
- Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Huanrong Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanhong Qu
- Oncology Department of Laiyang People's Hospital, Laiyang, China
| | - Kaiyuan Guo
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wang Ma
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lijun Fu
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Sun Q, Liu Z, Xu X, Yang Y, Han X, Wang C, Song F, Mou Y, Li Y, Song X. Identification of a circRNA/miRNA/mRNA ceRNA Network as a Cell Cycle-Related Regulator for Chronic Sinusitis with Nasal Polyps. J Inflamm Res 2022; 15:2601-2615. [PMID: 35494315 PMCID: PMC9045834 DOI: 10.2147/jir.s358387] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 04/05/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose To explore the mechanisms by which circRNA/miRNA/mRNA competitive endogenous RNAs (ceRNA) networks regulate CRSwNP. Methods The expression profiles of circRNAs, miRNAs, and mRNAs from patients with CRSwNP and control subjects were acquired from the Gene Expression Omnibus database. The circRNA/miRNA/mRNA ceRNA network was constructed based on the predicted circRNA–miRNA interactions and miRNA–mRNA interactions. Hub-mRNAs were screened by protein–protein interaction network analysis and Cytoscape molecular complex detection. The expression of factors in tissue and in hsa_circ_0031594 siRNA transfection cells was verified by RT-qPCR and the association between them was revealed by Spearman correlation analysis. Receiver operating characteristic curve analysis was performed with the pROC R package. Results The differential expression of 5423 circRNAs, 415 miRNAs, and 3673 mRNAs was identified in CRSwNP subjects compared to control subjects. Among these, 9 circRNAs, 39 miRNAs, and 78 mRNAs were screened to construct a ceRNA network. Ultimately, a subnetwork including circRNA hsa_circ_0031594, hsa-miR-1260b, hsa-miR-6507-5p, NCAPG2, RACGAP1, CHEK1 and PRC1 was screened out. RT-qPCR validated that the expression of hsa_circ_0031594, NCAPG2, PRC1 was significantly increased, and hsa-miR-1260b and hsa-miR-6507-5p were expressed significantly less in patients with CRSwNP than in control subjects. In addition, the AUCs of hsa_circ_0031594, hsa-miR-1260b, hsa-miR-6507-5p, NCAPG2, and PRC1 to discriminate CRSwNP patients were 0.995, 0.842, 0.862, 0.765, and 0.816. Spearman correlation showed that the expression of hsa_circ_0031594 was negatively correlated with hsa-miR-1260b and hsa-miR-6507-5p, and positively correlated with NCAPG2 and PRC1. In human nasal epithelial cell (HNEpC) line, knocking down hsa_circ_0031594 could increase the expression of hsa-miR-1260b and hsa-miR-6507-5p, and reduce the expression of NCAPG2 and PRC1. Conclusion CeRNA networks including hsa_circ_0031594, hsa-miR-1260b, and NCAPG2, and hsa_circ_0031594, hsa-miR-6507-5p, and PRC1 may be key regulators for CRSwNP occurrence, and may be potential targets for the pathogenesis and treatment development of CRSwNP.
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Affiliation(s)
- Qi Sun
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, People’s Republic of China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, People’s Republic of China
| | - Zhen Liu
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, People’s Republic of China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, People’s Republic of China
| | - Xiangya Xu
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, People’s Republic of China
| | - Yujuan Yang
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, People’s Republic of China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, People’s Republic of China
| | - Xiao Han
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, People’s Republic of China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, People’s Republic of China
| | - Cai Wang
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, People’s Republic of China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, People’s Republic of China
- School of Clinical Medicine, Weifang Medical University, Weifang, People’s Republic of China
| | - Fei Song
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, People’s Republic of China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, People’s Republic of China
- Department of Binzhou Medical University, Clinical Medical College Second, Binzhou Medical University, Yantai, People’s Republic of China
| | - Yakui Mou
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, People’s Republic of China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, People’s Republic of China
| | - Yumei Li
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, People’s Republic of China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, People’s Republic of China
| | - Xicheng Song
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, People’s Republic of China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, People’s Republic of China
- Correspondence: Xicheng Song; Yumei Li, Department of Otolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, 264000, People’s Republic of China, Tel +860535-6691999, Fax +860535-6240341, Email ;
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Poojari R, Mohanty B, Kadwad V, Suryawanshi D, Chaudhari P, Khade B, Srivastava R, Gupta S, Panda D. Combinatorial cetuximab targeted polymeric nanocomplexes reduce PRC1 level and abrogate growth of metastatic hepatocellular carcinoma in vivo with efficient radionuclide uptake. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2022; 41:102529. [PMID: 35104671 DOI: 10.1016/j.nano.2022.102529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 12/27/2021] [Accepted: 01/16/2022] [Indexed: 06/14/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most aggressive form of cancer with poor drug responses. Developing an effective drug treatment remains a major unmet clinical need for HCC. We report a comprehensive study of combinatorial Cetuximab (Cet) targeted polymeric poly(D, L-lactide-co-glycolide)-b-poly(ethylene glycol) nanocomplexes delivery of Combretastatin A4 (CA4) and 2-Methoxyestradiol (2ME) (Cet-PLGA-b-PEG-CA4 NP + Cet-PLGA-b-PEG-2ME NP) against metastatic HCC in SCID mice. 125I-Cet-PLGA-b-PEG NP showed potent accumulation and retention in HCC tumors with longer circulation time up to 48 h (18 ± 1.0% ID/g, P < .0001). Combinatorial treatment with targeted polymeric nanocomplexes presented significant tumor growth inhibition (85%, P < .0001) than the free drug combinatorial counterpart, effectively inhibited orthotopic HCC and prevented lung metastasis. Combinatorial nanocomplexes treatment significantly blocked PRC1, a novel target of therapeutic response against HCC. Thus, the combinatorial cetuximab-targeted polymeric nanocomplexes possess superior antitumor activity against metastatic HCC and provide supports for the clinical translation ahead.
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Affiliation(s)
- Radhika Poojari
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India.
| | - Bhabani Mohanty
- Comparative Oncology and Small Animal Imaging Facility, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
| | - Vijay Kadwad
- Radiopharmaceuticals Production, Board of Radiation and Isotope Technology (BRIT), Navi Mumbai, India
| | | | - Pradip Chaudhari
- Comparative Oncology and Small Animal Imaging Facility, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India; Homi Bhabha National Institute (HBNI), Training School Complex, Anushakti Nagar, Mumbai, India
| | - Bharat Khade
- Epigenetics and Chromatin Biology Group, ACTREC-TMC, Navi Mumbai, India
| | - Rohit Srivastava
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India
| | - Sanjay Gupta
- Epigenetics and Chromatin Biology Group, ACTREC-TMC, Navi Mumbai, India; Homi Bhabha National Institute (HBNI), Training School Complex, Anushakti Nagar, Mumbai, India
| | - Dulal Panda
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India.
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NAP1L1 promotes tumor proliferation through HDGF/C-JUN signaling in ovarian cancer. BMC Cancer 2022; 22:339. [PMID: 35351053 PMCID: PMC8962469 DOI: 10.1186/s12885-022-09356-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 02/25/2022] [Indexed: 11/23/2022] Open
Abstract
Background Nucleosome assembly protein 1-like 1 (NAP1L1) is highly expressed in various types of cancer and plays an important role in carcinogenesis, but its specific role in tumor development and progression remains largely unknown. In this study, we suggest the potential of NAP1L1 as a prognostic biomarker and therapeutic target for the treatment of ovarian cancer (OC). Methods In our study, a tissue microarray (TMA) slide containing specimens from 149 patients with OC and 11 normal ovarian tissues underwent immunohistochemistry (IHC) to analyze the correlation between NAP1L1 expression and clinicopathological features. Loss-of- function experiments were performed by transfecting siRNA and following lentiviral gene transduction into SKOV3 and OVCAR3 cells. Cell proliferation and the cell cycle were assessed by the Cell Counting Kit-8, EDU assay, flow cytometry, colony formation assay, and Western blot analysis. In addition, co-immunoprecipitation (Co-IP) and immunofluorescence assays were performed to confirm the relationship between NAP1L1 and its potential targets in SKOV3/OVCAR3 cells. Results High expression of NAP1L1 was closely related to poor clinical outcomes in OC patients. After knocking down NAP1L1 by siRNA or shRNA, both SKOV3 and OVCAR3 cells showed inhibition of cell proliferation, blocking of the G1/S phase, and increased apoptosis in vitro. Mechanism analysis indicated that NAP1L1 interacted with hepatoma-derived growth factor (HDGF) and they were co-localized in the cytoplasm. Furthermore, HDGF can interact with jun proto-oncogene (C-JUN), an oncogenic transformation factor that induces the expression of cyclin D1 (CCND1). Overexpressed HDGF in NAP1L1 knockdown OC cells not only increased the expression of C-JUN and CCND1, but it also reversed the suppressive effects of si-NAP1L1 on cell proliferation. Conclusions Our data demonstrated that NAP1L1 could act as a prognostic biomarker in OC and can interact with HDGF to mediate the proliferation of OC, and this process of triggered proliferation may contribute to the activation of HDGF/C-JUN signaling in OC cells. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09356-z.
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The aberrant upregulation of exon 10-inclusive SREK1 through SRSF10 acts as an oncogenic driver in human hepatocellular carcinoma. Nat Commun 2022; 13:1363. [PMID: 35296659 PMCID: PMC8927159 DOI: 10.1038/s41467-022-29016-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 02/23/2022] [Indexed: 12/13/2022] Open
Abstract
Deregulation of alternative splicing is implicated as a relevant source of molecular heterogeneity in cancer. However, the targets and intrinsic mechanisms of splicing in hepatocarcinogenesis are largely unknown. Here, we report a functional impact of a Splicing Regulatory Glutamine/Lysine-Rich Protein 1 (SREK1) variant and its regulator, Serine/arginine-rich splicing factor 10 (SRSF10). HCC patients with poor prognosis express higher levels of exon 10-inclusive SREK1 (SREK1L). SREK1L can sustain BLOC1S5-TXNDC5 (B-T) expression, a targeted gene of nonsense-mediated mRNA decay through inhibiting exon-exon junction complex binding with B-T to exert its oncogenic role. B-T plays its competing endogenous RNA role by inhibiting miR-30c-5p and miR-30e-5p, and further promoting the expression of downstream oncogenic targets SRSF10 and TXNDC5. Interestingly, SRSF10 can act as a splicing regulator for SREK1L to promote hepatocarcinogenesis via the formation of a SRSF10-associated complex. In summary, we demonstrate a SRSF10/SREK1L/B-T signalling loop to accelerate the hepatocarcinogenesis. Alternative splicing is dysregulated in hepatocellular carcinoma. Here, the authors investigate the role of the splice variant of Splicing Regulatory Glutamic Acid and Lysine Rich Protein 1 (SREK1) and its upstream regulator, Serine/arginine-rich splicing factor 10 (SRSF10) in sustaining the oncogenic signal.
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Huang X, Fan M, Huang W. Pleiotropic roles of FXR in liver and colorectal cancers. Mol Cell Endocrinol 2022; 543:111543. [PMID: 34995680 PMCID: PMC8818033 DOI: 10.1016/j.mce.2021.111543] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 12/15/2021] [Accepted: 12/20/2021] [Indexed: 12/01/2022]
Abstract
Nuclear receptor farnesoid X receptor (FXR) is generally considered a cell protector of enterohepatic tissues and a suppressor of liver cancer and colorectal carcinoma (CRC). Loss or reduction of FXR expression occurs during carcinogenesis, and the FXR level is inversely associated with the aggressive behaviors of the malignancy. Global deletion of FXR and tissue-specific deletion of FXR display distinct effects on tumorigenesis. Epigenetic silencing and inflammatory context are two main contributors to impaired FXR expression and activity. FXR exerts its antitumorigenic function via the following mechanisms: 1) FXR regulates multiple metabolic processes, notably bile acid homeostasis; 2) FXR antagonizes hepatic and enteric inflammation; 3) FXR impedes aberrant activation of some cancer-related pathways; and 4) FXR downregulates a number of oncogenes while upregulating some tumor suppressor genes. Restoring FXR functions via its agonists provides a therapeutic approach for patients with liver cancer and CRC. However, an in-depth understanding of the species-specific pharmacological effects is a prerequisite for assessing the clinical safety and efficacy of FXR agonists in human cancer treatment.
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Affiliation(s)
- Xiongfei Huang
- Department of Pathology and Institute of Oncology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350004, PR China; Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, 350108, PR China.
| | - Mingjie Fan
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA, 91010, USA
| | - Wendong Huang
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA, 91010, USA.
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Novel Gene Signatures as Prognostic Biomarkers for Predicting the Recurrence of Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14040865. [PMID: 35205612 PMCID: PMC8870597 DOI: 10.3390/cancers14040865] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 02/04/2022] [Accepted: 02/07/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary A high percentage of patients who undergo surgical resection for hepatocellular carcinoma (HCC) experience recurrence. Therefore, identification of accurate molecular markers for predicting recurrence of HCC is important. We analyzed recurrence and non-recurrence HCC tissues using two public omics datasets comprising microarray and RNA-sequencing and found novel gene signatures associated with recurrent HCC. These molecules might be used to not only predict for recurrence of HCC but also act as potential prognostic indicators for patients with HCC. Abstract Hepatocellular carcinoma (HCC) has a high rate of cancer recurrence (up to 70%) in patients who undergo surgical resection. We investigated prognostic gene signatures for predicting HCC recurrence using in silico gene expression analysis. Recurrence-associated gene candidates were chosen by a comparative analysis of gene expression profiles from two independent whole-transcriptome datasets in patients with HCC who underwent surgical resection. Five promising candidate genes, CETN2, HMGA1, MPZL1, RACGAP1, and SNRPB were identified, and the expression of these genes was evaluated using quantitative reverse transcription PCR in the validation set (n = 57). The genes CETN2, HMGA1, RACGAP1, and SNRPB, but not MPZL1, were upregulated in patients with recurrent HCC. In addition, the combination of HMGA1 and MPZL1 demonstrated the best area under the curve (0.807, 95% confidence interval [CI] = 0.681–0.899) for predicting HCC recurrence. In terms of clinicopathological correlation, CETN2, MPZL1, RACGAP1, and SNRPB were upregulated in patients with microvascular invasion, and the expression of MPZL1 and SNRPB was increased in proportion to the Edmonson tumor differentiation grade. Additionally, overexpression of CETN2, HMGA1, and RACGAP1 correlated with poor overall survival (OS) and disease-free survival (DFS) in the validation set. Finally, Cox regression analysis showed that the expression of serum alpha-fetoprotein and RACGAP1 significantly affected OS, whereas platelet count, microvascular invasion, and HMGA1 expression significantly affected DFS. In conclusion, HMGA1 and RACGAP1 may be potential prognostic biomarkers for predicting the recurrence of HCC after surgical resection.
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Mo M, Liu B, Luo Y, Tan JHJ, Zeng X, Zeng X, Huang D, Li C, Liu S, Qiu X. Construction and Comprehensive Analysis of a circRNA-miRNA-mRNA Regulatory Network to Reveal the Pathogenesis of Hepatocellular Carcinoma. Front Mol Biosci 2022; 9:801478. [PMID: 35141281 PMCID: PMC8819184 DOI: 10.3389/fmolb.2022.801478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 01/03/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Circular RNAs (circRNAs) have been demonstrated to be closely related to the carcinogenesis of human cancer in recent years. However, the molecular mechanism of circRNAs in the pathogenesis of hepatocellular carcinoma (HCC) has not been fully elucidated. We aimed to identify critical circRNAs and explore their potential regulatory network in HCC.Methods: The robust rank aggregation (RRA) algorithm and weighted gene co-expression network analysis (WGCNA) were conducted to unearth the differentially expressed circRNAs (DEcircRNAs) in HCC. The expression levels of DEcircRNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR). A circRNA-miRNA-mRNA regulatory network was constructed by computational biology, and protein-protein interaction (PPI) network, functional enrichment analysis, survival analysis, and infiltrating immune cells analysis were performed to uncover the potential regulatory mechanisms of the network.Results: A total of 22 DEcircRNAs were screened out from four microarray datasets (GSE94508, GSE97332, GSE155949, and GSE164803) utilizing the RRA algorithm. Meanwhile, an HCC-related module containing 404 circRNAs was identified by WGCNA analysis. After intersection, only four circRNAs were recognized in both algorithms. Following qRT-PCR validation, three circRNAs (hsa_circRNA_091581, hsa_circRNA_066568, and hsa_circRNA_105031) were chosen for further analysis. As a result, a circRNA-miRNA-mRNA network containing three circRNAs, 17 miRNAs, and 222 mRNAs was established. Seven core genes (ESR1, BUB1, PRC1, LOX, CCT5, YWHAZ, and DDX39B) were determined from the PPI network of 222 mRNAs, and a circRNA-miRNA-hubgene network was also constructed. Functional enrichment analysis suggested that these seven hub genes were closely correlated with several cancer related pathways. Survival analysis revealed that the expression levels of the seven core genes were significantly associated with the prognosis of HCC patients. In addition, we also found that these seven hub genes were remarkably related to the infiltrating levels of immune cells.Conclusion: Our research identified three pivotal HCC-related circRNAs and provided novel insights into the underlying mechanisms of the circRNA-miRNA-mRNA regulatory network in HCC.
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Affiliation(s)
- Meile Mo
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, China
| | - Bihu Liu
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, China
| | - Yihuan Luo
- Department of Acute Care Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jennifer Hui Juan Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Xi Zeng
- Department of Occupational and Environmental Health, School of Public Health, Guilin Medical University, Guilin, China
| | - Xiaoyun Zeng
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, China
| | - Dongping Huang
- Department of Sanitary Chemistry, School of Public Health, Guangxi Medical University, Nanning, China
| | - Changhua Li
- Department of Acute Care Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Shun Liu
- Department of Maternal, Child and Adolescent Health, School of Public Health, Guangxi Medical University, Nanning, China
- *Correspondence: Xiaoqiang Qiu, ; Shun Liu,
| | - Xiaoqiang Qiu
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, China
- *Correspondence: Xiaoqiang Qiu, ; Shun Liu,
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Meng J, Wei Y, Deng Q, Li L, Li X. Study on the expression of TOP2A in hepatocellular carcinoma and its relationship with patient prognosis. Cancer Cell Int 2022; 22:29. [PMID: 35033076 PMCID: PMC8761301 DOI: 10.1186/s12935-021-02439-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 12/30/2021] [Indexed: 11/18/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is a primary liver cancer with a high mortality rate. However, the molecular mechanism of HCC formation remains to be explored and studied. Objective To investigate the expression of TOP2A in hepatocellular carcinoma (HCC) and its prognosis. Methods The data set of hepatocellular carcinoma was downloaded from GEO database for differential gene analysis, and hub gene was identified by Cytoscape. GEPIA was used to verify the expression of HUB gene and evaluate its prognostic value. Then TOP2A was selected as the research object of this paper by combining literature and clinical sample results. Firstly, TIMER database was used to study TOP2A, and the differential expression of TOP2A gene between normal tissues and cancer tissues was analyzed, as well as the correlation between TOP2A gene expression and immune infiltration of HCC cells. Then, the expression of top2a-related antibodies was analyzed using the Human Protein Atlas database, and the differential expression of TOP2A was verified by immunohistochemistry. Then, SRTING database and Cytoscape were used to establish PPI network for TOP2A and protein–protein interaction analysis was performed. The Oncomine database and cBioPortal were used to express and identify TOP2A mutation-related analyses. The expression differences of TOP2A gene were identified by LinkedOmics, and the GO and KEGG pathways were analyzed in combination with related genes. Finally, Kaplan–Meier survival analysis was performed to analyze the clinical and prognosis of HCC patients. Results TOP2A may be a new biomarker and therapeutic target for hepatocellular carcinoma. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02439-0.
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Affiliation(s)
- Jiali Meng
- Clinical Medicine, Guangxi Medical University, Nanning, Guangxi, China
| | - Yuanchao Wei
- Clinical Medicine, Guangxi Medical University, Nanning, Guangxi, China
| | - Qing Deng
- Clinical Medicine, Guangxi Medical University, Nanning, Guangxi, China
| | - Ling Li
- Department of Pathology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Xiaolong Li
- Department of Cell Biology and Genetics, School of Pre-Clinical Medicine, Key Laboratory of Longevity and Agingrelated Diseases of Chinese Ministry of Education, Guangxi Medical University, Nanning, 530021, China.
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Yang Z, Wu X, Li J, Zheng Q, Niu J, Li S. CCNB2, CDC20, AURKA, TOP2A, MELK, NCAPG, KIF20A, UBE2C, PRC1, and ASPM May Be Potential Therapeutic Targets for Hepatocellular Carcinoma Using Integrated Bioinformatic Analysis. Int J Gen Med 2022; 14:10185-10194. [PMID: 34992437 PMCID: PMC8710976 DOI: 10.2147/ijgm.s341379] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 12/09/2021] [Indexed: 01/14/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is a highly malignant, recurrent and drug-resistant tumor, and patients often lose the opportunity for surgery when they are diagnosed. Abnormal gene expression is closely related to the occurrence of HCC. The aim of the present study was to identify the differentially expressed genes (DEGs) between tumor tissue and non-tumor tissue of HCC samples in order to investigate the mechanisms of liver cancer. Methods The gene expression profile (GSE62232, GSE89377, and GSE112790) was downloaded from the Gene Expression Omnibus (GEO) and analyzed using the online tool GEO2R to identify differentially expressed genes (DEGs). Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed using the Database for Annotation, Visualization and Integrated Discovery. Protein–protein interaction (PPI) of these DEGs was analyzed based on the Search Tool for the Retrieval of Interacting Genes database and visualized by Cytoscape software. In addition, we used the online Kaplan–Meier plotter survival analysis tool to evaluate the prognostic value of hub genes expression. HPA database was used to reveal the differences in protein level of hub genes. Results A total of 50 upregulated DEGs and 122 downregulated DEGs were identified. Among them, ten hub genes with a high degree of connectivity were picked out. Overexpression of these hub genes was associated with unfavorable prognosis of HCC. Conclusion Our study suggests that CCNB2, CDC20, AURKA, TOP2A, MELK, NCAPG, KIF20A, UBE2C, PRC1, and ASPM were overexpressed in HCC compared with normal liver tissue. Overexpression of these genes was an unfavorable prognostic factor of HCC patients. Further study is needed to explore the value of them in the diagnosis and treatment of HCC. ![]()
Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/6-kRy19SREg
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Affiliation(s)
- Zhiqiang Yang
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Xinglang Wu
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Junbo Li
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Qiang Zheng
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Junwei Niu
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Shengwei Li
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
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Wang J, Wang C, Yang L, Li K. Identification of the critical genes and miRNAs in hepatocellular carcinoma by integrated bioinformatics analysis. Med Oncol 2022; 39:21. [PMID: 34982264 DOI: 10.1007/s12032-021-01622-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 11/29/2021] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is a global health problem with complex etiology and pathogenesis. Microarray data are increasingly being used as a novel and effective method for cancer pathogenesis analysis. An integrative analysis of genes and miRNA for HCC was conducted to unravel the potential prognosis of HCC. Two gene microarray datasets (GSE89377 and GSE101685) and two miRNA expression profiles (GSE112264 and GSE113740) were obtained from Gene Expression Omnibus database. A total of 177 differently expressed genes (DEGs) and 80 differently expressed miRNAs (DEMs) were screened out. Functional enrichment of DEGs was proceeded by Clue GO and these genes were significantly enriched in the chemical carcinogenesis pathway. A protein-protein interaction network was then established on the STRING platform, and ten hub genes (CDC20, TOP2A, ASPM, NCAPG, AURKA, CYP2E1, HMMR, PRC1, TYMS, and CYP4A11) were visualized via Cytoscape software. Then, a miRNA-target network was established to identify the hub dysregulated miRNA. A key miRNA (hsa-miR-124-3p) was filtered. Finally, the miRNA-target-transcription factor network was constructed for hsa-miR-124-3p. The network for hsa-miR-124-3p included two transcription factors (TFs) and five targets. These identified DEGs and DEMs, TFs, targets, and regulatory networks may help advance our understanding of the underlying pathogenesis of HCC.
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Affiliation(s)
- Jun Wang
- School of Biological Food and Environment, Hefei University, Hefei, 230601, China.
| | - Chuyan Wang
- School of Biological Food and Environment, Hefei University, Hefei, 230601, China
| | - Liuqing Yang
- School of Biological Food and Environment, Hefei University, Hefei, 230601, China
| | - Kexin Li
- School of Biological Food and Environment, Hefei University, Hefei, 230601, China
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