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Zhao J, Zhang T, Wu P, Qiu J, Wu K, Shi L, Zhu Q, Zhou J. circRNA-0015004 act as a ceRNA to promote RCC2 expression in hepatocellular carcinoma. Sci Rep 2024; 14:16913. [PMID: 39043840 PMCID: PMC11266727 DOI: 10.1038/s41598-024-67819-8] [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: 04/04/2024] [Accepted: 07/16/2024] [Indexed: 07/25/2024] Open
Abstract
Although circular RNAs (circRNA) have been demonstrated to modulate tumor initiation and progression, their roles in the proliferation of hepatocellular carcinoma (HCC) are still poorly understood. Based on the analysis of GEO data (GSE12174), hsa-circRNA-0015004 (circ-0015004) was screened and validated in 80 sets of HCC specimens. Subcellular fractionation analysis was designed to determine the cellular location of circ-0015004. Colony formation and cell counting kit-8 were performed to investigate the role of circ-0015004 in HCC. Dual-luciferase reporter gene assays, RNA immunoprecipitation and chromatin immunoprecipitation were employed to verify the interaction among circ-0015004, miR-330-3p and regulator of chromatin condensation 2 (RCC2). The expression level of circ-0015004 was significantly upregulated in HCC cell lines and HCC tissues. HCC patients with higher circ-0015004 levels displayed shorter overall survival, and higher tumor size and TNM stage. Moreover, knockdown of circ-0015004 significantly reduced HCC cell proliferation in vitro and inhibited the growth of HCC in nude mice. Mechanistic studies revealed that circ-0015004 could upregulate the expression of RCC2 by sponging miR-330-3p, thereby promoting HCC cell proliferation. Furthermore, we identified that Ying Yang 1 (YY1) could function as an important regulator of circ-0015004 transcription. This study systematically demonstrated the novel regulatory signaling of circ-0015004/miR-330-3p/RCC2 axis in promoting HCC progression, providing insight into HCC diagnosis and treatment from bench to clinic.
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MESH Headings
- Humans
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/metabolism
- RNA, Circular/genetics
- RNA, Circular/metabolism
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/metabolism
- Animals
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Gene Expression Regulation, Neoplastic
- Cell Proliferation/genetics
- Mice
- Cell Line, Tumor
- Male
- Female
- Guanine Nucleotide Exchange Factors/genetics
- Guanine Nucleotide Exchange Factors/metabolism
- Cell Cycle Proteins/genetics
- Cell Cycle Proteins/metabolism
- Mice, Nude
- Middle Aged
- YY1 Transcription Factor/metabolism
- YY1 Transcription Factor/genetics
- Up-Regulation
- RNA, Competitive Endogenous
- Chromosomal Proteins, Non-Histone
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Affiliation(s)
- Jie Zhao
- Department of General Surgery, Wujin Hospital of Traditional Chinese Medicine, Changzhou, China
| | - Tong Zhang
- Department of Hepatobiliary Surgery, Xinghua People's Hospital Affiliated Yangzhou University, Xinghua, China
| | - Peng Wu
- Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Jiajing Qiu
- Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Kejia Wu
- The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Longqing Shi
- The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China.
| | - Qiang Zhu
- Children's Hospital of Nanjing Medical University, Nanjing, China.
| | - Jun Zhou
- Children's Hospital of Nanjing Medical University, Nanjing, China.
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2
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Tu K, Li X, Zhang Q, Huang W, Xie D. A data-adaptive methods in detecting exogenous methyltransferase accessible chromatin in human genome using nanopore sequencing. Bioinformatics 2024; 40:btae206. [PMID: 38613848 PMCID: PMC11256936 DOI: 10.1093/bioinformatics/btae206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 03/15/2024] [Accepted: 04/12/2024] [Indexed: 04/15/2024] Open
Abstract
MOTIVATION Identifying chromatin accessibility is one of the key steps in studying the regulation of eukaryotic genomes. The combination of exogenous methyltransferase and nanopore sequencing provides an strategy to identify open chromatin over long genomic ranges at the single-molecule scale. However, endogenous methylation, non-open-chromatin-specific exogenous methylation and base-calling errors limit the accuracy and hinders its application to complex genomes. RESULTS We systematically evaluated the impact of these three influence factors, and developed a model-based computational method, methyltransferase accessible genome region finder (MAGNIFIER), to address the issues. By incorporating control data, MAGNIFIER attenuates the three influence factors with data-adaptive comparison strategy. We demonstrate that MAGNIFIER is not only sensitive to identify the open chromatin with much improved accuracy, but also able to detect the chromatin accessibility of repetitive regions that are missed by NGS-based methods. By incorporating long-read RNA-seq data, we revealed the association between the accessible Alu elements and non-classic gene isoforms. AVAILABILITY AND IMPLEMENTATION Freely available on web at https://github.com/Goatofmountain/MAGNIFIER.
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Affiliation(s)
- Kailing Tu
- National Frontier Center of Disease Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610000, China
| | - Xuemei Li
- National Frontier Center of Disease Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610000, China
| | - Qilin Zhang
- National Frontier Center of Disease Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610000, China
| | - Wei Huang
- School of Mathematics and Statistics, Key Laboratory for Applied Statistics of the Ministry of Education, Northeast Normal University, Changchun 130024, China
| | - Dan Xie
- National Frontier Center of Disease Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610000, China
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3
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Choquet H, Jiang C, Yin J, Kim Y, Hoffmann TJ, Jorgenson E, Asgari MM. Multi-ancestry genome-wide meta-analysis identifies novel basal cell carcinoma loci and shared genetic effects with squamous cell carcinoma. Commun Biol 2024; 7:33. [PMID: 38182794 PMCID: PMC10770328 DOI: 10.1038/s42003-023-05753-7] [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: 02/02/2023] [Accepted: 12/28/2023] [Indexed: 01/07/2024] Open
Abstract
Basal cell carcinoma (BCC) is one of the most common malignancies worldwide, yet its genetic determinants are incompletely defined. We perform a European ancestry genome-wide association (GWA) meta-analysis and a Hispanic/Latino ancestry GWA meta-analysis and meta-analyze both in a multi-ancestry GWAS meta-analysis of BCC, totaling 50,531 BCC cases and 762,234 controls from four cohorts (GERA, Mass-General Brigham Biobank, UK Biobank, and 23andMe research cohort). Here we identify 122 BCC-associated loci, of which 36 were novel, and subsequently fine-mapped these associations. We also identify an association of the well-known pigment gene SLC45A2 as well as associations at RCC2 and CLPTM1L with BCC in Hispanic/Latinos. We examine these BCC loci for association with cutaneous squamous cell carcinoma (cSCC) in 16,407 SCC cases and 762,486 controls of European ancestry, and 33 SNPs show evidence of association. Our study findings provide important insights into the genetic basis of BCC and cSCC susceptibility.
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Affiliation(s)
- Hélène Choquet
- Kaiser Permanente Northern California (KPNC), Division of Research, Oakland, CA, USA.
| | - Chen Jiang
- Kaiser Permanente Northern California (KPNC), Division of Research, Oakland, CA, USA
| | - Jie Yin
- Kaiser Permanente Northern California (KPNC), Division of Research, Oakland, CA, USA
| | - Yuhree Kim
- Department of Dermatology, Massachusetts General Hospital, Boston, MA, USA
- Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA
| | - Thomas J Hoffmann
- Institute for Human Genetics, University of California, San Francisco (UCSF), San Francisco, CA, USA
- Department of Epidemiology and Biostatistics, UCSF, San Francisco, CA, USA
| | | | - Maryam M Asgari
- Department of Dermatology, Massachusetts General Hospital, Boston, MA, USA
- Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA
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4
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Wang S, Lei Z, Liu W, Xiong J, Shi Y, Yang L, Gao Q, Le K, Zhang B. RCC2 promotes prostate cancer cell proliferation and migration through Hh/GLI1 signaling pathway and cancer stem-like cells. Biol Direct 2023; 18:80. [PMID: 38008751 PMCID: PMC10680210 DOI: 10.1186/s13062-023-00439-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 11/17/2023] [Indexed: 11/28/2023] Open
Abstract
BACKGROUND Regulator of chromosome condensation 2 (RCC2) was a telophase disk-binding protein on mitosis, and functions as an oncogene in many human cancers. However, its role on prostate cancer (PCa) was unknown. The goal of this study is to explore the function of RCC 2 on PCa development. METHODS The expression of RCC2 and its methylation level, its correlation with lymph node metastasis or disease-free survival (DFS) was analyzed using TCGA database. The effect of RCC2 on PCa cell proliferation, migration and invasion were detected using CCK-8, cell colony formation, Transwell and wood healing assays. RNA-seq and GSEA analysis were used to search the downstream genes and pathways of RCC2 in mediated PCa progression. Western blot was used to detect the proteins in PCa cells transfected with indicated siRNAs or plasmids. RESULTS RCC2 had high expression and low promoter methylation level in PCa, and its expression was correlated with regional node metastasis and disease-free survival. Cell proliferation, migration, invasion and EMT of PCa cells in vitro were greatly enhanced after RCC2 overexpression, while the RCC2 knockdown suppressed these processes. RNA-seq and GSEA results showed the Hedgehog signaling regulator Gli1 and Gli3 were involved in RCC2 knockdown DU145 cells. Gli1 was also a marker of cancer stem-like cells (CSCs). Mechanistically, RCC2 induced cell growth, EMT, CSCs markers through Gli1; inhibiting Gli1 expression using siGli1 or GLI inhibitor suppressed cell progression in vitro and tumor growth in vivo. CONCLUSION In summary, RCC2 promoted PCa development through Hh/Gli1 signaling pathway via regulating EMT and CSCs.
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Affiliation(s)
- Shenghan Wang
- Department of Urology, Aerospace Center Hospital, No.15, Yuquan Road, Haidian District, Beijing, 100049, China
| | - Zhentao Lei
- Department of Urology, Aerospace Center Hospital, No.15, Yuquan Road, Haidian District, Beijing, 100049, China
| | - Wei Liu
- Department of Urology, Aerospace Center Hospital, No.15, Yuquan Road, Haidian District, Beijing, 100049, China
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jie Xiong
- Department of Urology, Aerospace Center Hospital, No.15, Yuquan Road, Haidian District, Beijing, 100049, China
| | - Yuqiang Shi
- Department of Urology, Aerospace Center Hospital, No.15, Yuquan Road, Haidian District, Beijing, 100049, China
| | - Lin Yang
- Department of Urology, Aerospace Center Hospital, No.15, Yuquan Road, Haidian District, Beijing, 100049, China
| | - Qiang Gao
- Department of Urology, Aerospace Center Hospital, No.15, Yuquan Road, Haidian District, Beijing, 100049, China
| | - Kai Le
- Department of Urology, Aerospace Center Hospital, No.15, Yuquan Road, Haidian District, Beijing, 100049, China
| | - Bao Zhang
- Department of Urology, Aerospace Center Hospital, No.15, Yuquan Road, Haidian District, Beijing, 100049, China.
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Karimi K, Mojtabavi S, Tehrany PM, Nejad MM, Rezaee A, Mohtashamian S, Hamedi E, Yousefi F, Salmani F, Zandieh MA, Nabavi N, Rabiee N, Ertas YN, Salimimoghadam S, Rashidi M, Rahmanian P, Hushmandi K, Yu W. Chitosan-based nanoscale delivery systems in hepatocellular carcinoma: Versatile bio-platform with theranostic application. Int J Biol Macromol 2023; 242:124935. [PMID: 37230442 DOI: 10.1016/j.ijbiomac.2023.124935] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/13/2023] [Accepted: 05/15/2023] [Indexed: 05/27/2023]
Abstract
The field of nanomedicine has provided a fresh approach to cancer treatment by addressing the limitations of current therapies and offering new perspectives on enhancing patients' prognoses and chances of survival. Chitosan (CS) is isolated from chitin that has been extensively utilized for surface modification and coating of nanocarriers to improve their biocompatibility, cytotoxicity against tumor cells, and stability. HCC is a prevalent kind of liver tumor that cannot be adequately treated with surgical resection in its advanced stages. Furthermore, the development of resistance to chemotherapy and radiotherapy has caused treatment failure. The targeted delivery of drugs and genes can be mediated by nanostructures in treatment of HCC. The current review focuses on the function of CS-based nanostructures in HCC therapy and discusses the newest advances of nanoparticle-mediated treatment of HCC. Nanostructures based on CS have the capacity to escalate the pharmacokinetic profile of both natural and synthetic drugs, thus improving the effectiveness of HCC therapy. Some experiments have displayed that CS nanoparticles can be deployed to co-deliver drugs to disrupt tumorigenesis in a synergistic way. Moreover, the cationic nature of CS makes it a favorable nanocarrier for delivery of genes and plasmids. The use of CS-based nanostructures can be harnessed for phototherapy. Additionally, the incur poration of ligands including arginylglycylaspartic acid (RGD) into CS can elevate the targeted delivery of drugs to HCC cells. Interestingly, smart CS-based nanostructures, including ROS- and pH-sensitive nanoparticles, have been designed to provide cargo release at the tumor site and enhance the potential for HCC suppression.
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Affiliation(s)
- Kimia Karimi
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Sarah Mojtabavi
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | | | - Melina Maghsodlou Nejad
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Aryan Rezaee
- Iran University of Medical Sciences, Tehran, Iran
| | - Shahab Mohtashamian
- Department of Biomedical Engineering, Faculty of Chemical Engineering, Tarbiat Modares University, Tehran, Iran
| | - Erfan Hamedi
- Department of Aquatic Animal Health & Diseases, Department of Clinical Sciences, Faculty of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Farnaz Yousefi
- Department of Clinical Science, Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Farshid Salmani
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Mohammad Arad Zandieh
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Noushin Nabavi
- Department of Urological Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H3Z6, Canada
| | - Navid Rabiee
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA 6150, Australia; School of Engineering, Macquarie University, Sydney, New South Wales 2109, Australia
| | - Yavuz Nuri Ertas
- Department of Biomedical Engineering, Erciyes University, Kayseri, Turkey; ERNAM-Nanotechnology Research and Application Center, Erciyes University, Kayseri, Türkiye
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Parham Rahmanian
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran.
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
| | - Wei Yu
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, China.
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6
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Gong S, Wu H, Wu C, Duan Y, Zhang B, Wu P, Tang J, Fu J. A human pan-cancer system analysis of regulator of chromatin condensation 2. Heliyon 2023; 9:e13599. [PMID: 36865448 PMCID: PMC9970930 DOI: 10.1016/j.heliyon.2023.e13599] [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: 09/25/2022] [Revised: 01/30/2023] [Accepted: 02/05/2023] [Indexed: 02/12/2023] Open
Abstract
Regulation of chromosome condensation 2 (RCC2) is associated with the cell cycle and is a crucial regulator of the chromatin condensation 1 (RCC1) family. The members of this family were normally regulators in the process of DNA replication and nucleocytoplasmic transport. RCC2 overexpression may lead to tumor formation and poor prognosis in some tumors including breast cancer and lung adenocarcinoma. However, the possible role of RCC2 in tumor formation and its prognostic function remains unclear. In this study, expression analysis from databases including The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) were combined to perform the first integrative and comprehensive analysis of RCC2 in human pan-cancer. RCC2 was highly expressed in most tumors which may lead to a poor prognosis. RCC2 expression was associated with immune/stromal infiltration, immune checkpoints, tumor mutational burden, and microsatellite instability. Thus, RCC2 could be a novel biomarker for prognosis and a promising cancer therapy target.
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Affiliation(s)
- Siming Gong
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China,Institute of Anatomy, University of Leipzig, Leipzig, Germany
| | - Hao Wu
- Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Changwu Wu
- Institute of Anatomy, University of Leipzig, Leipzig, Germany
| | - Yingjuan Duan
- Faculty of Chemistry and Mineralogy, University of Leipzig, Leipzig, Germany
| | - Bixi Zhang
- Department of Pathology, Hunan Provincial People's Hospital, Hunan Normal University, Changsha, China
| | - Panfeng Wu
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Juyu Tang
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Jinfei Fu
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China,Corresponding author. Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China.
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LncRNA HOTAIR enhances RCC2 to accelerate cervical cancer progression by sponging miR-331-3p. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2023; 25:1650-1660. [PMID: 36593385 DOI: 10.1007/s12094-022-03059-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 12/21/2022] [Indexed: 01/03/2023]
Abstract
PURPOSE Long noncoding RNAs (lncRNAs) have been gradually regarded as influential indicators of various cancers. The present study aimed to identify the effects of lncRNA HOTAIR on cervical cancer progression. METHODS RNA and protein expressions were quantified by RT-qPCR and western blot assays. Fluorescence in situ hybridization (FISH) assay was carried out to examine the intracellular location of HOTAIR. Cancer cell viability and mobility were detected by CCK-8, colony formation, transwell and wound healing assays. Binding relationships between miR-331-3p and HOTAIR/RCC2 were validated by luciferase reporter assay. RESULTS RT-qPCR assays showed that HOTAIR levels were notably upregulated in cervical cancer tissues and cell lines. Furthermore, a fluorescence in situ hybridization (FISH) assay suggested that HOTAIR was mostly located in the cytoplasm of cancer cells, indicating a sponging function. CCK-8, colony formation, Transwell and wound-healing assays indicated that knockdown of HOTAIR in HeLa and SiHa cells significantly reduced cell growth, migration and invasion. Subsequently, miR-331-3p was proven to be the target molecule of HOTAIR. In addition, results from Pearson's correlation analysis indicated negative correlation between HOTAIR and miR-331-3p in cervical cancer tissues. HOTAIR negatively modulated miR-331-3p expression. Ultimately, the target gene of miR-331-3p was verified to be RCC2, and miR-331-3p negatively modulated RCC2 expression. In addition, analysis on clinical cervical cancer tissues confirmed the negative correlation between miR-331-3p and RCC2. HOTAIR and RCC2 showed oncogenic functions in HeLa and SiHa cells, while miR-331-3p exerted the reverse effect. CONCLUSIONS HOTAIR plays a carcinogenic role in cervical cancer by targeting the miR-331-3p/RCC2 axis. Moreover, clinical cervical cancer tissues confirmed the negative correlation between miR-331-3p with lncRNA HOTAIR and RCC2. These data suggested an underlying therapeutic target for cervical cancer.
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8
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Paskeh MDA, Ghadyani F, Hashemi M, Abbaspour A, Zabolian A, Javanshir S, Razzazan M, Mirzaei S, Entezari M, Goharrizi MASB, Salimimoghadam S, Aref AR, Kalbasi A, Rajabi R, Rashidi M, Taheriazam A, Sethi G. Biological impact and therapeutic perspective of targeting PI3K/Akt signaling in hepatocellular carcinoma: Promises and Challenges. Pharmacol Res 2023; 187:106553. [PMID: 36400343 DOI: 10.1016/j.phrs.2022.106553] [Citation(s) in RCA: 71] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/09/2022] [Accepted: 11/10/2022] [Indexed: 11/17/2022]
Abstract
Cancer progression results from activation of various signaling networks. Among these, PI3K/Akt signaling contributes to proliferation, invasion, and inhibition of apoptosis. Hepatocellular carcinoma (HCC) is a primary liver cancer with high incidence rate, especially in regions with high prevalence of viral hepatitis infection. Autoimmune disorders, diabetes mellitus, obesity, alcohol consumption, and inflammation can also lead to initiation and development of HCC. The treatment of HCC depends on the identification of oncogenic factors that lead tumor cells to develop resistance to therapy. The present review article focuses on the role of PI3K/Akt signaling in HCC progression. Activation of PI3K/Akt signaling promotes glucose uptake, favors glycolysis and increases tumor cell proliferation. It inhibits both apoptosis and autophagy while promoting HCC cell survival. PI3K/Akt stimulates epithelial-to-mesenchymal transition (EMT) and increases matrix-metalloproteinase (MMP) expression during HCC metastasis. In addition to increasing colony formation capacity and facilitating the spread of tumor cells, PI3K/Akt signaling stimulates angiogenesis. Therefore, silencing PI3K/Akt signaling prevents aggressive HCC cell behavior. Activation of PI3K/Akt signaling can confer drug resistance, particularly to sorafenib, and decreases the radio-sensitivity of HCC cells. Anti-cancer agents, like phytochemicals and small molecules can suppress PI3K/Akt signaling by limiting HCC progression. Being upregulated in tumor tissues and clinical samples, PI3K/Akt can also be used as a biomarker to predict patients' response to therapy.
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Affiliation(s)
- Mahshid Deldar Abad Paskeh
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Fatemeh Ghadyani
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Alireza Abbaspour
- Cellular and Molecular Research Center,Qazvin University of Medical Sciences, Qazvin, Iran
| | - Amirhossein Zabolian
- Resident of department of Orthopedics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Salar Javanshir
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehrnaz Razzazan
- Medical Student, Student Research Committee, Golestan University of Medical Sciences, Gorgan, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Translational Sciences, Xsphera Biosciences Inc. 6, Tide Street, Boston, MA 02210, USA
| | - Alireza Kalbasi
- Department of Pharmacy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Romina Rajabi
- Faculty of Veterinary Medicine, Islamic Azad University, Science and Research Branch, Tehran, Iran.
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.
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9
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Li X, Kang K, Peng Y, Shen L, Shen L, Zhou Y. Comprehensive analysis of the expression profile and clinical implications of regulator of chromosome condensation 2 in pan-cancers. Aging (Albany NY) 2022; 14:9221-9242. [PMID: 36441563 PMCID: PMC9740375 DOI: 10.18632/aging.204403] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 11/16/2022] [Indexed: 11/28/2022]
Abstract
The Regulator of Chromosome Condensation 2 (RCC2) is an important gene that regulates mitosis and cytoplasmic division in the cell cycle. Although there have been reported in several individual tumors, an integrative analysis of RCC2 and its clinical significance across diverse cancer types is poorly elucidated. In this study, we performed integrative bioinformatics analyses to profile the expression landscape and assess the prognostic value of RCC2 in pan-cancers. Correlations between RCC2 expression and tumor-infiltrating immune cells, tumor mutation burden (TMB), microsatellite instability (MSI), chemokine and their receptors were analyzed using TCGA, ESTIMATE algorithm, and TISIDB database. We also explored the potential molecular functions of RCC2 through functional enrichment analysis and protein interaction networks. We discovered that RCC2 was highly expressed in various tumor tissues and was closely associated with cancer prognosis. Different RCC2-associated immune infiltration patterns were exhibited in different tumor-infiltrating immune cells. In addition, the RCC2 had a potential role in regulating the tumor immune microenvironment and the formation of cancer-associated fibroblasts (CAFs). Meanwhile, RCC2 showed a significant correlation with TMB, MSI, chemokines and their receptors in different tumor types. The role of RCC2 as a clinical therapeutic target was further revealed from the perspective of the immune microenvironment. In conclusion, RCC2 is closely associated with tumorigenesis and cancer-immune infiltration, and could be a promising prognostic and therapeutic biomarker in diverse cancers.
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Affiliation(s)
- Xuanxuan Li
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Kuo Kang
- Department of General Surgery, Xiangya Hospital Central South University, Changsha, Hunan 410008, China
- Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumor, Xiangya Hospital Central South University, Changsha, Hunan 410008, China
| | - Yuanhao Peng
- NHC Key Laboratory of Carcinogenesis, Cancer Research Institute and School of Basic Medicine, Central South University, Changsha, Hunan 410078, China
| | - Lin Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Liangfang Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yangying Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
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10
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Zhang N, Shen Y, Li H, Chen Y, Zhang P, Lou S, Deng J. The m6A reader IGF2BP3 promotes acute myeloid leukemia progression by enhancing RCC2 stability. Exp Mol Med 2022; 54:194-205. [PMID: 35217832 PMCID: PMC8894383 DOI: 10.1038/s12276-022-00735-x] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 12/07/2021] [Accepted: 12/27/2021] [Indexed: 11/16/2022] Open
Abstract
N6-methyladenosine (m6A) is the most abundant posttranscriptional modification of mRNA in eukaryotes. Recent evidence suggests that dysregulated m6A-associated proteins and m6A modifications play a pivotal role in the initiation and progression of diseases such as cancer. Here, we identified that IGF2BP3 is specifically overexpressed in acute myeloid leukemia (AML), a subtype of leukemia associated with poor prognosis and high genetic risk. IGF2BP3 is required for maintaining AML cell survival in an m6A-dependent manner, and knockdown of IGF2BP3 dramatically suppresses the apoptosis, reduces the proliferation, and impairs the leukemic capacity of AML cells in vitro and in vivo. Mechanistically, IGF2BP3 interacts with RCC2 mRNA and stabilizes the expression of m6A-modified RNA. Thus, we provided compelling evidence demonstrating that the m6A reader IGF2BP3 contributes to tumorigenesis and poor prognosis in AML and can serve as a target for the development of cancer therapeutics. Inhibiting a protein that is overexpressed in the bone marrow of acute myeloid leukemia patients may prove valuable in treating the disease. Recent research has demonstrated the important role played by epigenetics in cancers – for example, disruption to a common mRNA modification known as m6A can result in cancer initiation and progression. Jianchuan Deng and co-workers at Chongqing Medical Universit0y, China, examined the role of an m6A-related protein called IGF2BP3 in mice models and samples from leukemia patients. IGF2BP3 was overexpressed in patients’ bone marrows, the levels of the protein correlating with extent of proliferation of leukemia cells and poor prognosis. IGF2BP3 stabilises the activity of a known cancer-related protein, promoting leukemia progression. Blocking IGF2BP3 expression reduced cell proliferation and impaired activity of leukemic cells, suggesting the protein may be a useful therapeutic target.
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Affiliation(s)
- Nan Zhang
- Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Yan Shen
- Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Huan Li
- Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Ying Chen
- Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Ping Zhang
- Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Shifeng Lou
- Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Jianchuan Deng
- Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
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11
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Zhang N, Shen Y, Li H, Chen Y, Zhang P, Lou S, Deng J. The m6A reader IGF2BP3 promotes acute myeloid leukemia progression by enhancing RCC2 stability. Exp Mol Med 2022; 54:194-205. [DOI: 4.doi: 10.1038/s12276-022-00735-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 12/07/2021] [Accepted: 12/27/2021] [Indexed: 05/14/2025] Open
Abstract
AbstractN6-methyladenosine (m6A) is the most abundant posttranscriptional modification of mRNA in eukaryotes. Recent evidence suggests that dysregulated m6A-associated proteins and m6A modifications play a pivotal role in the initiation and progression of diseases such as cancer. Here, we identified that IGF2BP3 is specifically overexpressed in acute myeloid leukemia (AML), a subtype of leukemia associated with poor prognosis and high genetic risk. IGF2BP3 is required for maintaining AML cell survival in an m6A-dependent manner, and knockdown of IGF2BP3 dramatically suppresses the apoptosis, reduces the proliferation, and impairs the leukemic capacity of AML cells in vitro and in vivo. Mechanistically, IGF2BP3 interacts with RCC2 mRNA and stabilizes the expression of m6A-modified RNA. Thus, we provided compelling evidence demonstrating that the m6A reader IGF2BP3 contributes to tumorigenesis and poor prognosis in AML and can serve as a target for the development of cancer therapeutics.
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12
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ZC3H13 Inhibits the Progression of Hepatocellular Carcinoma through m 6A-PKM2-Mediated Glycolysis and Enhances Chemosensitivity. JOURNAL OF ONCOLOGY 2022; 2021:1328444. [PMID: 35003256 PMCID: PMC8736703 DOI: 10.1155/2021/1328444] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/14/2021] [Accepted: 12/16/2021] [Indexed: 12/15/2022]
Abstract
Objective N6-Methyladenosine (m6A) is the most prevalent RNA epigenetic modulation in eukaryotic cells, which serves a critical role in diverse physiological processes. Emerging evidences indicate the prognostic significance of m6A regulator ZC3H13 in hepatocellular carcinoma (HCC). Herein, this study was conducted for revealing biological functions and mechanisms of ZC3H13 in HCC. Methods Expression of ZC3H13 was examined in collected HCC and normal tissues, and its prognostic significance was investigated in a public database. Gain/loss of functional assays were presented for defining the roles of ZC3H13 in HCC progression. The specific interactions of ZC3H13 with PKM2 were validated in HCC cells via mRNA stability, RNA immunoprecipitation, and luciferase reporter and MeRIP-qPCR assays. Moreover, rescue experiments were carried out for uncovering the mechanisms. Results ZC3H13 expression was downregulated in HCC, and its loss was in relation to dismal survival outcomes. Functionally, overexpressed ZC3H13 suppressed proliferation, migration, and invasion and elevated apoptotic levels of HCC cells. Moreover, ZC3H13 overexpression sensitized to cisplatin and weakened metabolism reprogramming of HCC cells. Mechanically, ZC3H13-induced m6A modified patterns substantially abolished PKM2 mRNA stability. ZC3H13 facilitated malignant behaviors of HCC cells through PKM2-dependent glycolytic signaling. Conclusion Collectively, ZC3H13 suppressed the progression of HCC through m6A-PKM2-mediated glycolysis and sensitized HCC cells to cisplatin, which offered a fresh insight into HCC therapy.
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Wu Q, Liu F, Ge M, Laster KV, Wei L, Du R, Jiang M, Zhang J, Zhi Y, Jin G, Zhao S, Kim DJ, Dong Z, Liu K. BRD4 drives esophageal squamous cell carcinoma growth by promoting RCC2 expression. Oncogene 2022; 41:347-360. [PMID: 34750516 DOI: 10.1038/s41388-021-02099-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 10/18/2021] [Accepted: 10/25/2021] [Indexed: 12/24/2022]
Abstract
The low survival rate of esophageal squamous cell carcinoma patients is primarily attributed to technical limitations and a lack of insight regarding the molecular mechanisms contributing to its progression. Alterations in epigenetic modulators are critical to cancer development and prognosis. BRD4, a chromatin reader protein, plays an essential role in regulating oncogene expression. Here, we investigated the contributing role of BRD4 and its related mechanisms in the context of ESCC tumor progression. Our observations showed that BRD4 transcript and protein expression levels are significantly increased in ESCC patient tissues. Genetic or pharmacological inhibition of BRD4 suppressed ESCC cell proliferation in vitro and in vivo. Proteomic and transcriptomic analyses were subsequently used to deduce the potential targets of BRD4. Mechanistic studies showed that RCC2 is a downstream target of BRD4. Inhibition of either BRD4 or RCC2 resulted in decreased ESCC cell proliferation. The BRD4-TP73 interaction facilitated the binding of BRD4 complex to the promoter region of RCC2, and subsequently modulated RCC2 transcription. Furthermore, targeting BRD4 with inhibitors significantly decreased tumor volume in ESCC PDX models, indicating that BRD4 expression may contribute to tumor progression. Collectively, these findings suggest that BRD4 inhibition could be a promising strategy to treat ESCC by downregulating RCC2.
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Affiliation(s)
- Qiong Wu
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China
| | - Fangfang Liu
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China
| | - Mengmeng Ge
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China
| | | | - Lixiao Wei
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China
| | - Ruijuan Du
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China
| | - Ming Jiang
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China
| | - Jing Zhang
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China
| | - Yafei Zhi
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China
| | - Guoguo Jin
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China.,The Henan Luoyang Orthopedic Hospital, Zhengzhou, 450000, Henan, China
| | - Simin Zhao
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China.,Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Dong Joon Kim
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China. .,China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China.
| | - Zigang Dong
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China. .,China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China. .,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, 450000, Henan, China. .,Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, 450000, Henan, China.
| | - Kangdong Liu
- The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China. .,China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China. .,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, 450000, Henan, China. .,Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, 450000, Henan, China. .,Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, 450000, Henan, China.
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14
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Natu A, Singh A, Gupta S. Hepatocellular carcinoma: Understanding molecular mechanisms for defining potential clinical modalities. World J Hepatol 2021; 13:1568-1583. [PMID: 34904030 PMCID: PMC8637668 DOI: 10.4254/wjh.v13.i11.1568] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/12/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
Liver cancer is the sixth most commonly occurring cancer and costs millions of lives per year. The diagnosis of hepatocellular carcinoma (HCC) has relied on scanning techniques and serum-based markers such as α-fetoprotein. These measures have limitations due to their detection limits and asymptomatic conditions during the early stages, resulting in late-stage cancer diagnosis where targeted chemotherapy or systemic treatment with sorafenib is offered. However, the aid of conventional therapy for patients in the advanced stage of HCC has limited outcomes. Thus, it is essential to seek a new treatment strategy and improve the diagnostic techniques to manage the disease. Researchers have used the omics profile of HCC patients for sub-classification of tissues into different groups, which has helped us with prognosis. Despite these efforts, a promising target for treatment has not been identified. The hurdle in this situation is genetic and epigenetic variations in the tumor, leading to disparities in response to treatment. Understanding reversible epigenetic changes along with clinical traits help to define new markers for patient categorization and design personalized therapy. Many clinical trials of inhibitors of epigenetic modifiers (also known as epi-drugs) are in progress. Epi-drugs like azacytidine or belinostat are already approved for other cancer treatments. Furthermore, epigenetic changes have also been observed in drug-resistant HCC tumors. In such cases, combinatorial treatment of epi-drugs with systemic therapy or trans-arterial chemoembolization might re-sensitize resistant cells.
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Affiliation(s)
- Abhiram Natu
- Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, Maharashtra, India
| | - Anjali Singh
- Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, Maharashtra, India
| | - Sanjay Gupta
- Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, Maharashtra, India
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Guo K, Zhao C, Lang B, Wang H, Zheng H, Zhang F. Regulator of Chromosome Condensation 2 Modulates Cell Cycle Progression, Tumorigenesis, and Therapeutic Resistance. Front Mol Biosci 2021; 7:620973. [PMID: 33521058 PMCID: PMC7838589 DOI: 10.3389/fmolb.2020.620973] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 12/08/2020] [Indexed: 01/03/2023] Open
Abstract
Accurate regulation of cell cycle is important for normal tissue development and homeostasis. RCC2 (Regulator of Chromosome Condensation 2) play a role as chromosomal passenger complex (CPC) implicated in all cell cycle phases. RCC2 was initially identified as Ran guanine exchange factor (GEF) for small G proteins. Therefore, RCC2 plays a key role in oncogenesis of most cancers. RCC2 is implicated in Colorectal Cancer (CRC), Lung Adenocarcinoma (LUAD), breast cancer, and ovarian cancer. Expression level of RCC2 protein determines regulation of tumor cell proliferation, invasion, metastasis, and radio-chemotherapeutic resistance. In this review, we explored proteins that interact with RCC2 to modulate tumor development and cancer therapeutic resistance by regulation of cell cycle process through various signaling pathways.
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Affiliation(s)
- Kun Guo
- College of Life Sciences, Shanghai Normal University, Shanghai, China
| | - Cheng Zhao
- College of Life Sciences, Shanghai Normal University, Shanghai, China
| | - Bin Lang
- College of Life Sciences, Shanghai Normal University, Shanghai, China
| | - Huiqin Wang
- College of Life Sciences, Shanghai Normal University, Shanghai, China
| | - Hang Zheng
- College of Life Sciences, Shanghai Normal University, Shanghai, China
| | - Feng Zhang
- College of Life Sciences, Shanghai Normal University, Shanghai, China
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16
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Apken LH, Oeckinghaus A. The RAL signaling network: Cancer and beyond. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2020; 361:21-105. [PMID: 34074494 DOI: 10.1016/bs.ircmb.2020.10.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The RAL proteins RALA and RALB belong to the superfamily of small RAS-like GTPases (guanosine triphosphatases). RAL GTPases function as molecular switches in cells by cycling through GDP- and GTP-bound states, a process which is regulated by several guanine exchange factors (GEFs) and two heterodimeric GTPase activating proteins (GAPs). Since their discovery in the 1980s, RALA and RALB have been established to exert isoform-specific functions in central cellular processes such as exocytosis, endocytosis, actin organization and gene expression. Consequently, it is not surprising that an increasing number of physiological functions are discovered to be controlled by RAL, including neuronal plasticity, immune response, and glucose and lipid homeostasis. The critical importance of RAL GTPases for oncogenic RAS-driven cellular transformation and tumorigenesis still attracts most research interest. Here, RAL proteins are key drivers of cell migration, metastasis, anchorage-independent proliferation, and survival. This chapter provides an overview of normal and pathological functions of RAL GTPases and summarizes the current knowledge on the involvement of RAL in human disease as well as current therapeutic targeting strategies. In particular, molecular mechanisms that specifically control RAL activity and RAL effector usage in different scenarios are outlined, putting a spotlight on the complexity of the RAL GTPase signaling network and the emerging theme of RAS-independent regulation and relevance of RAL.
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Affiliation(s)
- Lisa H Apken
- Institute of Molecular Tumor Biology, Faculty of Medicine, University of Münster, Münster, Germany
| | - Andrea Oeckinghaus
- Institute of Molecular Tumor Biology, Faculty of Medicine, University of Münster, Münster, Germany.
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RCC2 Expression Stimulates ER-Positive Breast Tumorigenesis. JOURNAL OF ONCOLOGY 2020; 2020:5619462. [PMID: 32565805 PMCID: PMC7262660 DOI: 10.1155/2020/5619462] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 04/19/2020] [Accepted: 05/04/2020] [Indexed: 02/07/2023]
Abstract
Objective Regulator of chromosome condensation 2 (RCC2) has been reported to be involved in the regulation of cell cleavage. This study investigated the effect of RCC2 expression on breast tumorigenesis. Methods MCF-7 cells originating from estrogen receptor-positive (ER+) breast cancer were transfected with anti-RCC2 siRNA or RCC2-expressing plasmids. Cell proliferation, apoptosis, migration, and cytokine production in the transfected cells were examined using the CCK-8 assay, wound healing assay, and flow cytometry, respectively. PCR array was used to investigate the tumorigenic pathway of RCC2 in MCF-7 cells transfected with the anti-RCC2 siRNA. MCF-7 cells were also transfected with lentivirus-containing anti-RCC2 short hairpin RNA and were injected into BALB/c nude mice to generate tumor-bearing mice. Tumor growth in the mouse model was examined using magnetic resonance imaging by diffusion-weighted imaging analysis. Results Western blotting and immunohistochemistry detected significantly increased expression of RCC2 in ER + breast tumor tissues compared with breast fibroadenoma samples. Inhibiting RCC2 expression decreased cell migration and stimulated apoptosis in MCF-7 cells, while overexpressing RCC2 stimulated cell migration and inhibited apoptosis. The inhibition of RCC2 expression significantly decreased breast tumor growth and IL-6 levels in the tumor-bearing mice. PCR array demonstrated that inhibiting RCC2 expression significantly decreased the expression of IGF1 and TWIST1, two well-known tumor-enhancing genes, in MCF-7 cells; conversely, overexpressing RCC2 increased the expression levels of these two genes in the transfected cells. This result was verified in the mouse model following inhibition of RCC2 expression in MCF-7 cells. Additionally, estradiol-17β suppressed MCF-7 cell apoptosis, stimulated cell proliferation and cell migration, and increased RCC2, IGF1, and TWIST1 expression. The siRNA-mediated inhibition of RCC2 expression alleviated the inhibitory effects of estrogen on apoptosis in MCF-7 cells, while overexpressing RCC2 enhanced the estrogen-driven inhibition of apoptosis. Modifying RCC2 expression had no impact on MCF-7 cell proliferation in the presence or absence of estradiol-17β. Conclusions Our results suggest that estrogen-induced RCC2 expression prompts IGF1, TWIST1, and IL-6 expression, stimulates cell migration, and inhibits apoptosis to contribute to ER + breast tumorigenesis.
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