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Khayer N, Shabani S, Jalessi M, Joghataei MT, Mahjoubi F. A dynamic co-expression approach reveals Gins2 as a potential upstream modulator of HNSCC metastasis. Sci Rep 2025; 15:3322. [PMID: 39865116 PMCID: PMC11770085 DOI: 10.1038/s41598-024-82668-1] [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: 09/08/2024] [Accepted: 12/09/2024] [Indexed: 01/28/2025] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer that is notably associated with a high risk of lymph node metastasis, a major cause of cancer mortality. Current therapeutic options remain limited to surgery supplemented by radio- or chemotherapy; however, these interventions often result in high-grade toxicities. Distant metastasis significantly contributed to the poor prognosis and decreased survival rates. However, the underlying molecular mechanisms remain poorly understood. Disease-related "omics" data provide a comprehensive overview of gene relationships, helping to decode the complex molecular mechanisms involved. Interactions between biological molecules are complex and highly dynamic across various cellular conditions, making traditional co-expression methods inadequate for understanding these intricate relationships. In the present study, a novel three-way interaction approach was employed to uncover dynamic co-expression relationships underlying the metastatic nature of HNSCC. Subsequently, the biologically relevant triples from statistically significant ones were defined through gene set enrichment analysis and reconstruction of the gene regulatory network. Finally, the validity of biologically relevant triplets was assessed at the protein level. The results highlighted the "PI3K/AKT/mTOR (PAM) signaling pathway" as a disrupted pathway involved in the metastatic nature of HNSCC. Notably, Gins2, identified as a switch gene, along with the gene pair {Akt2, Anxa2}, formed a statistically significant and biologically relevant triplet. It suggests that Gins2 could serve as a potential upstream modulator in the PAM signaling pathway, playing a crucial role in the distant metastasis of HNSCC. In addition, survival analysis of significant switch genes indicated that two genes, C19orf33 and Usp13, may be especially important for prognostic purposes in HNSCC.
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Affiliation(s)
- Nasibeh Khayer
- Skull Base Research Center, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Samira Shabani
- Department of Clinical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Maryam Jalessi
- Skull Base Research Center, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Taghi Joghataei
- Cellular and Molecular Research Center , Iran University of Medical Sciences, Tehran, Iran.
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Frouzandeh Mahjoubi
- Department of Clinical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran.
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2
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Zu F, Chen C, Geng Q, Li H, Chan B, Luo G, Wu M, Ilmer M, Renz BW, Bentum-Ennin L, Gu H, Sheng W. Smad2 Cooperating with TGIF2 Contributes to EMT and Cancer Stem Cells Properties in Pancreatic Cancer via Co-Targeting SOX2. Int J Biol Sci 2025; 21:524-543. [PMID: 39781447 PMCID: PMC11705628 DOI: 10.7150/ijbs.102381] [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: 08/15/2024] [Accepted: 11/18/2024] [Indexed: 01/12/2025] Open
Abstract
The underlying mechanisms between cancer stem cells (CSC) and epithelial-mesenchymal transition (EMT) in pancreatic cancer (PC) remain unclear. In this study, we identified TGIF2 as a target gene of CSC using sncRNA and machine learning. TGIF2 is closely related to the expression of SOX2, EGFR, and E-cadherin, indicating poor prognosis. Mechanistically, TGIF2 promoted the EMT phenotype and CSC properties following the activation of SOX2, Slug, CD44, and ERGF/MAPK signaling, which were rescued by SOX2 silencing. TGIF2 silencing contributes to the opposite phenotype via SOX2. Notably, Smad2 cooperates with TGIF2 to co-regulate the SOX2 promoter, which in turn promotes EMT and CSC signaling by transactivating Slug and EGFR, respectively. The transactivation of EGFR/MAPK signaling by SOX2 promotes TGIF2 nuclear translocation, forming a positive feedback loop in vitro. Moreover, the interaction of TGIF2 and SOX2 with EGFR inhibitors promoted subcutaneous tumors and liver metastasis in vivo. Thus, the TGIF2/SOX2 axis contributes to CSC, EMT, and chemoresistance, providing a promising target for PC therapy.
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Affiliation(s)
- Fuqiang Zu
- Department of General Surgery, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - ChuanPing Chen
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Qilong Geng
- Department of Clinical Medicine, Anhui Medical University, Hefei, 230022, China
| | - Haoyu Li
- Department of Clinical Medicine, Anhui Medical University, Hefei, 230022, China
| | - Boyuan Chan
- Department of Clinical Medicine, Anhui Medical University, Hefei, 230022, China
| | - Guopei Luo
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Mengcheng Wu
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Matthias Ilmer
- German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Bernhard W Renz
- German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Lutterodt Bentum-Ennin
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
| | - Hao Gu
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
| | - Weiwei Sheng
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
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Huang L, Sun J, Ma Y, Chen H, Tian C, Dong M. MSI2 regulates NLK-mediated EMT and PI3K/AKT/mTOR pathway to promote pancreatic cancer progression. Cancer Cell Int 2024; 24:273. [PMID: 39097735 PMCID: PMC11297748 DOI: 10.1186/s12935-024-03444-9] [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: 02/17/2024] [Accepted: 07/09/2024] [Indexed: 08/05/2024] Open
Abstract
BACKGROUND The incidence of pancreatic cancer is increasing by years, and the 5-year survival rate is very low. Our team have revealed that Musashi2 (MSI2) could promote aggressive behaviors in pancreatic cancer by downregulating Numb and p53. MSI2 also facilitates EMT in pancreatic cancer induced by EGF through the ZEB1-ERK/MAPK signaling pathway. This study aims to further explore the molecular mechanisms of MSI2-regulated downstream pathways in pancreatic cancer. METHODS In vitro and in vivo experiments were conducted to investigate the role and mechanism of MSI2 in promoting malignant behaviors of pancreatic cancer through regulation of NLK. RESULTS Genes closely related to MSI2 were screened from the GEPIA and TCGA databases. We found that NLK showed the most significant changes in mRNA levels with consistent changes following MSI2 interference and overexpression. The high correlation between MSI2 and NLK was also observed at the protein level. Multivariate analysis revealed that both MSI2 and NLK were independent adverse indicators of survival in pancreatic cancer patients, as well as join together. In vitro, silencing or overexpressing NLK altered cell invasion and migration, by regulating EMT and the PI3K-AKT-mTOR pathway. Silencing MSI2 reduced protein expression in the EMT and PI3K-AKT-mTOR pathways, leading to decreased cell invasion and migration abilities, while these effects could be reversed by overexpression of NLK. In vivo, MSI2 silencing inhibited liver metastasis, which could be reversed by overexpressing NLK. Mechanistically, MSI2 directly binds to the translation regulatory region of NLK mRNA at positions 79-87 nt, enhancing its transcriptional activity and exerting post-transcriptional regulatory roles. The analysis of molecular docking showed the close relationship between MSI2 and NLK in pancreatic cancer patients. CONCLUSIONS Our findings elucidate the regulatory mechanisms of the MSI2-NLK axis in modulating aggressive behaviors of pancreatic cancer cells, which providing new evidence for therapeutic strategies in pancreatic cancer.
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Affiliation(s)
- Longping Huang
- Department of Gastrointestinal Surgery, The First Hospital, China Medical University, Shenyang, 110001, China
- Department of Gastroenterology and Hepatology, The Fourth People's Hospital of Shenyang, Shenyang, 110031, China
| | - Jian Sun
- Department of Gastrointestinal Surgery, The First Hospital, China Medical University, Shenyang, 110001, China
| | - Yuteng Ma
- Department of Gastrointestinal Surgery, The First Hospital, China Medical University, Shenyang, 110001, China
| | - He Chen
- Department of Gastroenterology and Hepatology, The Fourth People's Hospital of Shenyang, Shenyang, 110031, China
| | - Chen Tian
- Department of Gastrointestinal Surgery, The First Hospital, China Medical University, Shenyang, 110001, China
| | - Ming Dong
- Department of Gastrointestinal Surgery, The First Hospital, China Medical University, Shenyang, 110001, China.
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Chee CW, Mohd Hashim N, Abdullah I, Nor Rashid N. RNA Sequencing and Bioinformatics Analysis Reveals the Downregulation of DNA Replication Genes by Morindone in Colorectal Cancer Cells. Appl Biochem Biotechnol 2024; 196:3216-3233. [PMID: 37642925 DOI: 10.1007/s12010-023-04690-9] [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] [Accepted: 08/16/2023] [Indexed: 08/31/2023]
Abstract
Morindone, a natural anthraquinone compound, has been reported to have significant pharmacological properties in different cancers. However, its anticancer effects in colorectal cancer (CRC) and the underlying molecular mechanisms remain obscure. In this study, RNA sequencing was used to assess the differentially expressed genes (DEGs) following morindone treatment in two CRC cell lines, HCT116 and HT29 cells. Functional enrichment analysis of overlapping DEGs revealed that negative regulation of cell development from biological processes and the MAPK signalling pathway were the most significant Gene Ontology terms and Kyoto Encyclopaedia of Genes and Genome pathway, respectively. Seven hub genes were identified among the overlapping genes, including MCM5, MCM6, MCM10, GINS2, POLE2, PRIM1, and WDHD1. All hub genes were found downregulated and involved in DNA replication fork. Among these, GINS2 was identified as the most cancer-dependent gene in both cells with better survival outcomes. Validation was performed on seven hub genes with rt-qPCR, and the results were consistent with the RNA sequencing findings. Collectively, this study provides corroboration of the potential therapeutic benefits and suitable pharmacological targets of morindone in the treatment of CRC.
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Affiliation(s)
- Cheok Wui Chee
- Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - Najihah Mohd Hashim
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
- Centre for Natural Products Research and Drug Discovery, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
- Drug Design and Development Research Group, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - Iskandar Abdullah
- Drug Design and Development Research Group, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
- Department of Chemistry, Faculty of Science, Universiti Malaya, 50603, Kuala Lumpur, Malaysia
| | - Nurshamimi Nor Rashid
- Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.
- Centre for Natural Products Research and Drug Discovery, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.
- Drug Design and Development Research Group, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.
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5
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Gu M, Liu Y, Xin P, Guo W, Zhao Z, Yang X, Ma R, Jiao T, Zheng W. Fundamental insights and molecular interactions in pancreatic cancer: Pathways to therapeutic approaches. Cancer Lett 2024; 588:216738. [PMID: 38401887 DOI: 10.1016/j.canlet.2024.216738] [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: 01/08/2024] [Revised: 02/08/2024] [Accepted: 02/18/2024] [Indexed: 02/26/2024]
Abstract
The gastrointestinal tract can be affected by a number of diseases that pancreatic cancer (PC) is a malignant manifestation of them. The prognosis of PC patients is unfavorable and because of their diagnosis at advanced stage, the treatment of this tumor is problematic. Owing to low survival rate, there is much interest towards understanding the molecular profile of PC in an attempt in developing more effective therapeutics. The conventional therapeutics for PC include surgery, chemotherapy and radiotherapy as well as emerging immunotherapy. However, PC is still incurable and more effort should be performed. The molecular landscape of PC is an underlying factor involved in increase in progression of tumor cells. In the presence review, the newest advances in understanding the molecular and biological events in PC are discussed. The dysregulation of molecular pathways including AMPK, MAPK, STAT3, Wnt/β-catenin and non-coding RNA transcripts has been suggested as a factor in development of tumorigenesis in PC. Moreover, cell death mechanisms such as apoptosis, autophagy, ferroptosis and necroptosis demonstrate abnormal levels. The EMT and glycolysis in PC cells enhance to ensure their metastasis and proliferation. Furthermore, such abnormal changes have been used to develop corresponding pharmacological and nanotechnological therapeutics for PC.
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Affiliation(s)
- Ming Gu
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Yang Liu
- Department of Urology, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Peng Xin
- Department of Urology, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Wei Guo
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Zimo Zhao
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Xu Yang
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Ruiyang Ma
- Department of Otorhinolaryngology, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China.
| | - Taiwei Jiao
- Department of Gastroenterology and Endoscopy, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China.
| | - Wenhui Zheng
- Department of Anesthesiology, The Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110001, China.
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Zhai LL, Li WB, Chen LJ, Wang W, Ju TF, Yin DL. Curcumin inhibits the invasion and migration of pancreatic cancer cells by upregulating TFPI-2 to regulate ERK- and JNK-mediated epithelial-mesenchymal transition. Eur J Nutr 2024; 63:639-651. [PMID: 38129361 DOI: 10.1007/s00394-023-03296-5] [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: 04/29/2023] [Accepted: 11/28/2023] [Indexed: 12/23/2023]
Abstract
PURPOSE Pancreatic cancer (PC) is one of the most deadly human malignancies. Curcumin is a natural polyphenolic compound with wide-ranging pharmacological effects. Growing evidence suggests that curcumin has anticancer activity against PC, but the mechanism remains incompletely elucidated. This study aimed to investigate the effects and mechanisms of curcumin on the invasion and migration of PC cells. METHODS Effect of curcumin on tissue factor pathway inhibitor (TFPI)-2 mRNA expression in PC cells was initially identified using qRT-PCR. Cytotoxicity of curcumin was assessed with MTT assays and IC50 was calculated. Involvement of ERK and JNK pathways, as well as protein expression of TFPI-2 and epithelial-mesenchymal transition (EMT)-related markers, were detected using immunoblotting. Invasion and migration of PC cells were examined using Transwell assays. TFPI-2 expression was manipulated by transfection with siRNA and shRNA. Rescue assays were used to validate the effect of curcumin on cell invasion and migration via TFPI-2. RESULTS Curcumin increased the expression of TFPI-2 mRNA and protein in PC cells and attenuated cell invasion and migration. Curcumin also inhibited ERK and JNK pathways and EMT in PC cells. Knockdown of TFPI-2 partially reversed the inhibition of ERK and JNK pathways and EMT by curcumin. Mechanistically, curcumin upregulated TFPI-2, thereby inhibiting the ERK and JNK pathways, leading to the inhibition of EMT in PC cells. CONCLUSION Collectively, curcumin inhibits ERK- and JNK-mediated EMT through upregulating TFPI-2, which in turn suppresses the migration and invasion of PC cells. These findings provide new insights into the antitumor mechanism of curcumin.
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Affiliation(s)
- Lu-Lu Zhai
- Department of General Surgery, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, 17 Lujiang Road, Hefei, 230001, People's Republic of China
- Department of General Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, 261 Huansha Road, Hangzhou, 310006, People's Republic of China
- Department of General Surgery, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, People's Republic of China
| | - Wei-Bo Li
- Department of General Surgery, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, People's Republic of China
| | - Long-Jiang Chen
- Department of General Surgery, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, People's Republic of China
| | - Wei Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, 430060, People's Republic of China
| | - Tong-Fa Ju
- Department of General Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, 261 Huansha Road, Hangzhou, 310006, People's Republic of China.
| | - Da-Long Yin
- Department of General Surgery, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, 17 Lujiang Road, Hefei, 230001, People's Republic of China.
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7
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Cao Z, An Y, Lu Y. Altered N6-Methyladenosine Modification Patterns and Transcript Profiles Contributes to Cognitive Dysfunction in High-Fat Induced Diabetic Mice. Int J Mol Sci 2024; 25:1990. [PMID: 38396669 PMCID: PMC10889299 DOI: 10.3390/ijms25041990] [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: 12/15/2023] [Revised: 01/18/2024] [Accepted: 01/25/2024] [Indexed: 02/25/2024] Open
Abstract
N6-methyladenosine (m6A) constitutes the paramount post-transcriptional modification within eukaryotic mRNA. This modification is subjected to stimulus-dependent regulation within the central nervous system of mammals, being influenced by sensory experiences, learning processes, and injuries. The patterns of m6A methylation within the hippocampal region of diabetes cognitive impairment (DCI) has not been investigated. A DCI model was established by feeding a high-fat diet to C57BL/6J mice. m6A and RNA sequencing was conducted to profile the m6A-tagged transcripts in the hippocampus. Methylated RNA immunoprecipitation with next-generation sequencing and RNA sequencing analyses yielded differentially m6A-modified and expressed genes in the hippocampus of DCI mice, which were enriched in pathways involving synaptic transmission and axonal guidance. Mechanistic analyses revealed a remarkable change in m6A modification levels through alteration of the mRNA expression of m6A methyltransferases (METTL3 and METTL14) and demethylase (FTO) in the hippocampus of DCI mice. We identified a co-mediated specific RNA regulatory strategy that broadens the epigenetic regulatory mechanism of RNA-induced neurodegenerative disorders associated with metabolic and endocrine diseases.
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Affiliation(s)
- Zhaoming Cao
- School of Nursing, Peking University, Beijing 100191, China;
| | - Yu An
- Endocrinology Department, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China;
| | - Yanhui Lu
- School of Nursing, Peking University, Beijing 100191, China;
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Ashrafizadeh M, Luo K, Zhang W, Reza Aref A, Zhang X. Acquired and intrinsic gemcitabine resistance in pancreatic cancer therapy: Environmental factors, molecular profile and drug/nanotherapeutic approaches. ENVIRONMENTAL RESEARCH 2024; 240:117443. [PMID: 37863168 DOI: 10.1016/j.envres.2023.117443] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 09/17/2023] [Accepted: 10/17/2023] [Indexed: 10/22/2023]
Abstract
A high number of cancer patients around the world rely on gemcitabine (GEM) for chemotherapy. During local metastasis of cancers, surgery is beneficial for therapy, but dissemination in distant organs leads to using chemotherapy alone or in combination with surgery to prevent cancer recurrence. Therapy failure can be observed as a result of GEM resistance, threatening life of pancreatic cancer (PC) patients. The mortality and morbidity of PC in contrast to other tumors are increasing. GEM chemotherapy is widely utilized for PC suppression, but resistance has encountered its therapeutic impacts. The purpose of current review is to bring a broad concept about role of biological mechanisms and pathways in the development of GEM resistance in PC and then, therapeutic strategies based on using drugs or nanostructures for overcoming chemoresistance. Dysregulation of the epigenetic factors especially non-coding RNA transcripts can cause development of GEM resistance in PC and miRNA transfection or using genetic tools such as siRNA for modulating expression level of these factors for changing GEM resistance are suggested. The overexpression of anti-apoptotic proteins and survival genes can contribute to GEM resistance in PC. Moreover, supportive autophagy inhibits apoptosis and stimulates GEM resistance in PC cells. Increase in metabolism, glycolysis induction and epithelial-mesenchymal transition (EMT) stimulation are considered as other factors participating in GEM resistance in PC. Drugs can suppress tumorigenesis in PC and inhibit survival factors and pathways in increasing GEM sensitivity in PC. More importantly, nanoparticles can increase pharmacokinetic profile of GEM and promote its blood circulation and accumulation in cancer site. Nanoparticles mediate delivery of GEM with genes and drugs to suppress tumorigenesis in PC and increase drug sensitivity. The basic research displays significant connection among dysregulated pathways and GEM resistance, but the lack of clinical application is a drawback that can be responded in future.
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Affiliation(s)
- Milad Ashrafizadeh
- Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China; International Association for Diagnosis and Treatment of Cancer, Shenzhen, Guangdong, 518055, China; Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Kuo Luo
- Department of Oncology, Chongqing Hyheia Hospital, Chongqing, 4001331, China
| | - Wei Zhang
- Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Xianbin Zhang
- Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China.
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Shi J, Li W, Jia Z, Peng Y, Hou J, Li N, Meng R, Fu W, Feng Y, Wu L, Zhou L, Wang D, Shen J, Chang J, Wang Y, Cao J. Synaptotagmin 1 Suppresses Colorectal Cancer Metastasis by Inhibiting ERK/MAPK Signaling-Mediated Tumor Cell Pseudopodial Formation and Migration. Cancers (Basel) 2023; 15:5282. [PMID: 37958455 PMCID: PMC10649299 DOI: 10.3390/cancers15215282] [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: 09/18/2023] [Revised: 10/21/2023] [Accepted: 11/01/2023] [Indexed: 11/15/2023] Open
Abstract
Although synaptotagmin 1 (SYT1) has been identified participating in a variety of cancers, its role in colorectal cancer (CRC) remains an enigma. This study aimed to demonstrate the effect of SYT1 on CRC metastasis and the underlying mechanism. We first found that SYT1 expressions in CRC tissues were lower than in normal colorectal tissues from the CRC database and collected CRC patients. In addition to this, SYT1 expression was also lower in CRC cell lines than in the normal colorectal cell line. SYT1 expression was downregulated by TGF-β (an EMT mediator) in CRC cell lines. In vitro, SYT1 overexpression repressed pseudopodial formation and reduced cell migration and invasion of CRC cells. SYT1 overexpression also suppressed CRC metastasis in tumor-bearing nude mice in vivo. Moreover, SYT1 overexpression promoted the dephosphorylation of ERK1/2 and downregulated the expressions of Slug and Vimentin, two proteins tightly associated with EMT in tumor metastasis. In conclusion, SYT1 expression is downregulated in CRC. Overexpression of SYT1 suppresses CRC cell migration, invasion, and metastasis by inhibiting ERK/MAPK signaling-mediated CRC cell pseudopodial formation. The study suggests that SYT1 is a suppressor of CRC and may have the potential to be a therapeutic target for CRC.
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Affiliation(s)
- Jianyun Shi
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan 030606, China
| | - Wenjing Li
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan 030606, China
| | - Zhenhua Jia
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan 030606, China
| | - Ying Peng
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan 030606, China
| | - Jiayi Hou
- Department of Clinical Laboratory, Shanxi Provincial Academy of Traditional Chinese Medicine, Taiyuan 030071, China
| | - Ning Li
- Department of Gastrointestinal and Pancreatic Surgery & Hernia and Abdominal Surgery, Shanxi Provincial People’s Hospital, Taiyuan 030045, China
| | - Ruijuan Meng
- Department of Radiology, The First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan 030606, China
| | - Wei Fu
- Department of Radiology, The First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan 030606, China
| | - Yanlin Feng
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan 030606, China
| | - Lifei Wu
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan 030606, China
| | - Lan Zhou
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan 030606, China
| | - Deping Wang
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan 030606, China
| | - Jing Shen
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan 030606, China
| | - Jiasong Chang
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan 030606, China
| | - Yanqiang Wang
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan 030606, China
| | - Jimin Cao
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, and the Department of Physiology, Shanxi Medical University, Taiyuan 030606, China
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10
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Wan M, Dai J, Gan A, Wang J, Lin F, Zhang X, Lv X, Wu B, Yan T, Jia Y. A network pharmacology approach to investigate dehydrocostus lactone inhibits the proliferation and epithelial-mesenchymal transition of human gastric cancer cells via regulating the PI3K/Akt and extracellular signal-regulated kinases/mitogen-activated protein kinase signalling pathways. J Pharm Pharmacol 2023; 75:1344-1356. [PMID: 37403268 DOI: 10.1093/jpp/rgad065] [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: 03/16/2023] [Accepted: 06/22/2023] [Indexed: 07/06/2023]
Abstract
OBJECTIVES Dehydrocostus lactone (DHE), a sesquiterpene lactone, has been proven the significant inhibition of multiple cancer cells. However, there are limited reports on the activity of DHE in gastric cancer (GC). In this research, Network pharmacology predicted the anti-GC mechanism of DHE, and the prediction was verified by in-vitro experiments. METHODS Network pharmacology confirmed the major effect signalling pathway of DHE in treating GC. Cell viability assay, colony formation assay, wound healing assay, cell migration and invasion assay, apoptosis assay, western blot and real-time quantitative polymerase chain reaction verified the mechanism of DHE in GC cell lines. KEY FINDINGS The results showed that DHE inhibited the growth and metastasis of MGC803 and AGS GC cells. Mechanistically, the analysis results indicated that DHE significantly induced the apoptosis process by suppressing the PI3K/protein kinase B (Akt) signalling pathway, and inhibited epithelial-mesenchymal transition by suppressing the extracellular signal-regulated kinases (ERK)/MAPK signalling pathway. The Akt activator (SC79) inhibited DHE induced apoptosis, and DHE had similar effects with the ERK inhibitor (FR180204). CONCLUSIONS All results suggested that DHE was a potential natural chemotherapeutic drug in GC treatment.
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Affiliation(s)
- Meiqi Wan
- Faculty of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, China
| | - Jun Dai
- Faculty of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, China
| | - Anna Gan
- Faculty of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, China
| | - Jinyu Wang
- Faculty of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, China
| | - Fei Lin
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Xiaoying Zhang
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Xinyan Lv
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Bo Wu
- Faculty of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, China
| | - Tingxu Yan
- Faculty of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, China
| | - Ying Jia
- Faculty of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, China
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11
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Tomioka Y, Suetsugu T, Seki N, Tanigawa K, Hagihara Y, Shinmura M, Asai S, Kikkawa N, Inoue H, Mizuno K. The Molecular Pathogenesis of Tumor-Suppressive miR-486-5p and miR-486-3p Target Genes: GINS4 Facilitates Aggressiveness in Lung Adenocarcinoma. Cells 2023; 12:1885. [PMID: 37508549 PMCID: PMC10378275 DOI: 10.3390/cells12141885] [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: 06/20/2023] [Revised: 07/14/2023] [Accepted: 07/16/2023] [Indexed: 07/30/2023] Open
Abstract
The involvement of passenger strands of miRNAs in the molecular pathogenesis of human cancers is a recent concept in miRNA research, and it will broaden our understanding of the molecular mechanisms of miRNA-mediated cancer. The analysis of our miRNA signature of LUAD revealed that both strands of pre-miR-486 (miR-486-5p and miR-486-3p) were downregulated in LUAD tissues. Ectopic expression of both miRNAs induced cell cycle arrest in LUAD cells, suggesting both strands of miRNAs derived from pre-miR-486 were tumor suppressive. Our in silico analysis showed a total of 99 genes may be under the control of both miRNAs in LUAD cells. Importantly, among these targets, the high expression of seven genes (MKI67, GINS4, RRM2, HELLS, MELK, TIMELESS, and SAPCD2) predicted a poorer prognosis of LUAD patients (p < 0.05). We focused on GINS4, a DNA replication complex GINS protein that plays an essential role in the initiation of DNA replication. Our functional assays showed that GINS4 was directly controlled by both strands of pre-miR-486, and its aberrant expression facilitated the aggressive behavior of LUAD cells. GINS4 is attractive as a therapeutic target for this disease. MiRNA analysis, including passenger strands, will further improve our understanding of the molecular pathogenesis of LUAD.
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Affiliation(s)
- Yuya Tomioka
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Takayuki Suetsugu
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Naohiko Seki
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan
| | - Kengo Tanigawa
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Yoko Hagihara
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Masahiro Shinmura
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Shunichi Asai
- Head and Neck Surgery, Chiba Cancer Center, Nitona, Chiba 260-8717, Japan
| | - Naoko Kikkawa
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan
| | - Hiromasa Inoue
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Keiko Mizuno
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
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12
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Li X, Jiang S, Jiang T, Sun X, Guan Y, Fan S, Cheng Y. LEM Domain Containing 1 Acts as a Novel Oncogene and Therapeutic Target for Triple-Negative Breast Cancer. Cancers (Basel) 2023; 15:cancers15112924. [PMID: 37296887 DOI: 10.3390/cancers15112924] [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: 04/12/2023] [Revised: 05/17/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
Breast cancer is the most common deadly malignancy in women worldwide. In particular, triple-negative breast cancer (TNBC) exhibits the worst prognosis among four subtypes of breast cancer due to limited treatment options. Exploring novel therapeutic targets holds promise for developing effective treatments for TNBC. Here, we demonstrated for the first time that LEMD1 (LEM domain containing 1) is highly expressed in TNBC and contributes to reduced survival in TNBC patients, through analysis of both bioinformatic databases and collected patient samples. Furthermore, LEMD1 silencing not only inhibited the proliferation and migration of TNBC cells in vitro, but also abolished tumor formation of TNBC cells in vivo. Knockdown of LEMD1 enhanced the sensitivity of TNBC cells to paclitaxel. Mechanistically, LEMD1 promoted the progress of TNBC by activating the ERK signaling pathway. In summary, our study revealed that LEMD1 may act as a novel oncogene in TNBC, and targeting LEMD1 may be exploited as a promising therapeutic approach to enhance the efficacy of chemotherapy against TNBC.
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Affiliation(s)
- Xiangling Li
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China
- Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha 410011, China
| | - Shilong Jiang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Ting Jiang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Xinyuan Sun
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Yidi Guan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Songqing Fan
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Yan Cheng
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China
- Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha 410011, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha 410011, China
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13
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Si H, Zhang N, Shi C, Luo Z, Hou S. Tumor-suppressive miR-29c binds to MAPK1 inhibiting the ERK/MAPK pathway in pancreatic cancer. Clin Transl Oncol 2023; 25:803-816. [PMID: 36510038 DOI: 10.1007/s12094-022-02991-9] [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: 07/19/2022] [Accepted: 10/23/2022] [Indexed: 12/14/2022]
Abstract
INTRODUCTION GEO- and TCGA-based data analysis suggested the differential expression of miR-29c in pancreatic cancer. However, limited data are available on the downstream mechanistic actions of miR-29c, which may fuel the in vitro and in vivo studies of pancreatic cancer. METHODS The downstream target gene of miR-29c and the downstream ERK/MAPK pathway involved in pancreatic cancer were predicted by bioinformatics tools. Next, the expression of miR-29c and MAPK1 was determined in pancreatic cancer tissues and cells. After ectopic expression and depletion experiments in pancreatic cancer cells, oncogenic phenotypes of pancreatic cancer cells were tested by MTS assay, Transwell assay, and flow cytometry. Effects of miR-29c/MAPK1 on tumorigenic ability in vivo were evaluated in pancreatic cancer xenografts in nude mice. RESULTS Through differential analysis, five pancreatic cancer-related miRNAs (hsa-miR-29c, hsa-miR-107, hsa-miR-324-3p, hsa-miR-375, and hsa-miR-210) were screened out, among which miR-29c was selected as the key miRNA related to prognosis of pancreatic cancer patients. miR-29c could target and inhibit MAPK1 to suppress the activation of ERK/MAPK pathway. miR-29c was downregulated in pancreatic cancer, and its high expression was related to the good prognosis of pancreatic cancer patients. Both in vitro and in vivo experiments demonstrated that restoration of miR-29c inhibited oncogenic phenotypes of pancreatic cancer cells, as well as repressed tumorigenic ability of pancreatic cancer cells in nude mice. CONCLUSIONS Taken together, we unveil a novel miR-29c/MAPK1/ERK/MAPK axis that suppresses pancreatic cancer both in vitro and in vivo.
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Affiliation(s)
- Hongtao Si
- Department of Oncology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People's Republic of China
| | - Ning Zhang
- Department of Oncology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People's Republic of China
| | - Chang Shi
- Department of Oncology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People's Republic of China
| | - Zhanjiang Luo
- The Seventh Hospital of Handan, Handan, 056005, People's Republic of China
| | - Senlin Hou
- Ninth Department of General Surgery, The Second Hospital of Hebei Medical University, No. 215, Heping West Road, Shijiazhuang, 050000, People's Republic of China.
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14
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STMN2 overexpression promotes cell proliferation and EMT in pancreatic cancer mediated by WNT/β-catenin signaling. Cancer Gene Ther 2023; 30:472-480. [PMID: 36460804 DOI: 10.1038/s41417-022-00568-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 11/03/2022] [Accepted: 11/16/2022] [Indexed: 12/03/2022]
Abstract
STMN2, as a key regulator in microtubule disassembly and dynamics, has recently been shown to participate in cancer development. However, the corresponding role in pancreatic ductal adenocarcinoma (PC), to our knowledge, has not been reported yet. In the current study, we systematically investigate the potential role of STMN2 in the progression of PC in vitro and vivo. Overexpression of STMN2 was prevalently observed in 81 human cases of PC tissues compared with that in the paired adjacent pancreas (54.3% vs 18.5%, P < 0.01), which was positively associated with multiple advanced clinical stages of PC patients (tumor size, T stage, lymph-node metastasis and the poor prognosis). Meanwhile, a close correlation between high STMN2 and cytoplasmic/nuclear β-catenin expression (P = 0.007) was observed in PC tissues and cell lines. STMN2 overexpression induced EMT and cell proliferation in vitro via stimulating EMT-like cellular morphology, cell motility and proliferation, and the change of EMT (Snail1, E-cadherin and Vimentin) and Cyclin D1 signaling. However, XAV939 inhibited STMN2 overexpression-enhanced EMT and proliferation. Conversely, KY19382 reversed STMN2 silencing- inhibited EMT and cell proliferation in vitro. Furthermore, activated STMN2 and β-catenin were co-localized in cytoplasm/nuclear in vitro. β-catenin/TCF-mediated the transcription of STMN2 by the potential binding sites (TTCAAAG). Finally, STMN2 promoted subcutaneous tumor growth following the activation of EMT and Cyclin D1 signaling. STMN2 overexpression promotes the aggressive clinical stage of PC patients and promotes EMT and cell proliferation in vitro and vivo. β-catenin/TCF-mediated the transcription of STMN2.
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15
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Zhao XH, Yang T, Zheng MY, Zhao P, An LY, Qi YX, Yi KQ, Zhang PC, Sun DL. Cystathionine gamma-lyase (Cth) induces efferocytosis in macrophages via ERK1/2 to modulate intestinal barrier repair. Cell Commun Signal 2023; 21:17. [PMID: 36691021 PMCID: PMC9869634 DOI: 10.1186/s12964-022-01030-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Accepted: 12/24/2022] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND The inflammatory response induced by intestinal ischaemia‒reperfusion injury (I/R) is closely associated with infectious complications and mortality in critically ill patients, and the timely and effective clearance of apoptotic cells is an important part of reducing the inflammatory response. Studies have shown that the efferocytosis by phagocytes plays an important role. Recently, studies using small intestine organoid models showed that macrophage efferocytosis could promote the repair capacity of the intestinal epithelium. However, no studies have reported efferocytosis in the repair of I/R in animal models. RESULTS We used an in vivo efferocytosis assay and discovered that macrophage efferocytosis played an indispensable role in repairing and maintaining intestinal barrier function after I/R. In addition, the specific molecular mechanism that induced macrophage efferocytosis was Cth-ERK1/2 dependent. We found that Cth drove macrophage efferocytosis in vivo and in vitro. Overexpression/silencing Cth promoted/inhibited the ERK1/2 pathway, respectively, which in turn affected efferocytosis and mediated intestinal barrier recovery. In addition, we found that the levels of Cth and macrophage efferocytosis were positively correlated with the recovery of intestinal function in clinical patients. CONCLUSION Cth can activate the ERK1/2 signalling pathway, induce macrophage efferocytosis, and thus promote intestinal barrier repair. Video Abstract.
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Affiliation(s)
- Xiao-Hu Zhao
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University/Second Faculty of Clinical Medicine, Kunming Medical University, Kunming, 650101, China
| | - Ting Yang
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University/Second Faculty of Clinical Medicine, Kunming Medical University, Kunming, 650101, China
| | - Meng-Yao Zheng
- Department of Gastroenterology, Second Affiliated Hospital of Kunming Medical University/Second Faculty of Clinical Medicine, Kunming Medical University, Kunming, 650101, China
| | - Peinan Zhao
- Department of Medicine (Alfred Hospital), Central Clinical School, Monash University, 99 Commercial Rd, Melbourne, VIC, 3004, Australia
| | - Li-Ya An
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University/Second Faculty of Clinical Medicine, Kunming Medical University, Kunming, 650101, China
| | - Yu-Xing Qi
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University/Second Faculty of Clinical Medicine, Kunming Medical University, Kunming, 650101, China
| | - Ke-Qian Yi
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University/Second Faculty of Clinical Medicine, Kunming Medical University, Kunming, 650101, China
| | - Peng-Cheng Zhang
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University/Second Faculty of Clinical Medicine, Kunming Medical University, Kunming, 650101, China
| | - Da-Li Sun
- Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University/Second Faculty of Clinical Medicine, Kunming Medical University, Kunming, 650101, China.
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16
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GINS2 Promotes Osteosarcoma Tumorigenesis via STAT3/MYC Axis. JOURNAL OF ONCOLOGY 2023; 2023:8454142. [PMID: 36873736 PMCID: PMC9981285 DOI: 10.1155/2023/8454142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/06/2022] [Accepted: 11/25/2022] [Indexed: 02/25/2023]
Abstract
GINS2 is overexpressed in several cancers, but little is known about its role in osteosarcoma (OS). A series of in vivo and in vitro experiments were conducted to explore the role of GINS2 in OS. In this study, we demonstrated that GINS2 was found to be highly expressed in OS tissues and cell lines, which was associated with poor outcomes in OS patients. GINS2 knockdown hindered the growth and induced apoptosis in OS cell lines in vitro. Furthermore, GINS2 knockdown effectively inhibited the growth of a xenograft tumor in vivo. By using an Affymetrix gene chip and intelligent pathway analysis, it was demonstrated that the GINS2 knockdown could reduce the expression of several targeted genes and reduce the activity of the MYC signaling pathway. Mechanically, LC-MS, CoIP, and rescue experiments revealed that GINS2 promoted tumor progression through the STAT3/MYC axis in the OS. Moreover, GINS2 was associated with tumor immunity and may be a potential immunotherapeutic target for OS.
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17
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Meng W, Jiang Z, Zhang X, Cai B, Ma L, Guan Y. Comprehensive Pan-Cancer Analysis of GINS2 for Human Tumour Prognosis and as an Immunological Biomarker. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:3119721. [PMID: 36466552 PMCID: PMC9711967 DOI: 10.1155/2022/3119721] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 11/07/2022] [Accepted: 11/09/2022] [Indexed: 11/07/2023]
Abstract
BACKGROUND In recent years, more and more reports have shown that GINS complex subunit 2 (GINS2) plays an important role in the occurrence and progression of tumours. However, there is a lack of comprehensive and systematic research on its prognostic and immune effects in pan-cancer. Therefore, this study is aimed at investigating the prognostic value and immune-related role of GINS2 in human tumours and providing a comprehensive understanding of its carcinogenic mechanism in pan-cancer. METHODS We investigated different databases, including TIMER, TCGA, GTEX, CPTAC, GEPIA, and SangerBox. The study was carried out on the expression and prognosis of GINS2 in human tumours, immune infiltration and microenvironment, immune checkpoints, neoantigens, tumour mutational burden, microsatellite instability, mismatch repair (MMR) genes, methylation, cancer-associated fibroblasts (CAFs), and enrichment analysis of gene set. RESULTS GINS2 plays a potential carcinogenic role in various human tumours through mRNA and protein levels. It is highly expressed in most cancers, and its expression is significantly correlated with tumour prognosis. In addition, the expression of GINS2 is associated with immune microenvironment and immune infiltration, especially in brain lower-grade glioma, lung squamous cell carcinoma, TGCT, breast invasive carcinoma, and glioblastoma multiforme. At the same time, GINS2 is related to immune neoantigens and the expression profiles of immune checkpoint genes in pan-cancer. It also affects the expression of DNA MMR genes and methyltransferase in pan-cancer. Finally, the correlation between GINS2 and CAF abundance in most tumours was studied, and an enrichment analysis of GINS2 and its related proteins was also carried out. CONCLUSION This is the first study on GINS2 as a prognostic and immune mechanism in pan-cancer. GINS2 may be a valuable prognostic immunological biomarker of pan-cancer. This paper provides a relatively comprehensive understanding on the correlation of GINS2 with pan-cancer.
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Affiliation(s)
- Wei Meng
- Department of Urology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Zhaosheng Jiang
- Department of Urology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Xiang Zhang
- Department of Urology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Bo Cai
- Department of Urology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Limin Ma
- Department of Urology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Yangbo Guan
- Department of Urology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
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18
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Chen F, Zheng X, Liang W, Jiang C, Su D, Fu B. Long Noncoding RNA MIR600HG Binds to MicroRNA-125a-5p to Prevent Pancreatic Cancer Progression Via Mitochondrial Tumor Suppressor 1-Dependent Suppression of Extracellular Regulated Protein Kinases Signaling Pathway. Pancreas 2022; 51:1434-1443. [PMID: 37099789 DOI: 10.1097/mpa.0000000000002185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/28/2023]
Abstract
OBJECTIVES Significance of long noncoding RNAs in pancreatic cancer (PC) progression has been documented. Here, we identified a novel long noncoding RNA MIR600HG in PC and its underlying mechanism during PC progression. METHODS Through bioinformatics analysis, we selected MIR600HG, microRNA-125a-5p (miR-125a-5p), and mitochondrial tumor suppressor 1 (MTUS1) as objects with their expression patterns assayed in the collected PC tissues and PC cells. Pancreatic cancer cells were manipulated with ectopic expression and deficiency of MIR600HG, miR-125a-5p, and/or MTUS1 for assaying cell biological processes in vitro and tumorigenesis in vivo. RESULTS MIR600HG and MTUS1 levels were downregulated and miR-125a-5p was upregulated in PC tissues and cells. MIR600HG could bind to miR-125a-5p, while miR-125a-5p negatively targeted MTUS1. MIR600HG resulted in suppression in malignant properties of PCs. All these changes could be reversed by miR-125a-5p elevation. In addition, miR-125a-5p targeted MTUS1 to activate the extracellular regulated protein kinases signaling pathway. In vivo experiment also verified the inhibitory role of MIR600HG in PC. CONCLUSIONS Taken together, MIR600HG acts as an inhibitor for PC progression by upregulating miR-125a-5p-mediated MTUS1 through extracellular regulated protein kinases pathway.
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Affiliation(s)
- Fang Chen
- From the Intensive Care Unit, Affiliated Hospital of Zunyi Medical University
| | - Xiang Zheng
- Department of Medical Genetics, Zunyi Medical University, Zunyi, China
| | - Wenmei Liang
- From the Intensive Care Unit, Affiliated Hospital of Zunyi Medical University
| | - Chunxia Jiang
- From the Intensive Care Unit, Affiliated Hospital of Zunyi Medical University
| | - De Su
- From the Intensive Care Unit, Affiliated Hospital of Zunyi Medical University
| | - Bao Fu
- From the Intensive Care Unit, Affiliated Hospital of Zunyi Medical University
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19
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Shan DD, Zheng QX, Chen Z. Go-Ichi-Ni-San 2: A potential biomarker and therapeutic target in human cancers. World J Gastrointest Oncol 2022; 14:1892-1902. [PMID: 36310704 PMCID: PMC9611433 DOI: 10.4251/wjgo.v14.i10.1892] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/15/2022] [Accepted: 09/06/2022] [Indexed: 02/05/2023] Open
Abstract
Cancer incidence and mortality are increasing globally, leading to its rising status as a leading cause of death. The Go-Ichi-Ni-San (GINS) complex plays a crucial role in DNA replication and the cell cycle. The GINS complex consists of four subunits encoded by the GINS1, GINS2, GINS3, and GINS4 genes. Recent findings have shown that GINS2 expression is upregulated in many diseases, particularly tumors. For example, increased GINS2 expression has been found in cervical cancer, gastric adenocarcinoma, glioma, non-small cell lung cancer, and pancreatic cancer. It correlates with the clinicopathological characteristics of the tumors. In addition, high GINS2 expression plays a pro-carcinogenic role in tumor development by promoting tumor cell proliferation and migration, inhibiting tumor cell apoptosis, and blocking the cell cycle. This review describes the upregulation of GINS2 expression in most human tumors and the pathway of GINS2 in tumor development. GINS2 may serve as a new marker for tumor diagnosis and a new biological target for therapy.
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Affiliation(s)
- Dan-Dan Shan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Qiu-Xian Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
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20
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Zhou C, Chen Z, Xiao B, Xiang C, Li A, Zhao Z, Li H. Comprehensive analysis of GINS subunits prognostic value and ceRNA network in sarcoma. Front Cell Dev Biol 2022; 10:951363. [PMID: 36092720 PMCID: PMC9462653 DOI: 10.3389/fcell.2022.951363] [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: 05/23/2022] [Accepted: 07/29/2022] [Indexed: 11/13/2022] Open
Abstract
Background: The GINS complex, composed of GINS1/2/3/4 subunits, is an essential structure of Cdc45-MCM-GINS (CMG) helicase and plays a vital role in establishing the DNA replication fork and chromosome replication. Meanwhile, GINS genes have been associated with the poor prognosis of various malignancies. However, the abnormal expression of GINS genes and their diagnostic and prognostic value in sarcomas (SARC) remain unclear. Methods: Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier Plotter, Cancer cell line encyclopedia (CCLE), The University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN), R studio, and Tumor Immune Estimation Resource (TIMER) were used to analyze the expression profiles, prognostic value, biological function, ceRNA, and immune infiltration associated with GINS genes in sarcomas. Results: We found that GINS1/2/3/4 genes exhibited significantly upregulated transcription levels in SARC samples compared to non-tumor tissues and exhibited high expression levels in sarcoma cell lines. In addition, SARC patients with increased expression levels of GINS1/2/3/4 showed poorer survival rates. Immune infiltration analysis showed that GINS subunits were closely associated with the infiltration of immune cells in sarcomas. Conclusion: Our research identified GINS subunits as potential diagnostic and prognostic biological targets in SARC and elucidated their underlying effects in the genesis and progression of SARC. These results may provide new opportunities and research directions for targeted sarcoma therapy.
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Affiliation(s)
- Chuqiao Zhou
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China
- Orthopedic Biomedical Materials Engineering Laboratory of Hunan Province, Changsha, China
| | - Zhuoyuan Chen
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China
- Orthopedic Biomedical Materials Engineering Laboratory of Hunan Province, Changsha, China
| | - Bo Xiao
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China
- Orthopedic Biomedical Materials Engineering Laboratory of Hunan Province, Changsha, China
| | - Cheng Xiang
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China
- Orthopedic Biomedical Materials Engineering Laboratory of Hunan Province, Changsha, China
| | - Aoyu Li
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China
- Orthopedic Biomedical Materials Engineering Laboratory of Hunan Province, Changsha, China
| | - Ziyue Zhao
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China
- Orthopedic Biomedical Materials Engineering Laboratory of Hunan Province, Changsha, China
| | - Hui Li
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China
- Orthopedic Biomedical Materials Engineering Laboratory of Hunan Province, Changsha, China
- *Correspondence: Hui Li,
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21
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Liu Y, Su CY, Yan YY, Wang J, Li JJ, Fu JJ, Wang YQ, Zhang JY. Exosomes of A549 Cells Induced Migration, Invasion, and EMT of BEAS-2B Cells Related to let-7c-5p and miR-181b-5p. Front Endocrinol (Lausanne) 2022; 13:926769. [PMID: 35898472 PMCID: PMC9309177 DOI: 10.3389/fendo.2022.926769] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 06/03/2022] [Indexed: 12/24/2022] Open
Abstract
As carriers containing abundant biological information, exosomes could deliver the property of donor cells to recipient cells. Emerging studies have shown that tumor cells could secrete a mass of exosomes into the microenvironment to regulate bystander cells. However, the underlying mechanisms of such a phenomenon remain largely unexplored. In this research, we purified and identified the exosomes of A549 cells and found that A549-cell-derived exosomes promoted BEAS-2B cells migration, invasion, and epithelial-mesenchymal transition (EMT). Importantly, we observed that let-7c-5p and miR-181b-5p were attenuated in A549-cell-derived exosomes compared to BEAS-2B-cell-derived exosomes. The analysis of miRNA expression level in BEAS-2B cells indicated that incubation with A549-cell-derived exosomes reduced the expression levels of let-7c-5p and miR-181b-5p. In transient transfections assay, we found that downregulation of let-7c-5p and miR-181b-5p simultaneously showed stronger promotion of BEAS-2B cells migration and invasion than individually. Moreover, exosomes secreted from A549 cells with upregulated expression of let-7c-5p and miR-181b-5p significantly reduce their regulatory effect on BEAS-2B cells. Bioinformatics analyses revealed that let-7c-5p and miR-181b-5p inhibit the EMT process mainly by regulating focal adhesion and mitogen-activated protein kinase (MAPK) signaling pathway. Thus, our data demonstrated that A549-cell-derived exosomal let-7c-5p and miR-181b-5p could induce migration, invasion, and EMT in BEAS-2B cells, which might be regulated through focal adhesion and MAPK signaling pathway. The expression level of let-7c-5p and miR-181b-5p may show great significance for the early diagnosis of lung cancer.
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Affiliation(s)
- Yun Liu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target and Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Chao-Yue Su
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target and Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yan-Yan Yan
- School of Medicine, Shanxi Datong University, Datong, China
| | - Jian Wang
- School of Medicine, Shanxi Datong University, Datong, China
| | - Jia-Jun Li
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target and Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Ji-Jun Fu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target and Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yu-Qing Wang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target and Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jian-Ye Zhang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target and Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
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22
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Zhang Y, Hao X, Han G, Lu Y, Chen Z, Zhang L, Wu J, Wang X. E2F1-mediated GINS2 transcriptional activation promotes tumor progression through PI3K/AKT/mTOR pathway in hepatocellular carcinoma. Am J Cancer Res 2022; 12:1707-1726. [PMID: 35530279 PMCID: PMC9077065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 03/23/2022] [Indexed: 06/14/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has high morbidity and mortality rates. It is therefore imperative to study the underlying mechanism of HCC to identify potential prognostic biomarkers and therapeutic targets. Recently, GINS2 has been identified to be a cancer-promoting gene in different cancer types. Nevertheless, the exact mechanism of GINS2 in HCC remains to be elucidated. To systematically explore the significance of GINS2, we first assessed the relative expression of GINS2 in pan-cancers based on data obtained from the HCCDB, TIMER, and TCGA databases. Then, we explored the clinical significance of GINS2 in HCC through Kaplan-Meier method as well as univariate and multivariate cox regression analysis. Additionally, functional enrichment analysis of GINS2 was done through GO, KEGG, PPI network, and immune cell infiltration analyses. Functional experiments were also conducted to investigate the biological significance of GINS2 in HCC cell lines. Our research revealed that GINS2 is involved in HCC progression and highlighted its potential value as a crucial diagnostic and therapeutic target for HCC.
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Affiliation(s)
- Yao Zhang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical SciencesNanjing 210029, Jiangsu, China
| | - Xiaopei Hao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical SciencesNanjing 210029, Jiangsu, China
| | - Guoyong Han
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical SciencesNanjing 210029, Jiangsu, China
| | - Yiwei Lu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical SciencesNanjing 210029, Jiangsu, China
| | - Zhiqiang Chen
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical SciencesNanjing 210029, Jiangsu, China
| | - Long Zhang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical SciencesNanjing 210029, Jiangsu, China
| | - Jindao Wu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical SciencesNanjing 210029, Jiangsu, China
- State Key Laboratory of Reproductive Medicine, Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Xuehao Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical SciencesNanjing 210029, Jiangsu, China
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23
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Sheng W, Tang J, Cao R, Shi X, Ma Y, Dong M. Numb-PRRL promotes TGF-β1- and EGF-induced epithelial-to-mesenchymal transition in pancreatic cancer. Cell Death Dis 2022; 13:173. [PMID: 35197444 PMCID: PMC8866481 DOI: 10.1038/s41419-022-04609-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 01/18/2022] [Accepted: 02/01/2022] [Indexed: 01/10/2023]
Abstract
Isoform-specific functions of Numb in the development of cancers, especially in the initiation of epithelial-to-mesenchymal transition (EMT) remains controversial. We study the specific function of Numb-PRRL isoform in activated EMT of pancreatic ductal adenocarcinoma (PC), which is distinguished from our previous studies that only focused on the total Numb protein. Numb-PRRL isoform was specifically overexpressed and silenced in PC cells combining with TGF-β1 and EGF stimulus. We systematically explored the potential effect of Numb-PRRL in the activated EMT of PC in vitro and in vivo. The total Numb protein was overexpressed in the normal pancreatic duct and well-differentiated PC by IHC. However, Numb-PRRS isoform but not Numb-PRRL showed dominant expression in PC tissues. Numb-PRRL overexpression promoted TGF-β1-induced EMT in PANC-1 and Miapaca-2 cells. TGF-β1-induced EMT-like cell morphology, cell invasion, and migration were enhanced in Numb-PRRL overexpressing groups following the increase of N-cadherin, Vimentin, Smad2/3, Snail1, Snail2, and cleaved-Notch1 and the decrease of E-cadherin. Numb-PRRL overexpression activated TGFβ1-Smad2/3-Snail1 signaling was significantly reversed by the Notch1 inhibitor RO4929097. Conversely, Numb-PRRL silencing inhibited EGF-induced EMT in AsPC-1 and BxPC-3 cells following the activation of EGFR-ERK/MAPK signaling via phosphorylating EGFR at tyrosine 1045. In vivo, Numb-PRRL overexpression or silencing promoted or inhibited subcutaneous tumor size and distant liver metastases via regulating EMT and Snail signaling, respectively. Numb-PRRL promotes TGF-β1- and EGF-induced EMT in PC by regulating TGF-β1-Smad2/3-Snail and EGF-induced EGFR-ERK/MAPK signaling.
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Affiliation(s)
- Weiwei Sheng
- Department of Gastrointestinal Surgery, The First Hospital, China Medical University, 110001, Shenyang, Liaoning, China
| | - Jingtong Tang
- Department of Gastrointestinal Surgery, The First Hospital, China Medical University, 110001, Shenyang, Liaoning, China
| | - Rongxian Cao
- Department of Gastrointestinal Surgery, The First Hospital, China Medical University, 110001, Shenyang, Liaoning, China
| | - Xiaoyang Shi
- Department of Hernia and Abdominal Wall Surgery, Chaoyang Hospital, 100043, Beijing, China
| | - Yuteng Ma
- Department of Gastrointestinal Surgery, The First Hospital, China Medical University, 110001, Shenyang, Liaoning, China
| | - Ming Dong
- Department of Gastrointestinal Surgery, The First Hospital, China Medical University, 110001, Shenyang, Liaoning, China.
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24
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Zhong X, Zhang S, Zhang Y, Jiang Z, Li Y, Chang J, Niu J, Shi Y. HMGB3 is Associated With an Unfavorable Prognosis of Neuroblastoma and Promotes Tumor Progression by Mediating TPX2. Front Cell Dev Biol 2022; 9:769547. [PMID: 34988076 PMCID: PMC8721485 DOI: 10.3389/fcell.2021.769547] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 11/22/2021] [Indexed: 12/14/2022] Open
Abstract
Neuroblastoma (NB) is the most common solid tumor apart from central nervous system malignancies in children aged 0–14 years, and the outcomes of high-risk patients are dismal. High mobility group box 3 (HMGB3) plays an oncogenic role in many cancers; however, its biological role in NB is still unclear. Using data mining, we found that HMGB3 expression was markedly elevated in NB patients with unfavorable prognoses. When HMGB3 expression in NB cell lines was inhibited, cell proliferation, migration, and invasion were suppressed, and HMGB3 knockdown inhibited NB tumor development in mice. RT−PCR was employed to detect mRNA expression of nine coexpressed genes in response to HMGB3 knockdown, and TPX2 was identified. Furthermore, overexpression of TPX2 reversed the cell proliferation effect of HMGB3 silencing. Multivariate Cox regression analysis indicated that HMGB3 and TPX2 might be independent prognostic factors for overall survival and event-free survival, which showed the highest significance (p < 0.001). According to the nomogram predictor constructed, the integration of gene expression and clinicopathological features exhibited better prognostic prediction power. Furthermore, the random forest algorithm and receiver operating characteristic curves also showed that HMGB3 and TPX2 played important roles in discriminating the vital status (alive/dead) of patients in the NB datasets. Our informatics analysis and biological experiments suggested that HMGB3 is correlated with the unfavorable clinical outcomes of NB, and plays an important role in promoting cell growth, proliferation, and invasion in NB, potentially representing a new therapeutic target for tumor progression.
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Affiliation(s)
- Xiaodan Zhong
- Department of Pediatric Oncology, The First Hospital of Jilin University, Changchun, China
| | - Songling Zhang
- Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China
| | - Yutong Zhang
- Department of Pediatric Oncology, The First Hospital of Jilin University, Changchun, China
| | - Zongmiao Jiang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, China
| | - Yanan Li
- Department of Pediatrics, The First Hospital of Jilin University, Changchun, China
| | - Jian Chang
- Department of Pediatric Oncology, The First Hospital of Jilin University, Changchun, China
| | - Junqi Niu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Ying Shi
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
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25
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Feng H, Zeng J, Gao L, Zhou Z, Wang L. GINS Complex Subunit 2 Facilitates Gastric Adenocarcinoma Proliferation and Indicates Poor Prognosis. TOHOKU J EXP MED 2021; 255:111-121. [PMID: 34629365 DOI: 10.1620/tjem.255.111] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Gastric cancer is the one of the most lethal malignancies of digestive system. Identifying molecular biomarkers is invaluable in help predicting clinical outcomes and developing targeted chemotherapies. GINS complex subunit 2 (GINS2) plays an essential role in the initiation and elongation of DNA replication. Although there have been studies revealing the prognostic significance of GINS2 in breast cancer and lung cancer, its involvement and function in gastric cancer need to be elucidated. We retrospectively enrolled a cohort of gastric adenocarcinoma patients after surgical resection (n = 123). By analyzing the mRNA and protein levels of GINS2 in tissue samples, we found that GINS2 presented a higher expression in tumor tissues than in adjacent normal stomach tissues. Besides, GINS2 level was positively correlated with tumor size and gastric adenocarcinoma tumor stage, implying its potential role as a tumor promoter. Univariate and multivariate analyses identified that patients with lower GINS2 showed a better overall survival compared to those with higher GINS2 expression. In addition, cellular and xenograft experiments confirmed the role of GINS2 in facilitating tumor proliferation both in vitro and in vivo. To our knowledge, this is the initial finding on GINS2 in promoting gastric adenocarcinoma progression. In conclusion, our study revealed a pro-oncogenic role of GINS2 in gastric cancer.
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Affiliation(s)
- Hongjun Feng
- Department of Gastroenterology, Sanya Central Hospital (Hainan Third People's Hospital)
| | - Juntao Zeng
- Department of Gastroenterology, Sanya Central Hospital (Hainan Third People's Hospital)
| | - Lei Gao
- Department of Gastroenterology, Sanya Central Hospital (Hainan Third People's Hospital)
| | - Zhenzhen Zhou
- Department of Gastroenterology, Sanya Central Hospital (Hainan Third People's Hospital)
| | - Liya Wang
- Department of Gastroenterology, Sanya Central Hospital (Hainan Third People's Hospital)
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26
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Ranieri D, Guttieri L, Raffa S, Torrisi MR, Belleudi F. Role of FGFR2c and Its PKC ε Downstream Signaling in the Control of EMT and Autophagy in Pancreatic Ductal Adenocarcinoma Cells. Cancers (Basel) 2021; 13:4993. [PMID: 34638477 PMCID: PMC8508074 DOI: 10.3390/cancers13194993] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/27/2021] [Accepted: 10/01/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a treatment-resistant malignancy characterized by a high malignant phenotype including acquired EMT signature and deregulated autophagy. Since we have previously described that the aberrant expression of the mesenchymal FGFR2c and the triggering of the downstream PKCε signaling are involved in epidermal carcinogenesis, the aim of this work has been to assess the contribution of these oncogenic events also in the pancreatic context. Biochemical, molecular and immunofluorescence approaches showed that FGFR2c expression impacts on PDAC cell responsiveness to FGF2 in terms of intracellular signaling activation, upregulation of EMT-related transcription factors and modulation of epithelial and mesenchymal markers compatible with the pathological EMT. Moreover, shut-off via specific protein depletion of PKCε signaling, activated by high expression of FGFR2c resulted in a reversion of EMT profile, as well as in a recovery of the autophagic process. The detailed biochemical analysis of the intracellular signaling indicated that PKCε, bypassing AKT and directly converging on ERK1/2, could be a signaling molecule downstream FGFR2c whose inhibition could be considered as possible effective therapeutic approach in counteracting aggressive phenotype in cancer.
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Affiliation(s)
- Danilo Ranieri
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Luisa Guttieri
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Salvatore Raffa
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
- Laboratory of Ultrastructural Pathology, Unit of Medical Genetics and Advanced Cellular Diagnostics,Department of Diagnostic Sciences, Sant'Andrea University Hospital, 00189 Rome, Italy
| | - Maria Rosaria Torrisi
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
- Laboratory of Ultrastructural Pathology, Unit of Medical Genetics and Advanced Cellular Diagnostics,Department of Diagnostic Sciences, Sant'Andrea University Hospital, 00189 Rome, Italy
| | - Francesca Belleudi
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
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27
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Liu C, Hu C, Li J, Jiang L, Zhao C. Identification of Epithelial-Mesenchymal Transition-Related lncRNAs that Associated With the Prognosis and Immune Microenvironment in Colorectal Cancer. Front Mol Biosci 2021; 8:633951. [PMID: 33898515 PMCID: PMC8059639 DOI: 10.3389/fmolb.2021.633951] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 02/19/2021] [Indexed: 12/23/2022] Open
Abstract
Background: The expression of long non-coding RNA (lncRNA) is associated with the epithelial-mesenchymal transition (EMT) in tumorigenicity, but the role of EMT-related lncRNA in colorectal cancer (CRC) remains unclear. Methods: The clinical data and gene expression profile of CRC patients were obtained from The Cancer Genome Atlas database. Differential expression analysis, Cox regression model, and Kaplan-Meier analysis were used to study the relationship between EMT-related lncRNAs and the prognosis of CRC. Functional analysis and unsupervised clustering analysis were performed to explore the influence of certain lncRNAs on CRC. Finally, Cytoscape was used to construct mRNA-lncRNA networks. Results: Two signatures incorporating six and ten EMT-related lncRNAs were constructed for predicting the overall survival (OS) and disease-free survival (DFS), respectively. Kaplan-Meier survival curves indicated that patients in the high-risk group had a poorer prognosis than those in the low-risk group. The results of the functional analysis suggested that the P53 and ECM-receptor pathways affect the prognosis of CRC, and AL591178.1 is a key prognostic EMT-related lncRNA, which is negatively related to immune cells, P53 pathway, and ECM-receptor pathway. Conclusion: Six OS-related and ten DFS-related EMT-related lncRNAs were correlated with the prognosis of CRC by potentially affecting the immune microenvironment, and AL591178.1 plays a key role as a prognostic factor.
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Affiliation(s)
- Chuan Liu
- Graduate College, China Medical University, Shenyang, China
| | - Chuan Hu
- Department of Spinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jianyi Li
- Department of Spinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Liqing Jiang
- Graduate College, China Medical University, Shenyang, China
| | - Chengliang Zhao
- Department of Spinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
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28
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Xue H, Sun Z, Wu W, Du D, Liao S. Identification of Hub Genes as Potential Prognostic Biomarkers in Cervical Cancer Using Comprehensive Bioinformatics Analysis and Validation Studies. Cancer Manag Res 2021; 13:117-131. [PMID: 33447084 PMCID: PMC7802793 DOI: 10.2147/cmar.s282989] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 11/24/2020] [Indexed: 12/20/2022] Open
Abstract
Background Cervical cancer belongs to one of the most common female cancers; yet, the exact underlying mechanisms are still elusive. Recently, microarray and sequencing technologies have been widely used for screening biomarkers and molecular mechanism discovery in cancer studies. In this study, we aimed to analyse the microarray datasets using comprehensive bioinformatics tools and identified novel biomarkers associated with the prognosis of patients with cervical cancer. Methods The differentially expressed genes (DEGs) from Gene Expression Omnibus (GEO) datasets including GSE138080, GSE113942 and GSE63514 were analysed using GEO2R tool. The functional enrichment analysis was performed using g:Profiler tool. The protein-protein interaction (PPI) network construction and hub genes identification were performed using the STRING database and Cytoscape software, respectively. The hub genes were subjected to expression and survival analysis in the cervical cancer. The EdU incorporation and Cell Counting Kit-8 assays were performed to evaluate the effects of hub gene knockdown on the proliferation of cervical cancer cells. Results A total of 89 overlapping DEGs (63 up-regulated and 26 down-regulated genes) were identified in the microarray datasets. The functional enrichment analysis indicated that the overlapping DEGs were mainly associated with "DNA replication" and "cell cycle". Furthermore, the PPI network analysis revealed that the network contains 87 nodes and 309 edges. Sub-module analysis using the Molecular Complex Detection tool identified 21 hub genes from the PPI network. The expression levels of the 21 hub genes were all up-regulated in the cervical cancer tissues when compared to normal cervical tissues as analysed by GEPIA tool. The survival analysis showed that the low expression of cell division cycle 45 (CDC45), GINS complex subunit 2 (GINS2), minichromosome maintenance complex component 2 (MCM2) and proliferating cell nuclear antigen (PCNA) was significantly correlated with the shorter overall survival of patients with cervical cancer. Moreover, the protein expression levels of GINS2, MCM2 and PCNA, but not CDC45, were significantly up-regulated in the cervical cancer tissues when compared to normal cervical tissues. Finally, knockdown of MCM2 significantly suppressed the proliferation of HeLa and SiHa cells. Conclusion In conclusion, we screened a total of 89 overlapping DEGs from the GEO datasets, and further analysis identified four hub genes (CDC45, GINS2, MCM2 and PCNA) that were likely associated with the prognosis of patients with cervical cancer. MCM2 knockdown repressed the cervical cancer cell proliferation. The current findings may provide novel insights into understanding the pathophysiology of cervical cancer and develop therapeutic targets for patients with cervical cancer.
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Affiliation(s)
- Han Xue
- Department of Health Management, Shenzhen People's Hospital, Shenzhen City, Guangdong Province, People's Republic of China
| | - Zhaojun Sun
- Department of Dermatology, Shenzhen People's Hospital, Shenzhen City, GuangdongProvince, People's Republic of China
| | - Weiqing Wu
- Department of Health Management, Shenzhen People's Hospital, Shenzhen City, Guangdong Province, People's Republic of China
| | - Dong Du
- Department of Health Management, Shenzhen People's Hospital, Shenzhen City, Guangdong Province, People's Republic of China
| | - Shuping Liao
- Department of Health Management, Shenzhen People's Hospital, Shenzhen City, Guangdong Province, People's Republic of China
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