|
1
|
Albano F, Russi S, Laurino S, Mazzone P, Di Paola G, Zoppoli P, Amendola E, Balzamo C, Bartolo O, Ciuffi M, Ignomirelli O, Sgambato A, Galasso R, De Felice M, Falco G, Calice G. Representing ECM composition and EMT pathways in gastric cancer using a new metastatic gene signature. Front Cell Dev Biol 2024; 12:1481818. [PMID: 39563861 PMCID: PMC11573575 DOI: 10.3389/fcell.2024.1481818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 10/15/2024] [Indexed: 11/21/2024] Open
Abstract
Introduction Gastric cancer (GC) is an aggressive and heterogeneous malignancy marked by cellular and molecular diversity. In GC, cancer cells invade locally in the stomach at stage I and can progress to metastasis in distant organs by stage IV, where it often becomes fatal. Methods We analyzed gene expression profiles from 719 stage I and stage IV GC patients across seven public datasets, conducting functional enrichment analysis to identify a gene signature linked to disease progression. Additionally, we developed an in vitro model of a simplified extracellular matrix (ECM) for cell-based assays. Results Our analysis identified a progression-associated gene signature (APOD, COL1A2, FSTL1, GEM, LUM, and SPARC) that characterizes stage IV GC. This signature is associated with ECM organization and epithelial-to-mesenchymal transition (EMT), both of which influence the tumor microenvironment by promoting cell invasion and triggering EMT. Discussion This gene signature may help identify stage I GC patients at higher risk, offering potential utility in early-stage patient management. Furthermore, our experimental ECM model may serve as a platform for investigating molecular mechanisms underlying metastatic spread in gastric cancer.
Collapse
Affiliation(s)
- Francesco Albano
- Laboratory of Preclinical and Translational Research, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), Rionero inVulture, Italy
- Laboratory of Stem Cell Biology, Department of Biology, University Federico II of Napoli, Napoli, Italy
- Laboratory of Stemness and Tissue Regeneration, Biogem S.c.a.r.l., Ariano Irpino, Italy
| | - Sabino Russi
- Laboratory of Preclinical and Translational Research, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), Rionero inVulture, Italy
| | - Simona Laurino
- Laboratory of Preclinical and Translational Research, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), Rionero inVulture, Italy
| | - Pellegrino Mazzone
- Laboratory of Stemness and Tissue Regeneration, Biogem S.c.a.r.l., Ariano Irpino, Italy
| | - Giuseppina Di Paola
- Laboratory of Stemness and Tissue Regeneration, Biogem S.c.a.r.l., Ariano Irpino, Italy
| | - Pietro Zoppoli
- Department of Molecular Medicine and Medical Biotechnologies, University Federico II, Napoli, Italy
| | - Elena Amendola
- Laboratory of Stem Cell Biology, Department of Biology, University Federico II of Napoli, Napoli, Italy
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale "Gaetano Salvatore" (IEOS), Consiglio Nazionale delle Ricerche (CNR), Napoli, Italy
| | - Chiara Balzamo
- Laboratory of Stem Cell Biology, Department of Biology, University Federico II of Napoli, Napoli, Italy
| | - Ottavia Bartolo
- Endoscopy Unit, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), Rionero inVulture, Italy
| | - Mario Ciuffi
- Endoscopy Unit, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), Rionero inVulture, Italy
| | - Orazio Ignomirelli
- Endoscopy Unit, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), Rionero inVulture, Italy
| | - Alessandro Sgambato
- Department of Translational Medicine and Surgery, Catholic University of Sacro Cuore, Roma, Italy
- Scientific Direction, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB) Via Padre Pio 1, Rionero inVulture, Italy
| | - Rocco Galasso
- Scientific Direction, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB) Via Padre Pio 1, Rionero inVulture, Italy
| | - Mario De Felice
- Department of Molecular Medicine and Medical Biotechnologies, University Federico II, Napoli, Italy
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale "Gaetano Salvatore" (IEOS), Consiglio Nazionale delle Ricerche (CNR), Napoli, Italy
| | - Geppino Falco
- Laboratory of Stem Cell Biology, Department of Biology, University Federico II of Napoli, Napoli, Italy
- Laboratory of Stemness and Tissue Regeneration, Biogem S.c.a.r.l., Ariano Irpino, Italy
| | - Giovanni Calice
- Laboratory of Preclinical and Translational Research, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), Rionero inVulture, Italy
| |
Collapse
|
|
2
|
Ouyang Z, Zhu H, Liu Z, Tu C, Qu J, Lu Q, Xu M. Curcumin inhibits the proliferation and migration of osteosarcoma by regulating the expression of super -enhancer -associated genes. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2024; 49:541-552. [PMID: 39019783 PMCID: PMC11255199 DOI: 10.11817/j.issn.1672-7347.2024.230224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Indexed: 07/19/2024]
Abstract
OBJECTIVES Super-enhancer-associated genes may be closely related to the progression of osteosarcoma, curcumin exhibits a certain inhibitory effect on tumors such as osteosarcoma. This study aims to investigate the effects of curcumin on osteosarcoma in vitro and in vivo, and to determine whether curcumin can inhibit the progression of osteosarcoma by suppressing the expression of super-enhancer-associated genes LIM and senescent cell antigen-like-containing domain 1 (LIMS1), secreted protein acidic and rich in cysteine (SPARC), and sterile alpha motif domain containing 4A (SAMD4A). METHODS Human osteosarcoma cell lines (MG63 cells or U2OS cells) were treated with 5 to 50 μmol/L curcumin for 24, 48, and 72 hours, followed by the methyl thiazolyl tetrazolium (MTT) assay to detect cell viability. Cells were incubated with dimethyl sulfoxide (DMSO) or curcumin (2.5, 5.0 μmol/L) for 7 days, and a colony formation assay was used to measure in vitro cell proliferation. After treatment with DMSO or curcumin (10, 15 μmol/L), a scratch healing assay and a transwell migration assay were performed to evaluate cell migration ability. Real-time reverse transcription polymerase chain reaction (real-time RT-PCR) and Western blotting were used to detect mRNA and protein expression levels of LIMS1, SPARC, and SAMD4A in the cells. An osteosarcoma-bearing nude mouse model was established, and curcumin was administered via gavage for 14 days to assess the impact of curcumin on tumor volume and weight in vivo. Real-time RT-PCR was used to measure mRNA expression levels of LIMS1, SPARC, and SAMD4A in the cancer and adjacent tissues from 12 osteosarcoma patients. RESULTS After treating cells with different concentrations of curcumin for 24, 48, and 72 hours, cell viability were all significantly decreased. Compared with the DMSO group, the colony formation rates in the 2.5 μmol/L and 5.0 μmol/L curcumin groups significantly declined (both P<0.01). The scratch healing assay showed that, compared with the DMSO group, the migration rates of cells in the 10 μmol/L and 15 μmol/L curcumin groups were significantly reduced. The exception was the 10 μmol/L curcumin group at 24 h, where the migration rate of U2OS cells did not show a statistically significant difference (P>0.05), while all other differences were statistically significant (P<0.01 or P<0.001). The transwell migration assay results showed that the number of migrating cells in the 10 μmol/L and 15 μmol/L curcumin groups was significantly lower than that in the DMSO group (both P<0.001). In the in vivo tumor-bearing mouse experiment, the curcumin group showed a reduction in tumor mass (P<0.01) and a significant reduction in tumor volume (P<0.001) compared with the control group. Compared with the DMSO group, the mRNA expression levels of LIMS1, SPARC, and SAMD4A in the 10 μmol/L and 15 μmol/L curcumin groups were significantly down-regulated (all P<0.05). Additionally, the protein expression level of LIMS1 in U2OS cells in the 10 μmol/L curcumin group was significantly lower than that in the DMSO group (P<0.05). Compared with adjacent tissues, the mRNA expression level of SPARC in osteosarcoma tissues was significantly increased (P<0.001), while the mRNA expression levels of LIMS1 and SAMD4A did not show statistically significant differences (both P>0.05). CONCLUSIONS Curcumin inhibits the proliferation and migration of osteosarcoma both in vitro and in vivo, which may be associated with the inactivation of super-enhancer-associated gene LIMS1.
Collapse
Affiliation(s)
- Zhanbo Ouyang
- Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha 410011.
- Institute of Clinical Pharmacy, Second Xiangya Hospital, Central South University, Changsha 410011.
- Department of Pharmacy, Yueyang Central Hospital, Yueyang Hunan 414000.
| | - Haihong Zhu
- Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha 410011
- Institute of Clinical Pharmacy, Second Xiangya Hospital, Central South University, Changsha 410011
| | - Zhongyue Liu
- Department of Orthopaedics, Second Xiangya Hospital, Central South University, Changsha 410011
| | - Chao Tu
- Department of Orthopaedics, Second Xiangya Hospital, Central South University, Changsha 410011
| | - Jian Qu
- Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha 410011
- Institute of Clinical Pharmacy, Second Xiangya Hospital, Central South University, Changsha 410011
| | - Qiong Lu
- Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha 410011
- Institute of Clinical Pharmacy, Second Xiangya Hospital, Central South University, Changsha 410011
| | - Min Xu
- Department of Critical Care Medicine, Second Xiangya Hospital, Central South University, Changsha 410011, China.
| |
Collapse
|
|
3
|
Jiang S, Sun HF, Li S, Zhang N, Chen JS, Liu JX. SPARC: a potential target for functional nanomaterials and drugs. Front Mol Biosci 2023; 10:1235428. [PMID: 37577749 PMCID: PMC10419254 DOI: 10.3389/fmolb.2023.1235428] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 07/13/2023] [Indexed: 08/15/2023] Open
Abstract
Secreted protein acidic and rich in cysteine (SPARC), also termed osteonectin or BM-40, is a matricellular protein which regulates cell adhesion, extracellular matrix production, growth factor activity, and cell cycle. Although SPARC does not perform a structural function, it, however, modulates interactions between cells and the surrounding extracellular matrix due to its anti-proliferative and anti-adhesion properties. The overexpression of SPARC at sites, including injury, regeneration, obesity, cancer, and inflammation, reveals its application as a prospective target and therapeutic indicator in the treatment and assessment of disease. This article comprehensively summarizes the mechanism of SPARC overexpression in inflammation and tumors as well as the latest research progress of functional nanomaterials in the therapy of rheumatoid arthritis and tumors by manipulating SPARC as a new target. This article provides ideas for using functional nanomaterials to treat inflammatory diseases through the SPARC target. The purpose of this article is to provide a reference for ongoing disease research based on SPARC-targeted therapy.
Collapse
Affiliation(s)
- Shan Jiang
- School of Pharmacy, Heilongjiang University of Traditional Chinese Medicine, Harbin, China
- School of Pharmaceutical Sciences, Department of Rehabilitation and Healthcare, Hunan University of Medicine, Huaihua, China
| | - Hui-Feng Sun
- School of Pharmacy, Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Shuang Li
- School of Pharmaceutical Sciences, Department of Rehabilitation and Healthcare, Hunan University of Medicine, Huaihua, China
- College Pharmacy, Jiamusi University, Jiamusi, China
| | - Ning Zhang
- School of Pharmacy, Heilongjiang University of Traditional Chinese Medicine, Harbin, China
- School of Pharmaceutical Sciences, Department of Rehabilitation and Healthcare, Hunan University of Medicine, Huaihua, China
| | - Ji-Song Chen
- School of Pharmaceutical Sciences, Department of Rehabilitation and Healthcare, Hunan University of Medicine, Huaihua, China
| | - Jian-Xin Liu
- School of Pharmaceutical Sciences, Department of Rehabilitation and Healthcare, Hunan University of Medicine, Huaihua, China
- School of Pharmaceutical Sciences, University of South China, Hengyang, China
- Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| |
Collapse
|
|
4
|
Yin LK, Yuan HY, Liu JJ, Xu XL, Wang W, Bai XY, Wang P. Identification of survival-associated biomarkers based on three datasets by bioinformatics analysis in gastric cancer. World J Clin Cases 2023; 11:4763-4787. [PMID: 37584004 PMCID: PMC10424043 DOI: 10.12998/wjcc.v11.i20.4763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 04/11/2023] [Accepted: 06/06/2023] [Indexed: 07/06/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common malignant tumors with poor prognosis in terms of advanced stage. However, the survival-associated biomarkers for GC remains unclear. AIM To investigate the potential biomarkers of the prognosis of patients with GC, so as to provide new methods and strategies for the treatment of GC. METHODS RNA sequencing data from The Cancer Genome Atlas (TCGA) database of STAD tumors, and microarray data from Gene Expression Omnibus (GEO) database (GSE19826, GSE79973 and GSE29998) were obtained. The differentially expressed genes (DEGs) between GC patients and health people were picked out using R software (x64 4.1.3). The intersections were underwent between the above obtained co-expression of differential genes (co-DEGs) and the DEGs of GC from Gene Expression Profiling Interactive Analysis database, and Gene Ontology (GO) analysis, Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis, Gene Set Enrichment Analysis (GSEA), Protein-protein Interaction (PPI) analysis and Kaplan-Meier Plotter survival analysis were performed on these DEGs. Using Immunohistochemistry (IHC) database of Human Protein Atlas (HPA), we verified the candidate Hub genes. RESULTS With DEGs analysis, there were 334 co-DEGs, including 133 up-regulated genes and 201 down-regulated genes. GO enrichment analysis showed that the co-DEGs were involved in biological process, cell composition and molecular function pathways. KEGG enrichment analysis suggested the co-DEGs pathways were mainly enriched in ECM-receptor interaction, protein digestion and absorption pathways, etc. GSEA pathway analysis showed that co-DEGs mainly concentrated in cell cycle progression, mitotic cell cycle and cell cycle pathways, etc. PPI analysis showed 84 nodes and 654 edges for the co-DEGs. The survival analysis illustrated 11 Hub genes with notable significance for prognosis of patients were screened. Furtherly, using IHC database of HPA, we confirmed the above candidate Hub genes, and 10 Hub genes that associated with prognosis of GC were identified, namely BGN, CEP55, COL1A2, COL4A1, FZD2, MAOA, PDGFRB, SPARC, TIMP1 and VCAN. CONCLUSION The 10 Hub genes may be the potential biomarkers for predicting the prognosis of GC, which can provide new strategies and methods for the diagnosis and treatment of GC.
Collapse
Affiliation(s)
- Long-Kuan Yin
- Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
- Sichuan Key Laboratory of Medical Imaging, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Hua-Yan Yuan
- Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Jian-Jun Liu
- Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Xiu-Lian Xu
- Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Wei Wang
- Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Xiang-Yu Bai
- Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
- Sichuan Key Laboratory of Medical Imaging, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Pan Wang
- Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
- Sichuan Key Laboratory of Medical Imaging, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| |
Collapse
|
|
5
|
Identification of Cancer Driver Genes by Integrating Multiomics Data with Graph Neural Networks. Metabolites 2023; 13:metabo13030339. [PMID: 36984779 PMCID: PMC10052551 DOI: 10.3390/metabo13030339] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 02/20/2023] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
Cancer is a heterogeneous disease that is driven by the accumulation of both genetic and nongenetic alterations, so integrating multiomics data and extracting effective information from them is expected to be an effective way to predict cancer driver genes. In this paper, we first generate comprehensive instructive features for each gene from genomic, epigenomic, transcriptomic levels together with protein–protein interaction (PPI)-networks-derived attributes and then propose a novel semisupervised deep graph learning framework GGraphSAGE to predict cancer driver genes according to the impact of the alterations on a biological system. When applied to eight tumor types, experimental results suggest that GGraphSAGE outperforms several state-of-the-art computational methods for driver genes identification. Moreover, it broadens our current understanding of cancer driver genes from multiomics level and identifies driver genes specific to the tumor type rather than pan-cancer. We expect GGraphSAGE to open new avenues in precision medicine and even further predict drivers for other complex diseases.
Collapse
|
|
6
|
Sha Y, Mao AQ, Liu YJ, Li JP, Gong YT, Xiao D, Huang J, Gao YW, Wu MY, Shen H. Nidogen-2 (NID2) is a Key Factor in Collagen Causing Poor Response to Immunotherapy in Melanoma. Pharmgenomics Pers Med 2023; 16:153-172. [PMID: 36908806 PMCID: PMC9994630 DOI: 10.2147/pgpm.s399886] [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: 12/08/2022] [Accepted: 02/25/2023] [Indexed: 03/06/2023] Open
Abstract
Background The incidence of cutaneous melanoma continues to rise rapidly and has an extremely poor prognosis. Immunotherapy strategies are the most effective approach for patients who have developed metastases, but not all cases have been successful due to the complex and variable mechanisms of melanoma response to immune checkpoint inhibition. Methods We synthesized collagen-coding gene expression data (second-generation and single-cell sequencing) from public Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Bioinformatics analysis was performed using R software and several database resources such as Metascape database, Gene Set Cancer Analysis (GSCA) database, and Cytoscape software, etc., to investigate the biological mechanisms that may be related with collagens. Immunofluorescence and immunohistochemical staining were used to validate the expression and localization of Nidogen-2 (NID2). Results Melanoma patients can be divided into two collagen clusters. Patients with high collagen levels (C1) had a shorter survival than those with low collagen levels (C2) and were less likely to benefit from immunotherapy. We demonstrated that NID2 is a potential key factor in the collagen phenotype, is involved in fibroblast activation in melanoma, and forms a barrier to limit the proximity of CD8+ T cells to tumor cells. Conclusion We clarified the adverse effects of collagen on melanoma patients and identified NID2 as a potential therapeutic target.
Collapse
Affiliation(s)
- Yan Sha
- Departments of Dermatology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, People's Republic of China
| | - An-Qi Mao
- Departments of Dermatology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, People's Republic of China
| | - Yuan-Jie Liu
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, People's Republic of China
| | - Jie-Pin Li
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, People's Republic of China
| | - Ya-Ting Gong
- Departments of Rehabilitation, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, People's Republic of China
| | - Dong Xiao
- Departments of Dermatology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, People's Republic of China
| | - Jun Huang
- Departments of Dermatology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, People's Republic of China
| | - Yan-Wei Gao
- Departments of Dermatology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, People's Republic of China
| | - Mu-Yao Wu
- Departments of Rehabilitation, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, People's Republic of China
| | - Hui Shen
- Departments of Dermatology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, People's Republic of China
| |
Collapse
|
|
7
|
Cao Z, Zhang Z, Tang X, Liu R, Wu M, Wu J, Liu Z. Comprehensive analysis of tissue proteomics in patients with papillary thyroid microcarcinoma uncovers the underlying mechanism of lymph node metastasis and its significant sex disparities. Front Oncol 2022; 12:887977. [PMID: 36106120 PMCID: PMC9465038 DOI: 10.3389/fonc.2022.887977] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 08/10/2022] [Indexed: 11/24/2022] Open
Abstract
Background Lymph node metastasis (LNM) in papillary thyroid microcarcinoma (PTMC) is associated with an increased risk of recurrence and poor prognosis. Sex has been regarded as a critical risk factor for LNM. The present study aimed to investigate the molecular mechanisms underlying LNM and its significant sex disparities in PTMC development. Methods A direct data-independent acquisition (DIA) proteomics approach was used to identify differentially expressed proteins (DEPs) in PTMC tumorous tissues with or without LNM and from male and female patients with LNM. The functional annotation of DEPs was performed using bioinformatics methods. Furthermore, The Cancer Genome Atlas Thyroid Carcinoma (TCGA-THCA) dataset and immunohistochemistry (IHC) were used to validate selected DEPs. Results The proteomics profile in PTMC with LNM differed from that of PTMC without LNM. The metastasis-related DEPs were primarily enriched in categories associated with mitochondrial dysfunction and may promote tumor progression by activating oxidative phosphorylation and PI3K/AKT signaling pathways. Comparative analyses of these DEPs revealed downregulated expression of specific proteins with well-established links to tumor metastasis, such as SLC25A15, DIRAS2, PLA2R1, and MTARC1. Additionally, the proteomics profiles of male and female PTMC patients with LNM were dramatically distinguishable. An elevated level of ECM-associated proteins might be related to more LNM in male PTMC than in female PTMC patients. The upregulated expression levels of MMRN2 and NID2 correlated with sex disparities and showed a positive relationship with unfavorable variables, such as LNMs and poor prognosis. Conclusions The proteomics profiles of PTMC show significant differences associated with LNM and its sex disparities, which further expands our understanding of the functional networks and signaling pathways related to PTMC with LNM.
Collapse
Affiliation(s)
- Zhen Cao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zejian Zhang
- Department of Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoyue Tang
- Department of Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Rui Liu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mengwei Wu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianqiang Wu
- Department of Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Jianqiang Wu, ; Ziwen Liu,
| | - Ziwen Liu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Jianqiang Wu, ; Ziwen Liu,
| |
Collapse
|
|
8
|
Zhao LQ, Sun W, Zhang P, Gao W, Fang CY, Zheng AW. MFAP2 aggravates tumor progression through activating FOXM1/β-catenin-mediated glycolysis in ovarian cancer. Kaohsiung J Med Sci 2022; 38:772-780. [PMID: 35546486 DOI: 10.1002/kjm2.12546] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 02/21/2022] [Accepted: 03/18/2022] [Indexed: 11/08/2022] Open
Abstract
Ovarian cancer is one of the most common gynecological tumors that seriously endanger the health and quality of life of women. Microfibril-associated protein 2 (MFAP2) has been demonstrated to play crucial roles in the development of multiple tumors. However, the function of MFAP2 in ovarian cancer remains unclear. In this study, we found that MFAP2 was upregulated in ovarian cancer and cells and was positively correlated with FOXM1 and glycolysis-related genes. The results of Cell Count Kit-8, colony formation, and flow cytometry assays indicated that MFAP2 promoted cell proliferation. In addition, MFAP2 promotes cell proliferation, glucose uptake, lactate production; increases ATP levels, extracellular acidification ratio, and oxygen consumption ratio in ovarian cancer cells and increases the expression of glycolytic proteins. Further mechanistic analysis suggests that MFAP2 promotes FOXM1/β-catenin-mediated glycolysis signaling in ovarian cancer cells. Knockdown of MFAP2 inhibits ovarian cancer xenograft tumor growth and expression of Ki-67, MFAP2, FOXM1, GLUT1, HK2, and β-catenin in mice. In conclusion, MFAP2 promotes cell proliferation and glycolysis by modulating the FOXM1/β-catenin signaling pathway in ovarian cancer, which may offer a fresh insight into the treatment of ovarian cancer in the glycolysis pathway.
Collapse
Affiliation(s)
- Ling-Qin Zhao
- Department of Gynecologic Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Wei Sun
- Department of Gynecologic Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Ping Zhang
- Department of Gynecologic Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Wen Gao
- Department of Gynecologic Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Chen-Yan Fang
- Department of Gynecologic Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Ai-Wen Zheng
- Department of Gynecologic Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| |
Collapse
|
|
9
|
Pan-Cancer Analysis of Microfibrillar-Associated Protein 2 (MFAP2) Based on Bioinformatics and qPCR Verification. JOURNAL OF ONCOLOGY 2022; 2022:8423173. [PMID: 35211173 PMCID: PMC8863482 DOI: 10.1155/2022/8423173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/24/2021] [Accepted: 12/30/2021] [Indexed: 11/18/2022]
Abstract
MFAP2 has been reported to play an oncogenic role in several types of human cancers. However, the expression profile of MFAP2 in various cancers and its impact on prognosis and immune infiltration remain unclear. In this study, the mRNA expression and protein expression of MFAP2 in normal tissues, tumor cell lines, and 33 malignant tumor tissues were analyzed comprehensively using Genotype-Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE), and The Cancer Genome Atlas (TCGA), Oncomine and UALCAN databases, and the expression of MFAP2 in different grades and stages of cancers was assessed using Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and Tumor and Immune System Interaction Database (TISIDB). In general, MFAP2 showed distinct expression in most tumor and normal tissues, closely associated with higher tumor grade, higher tumor stage, and poor survival in multiple cancers. A search of the UALCAN database and the cBioPortal database revealed that this difference in mRNA level expression could be partly attributed to abnormal DNA methylation and mutations at the genomic level. In addition, MFAP2 expression was also associated with tumor mutation burden, microsatellite instability, and neoantigens in different cancer types. More importantly, the TIMER and TISIDB databases also showed that MFAP2 levels were significantly correlated with immune infiltration abundance and immune-related gene markers, as well as ESTIMATE scores. By qPCR, MFAP2 expression was validated in four kinds of tumor tissue samples. The present study combined several databases and performed a pan-cancer analysis of the expression profile, methylation, and mutation for MFAP2 and its implications for prognosis and immune infiltration, suggesting that MFAP2 could contribute to malignant properties of many tumors. MFAP2 may be an important biomarker with prognostic value and has the potential to be a target for tumor immunotherapy.
Collapse
|
|
10
|
Urbanova M, Buocikova V, Trnkova L, Strapcova S, Kajabova VH, Melian EB, Novisedlakova M, Tomas M, Dubovan P, Earl J, Bizik J, Svastova E, Ciernikova S, Smolkova B. DNA Methylation Mediates EMT Gene Expression in Human Pancreatic Ductal Adenocarcinoma Cell Lines. Int J Mol Sci 2022; 23:2117. [PMID: 35216235 PMCID: PMC8879087 DOI: 10.3390/ijms23042117] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 01/31/2022] [Accepted: 02/10/2022] [Indexed: 12/14/2022] Open
Abstract
Due to abundant stroma and extracellular matrix, accompanied by lack of vascularization, pancreatic ductal adenocarcinoma (PDAC) is characterized by severe hypoxia. Epigenetic regulation is likely one of the mechanisms driving hypoxia-induced epithelial-to-mesenchymal transition (EMT), responsible for PDAC aggressiveness and dismal prognosis. To verify the role of DNA methylation in this process, we assessed gene expression and DNA methylation changes in four PDAC cell lines. BxPC-3, MIA PaCa-2, PANC-1, and SU.86.86 cells were exposed to conditioned media containing cytokines and inflammatory molecules in normoxic and hypoxic (1% O2) conditions for 2 and 6 days. Cancer Inflammation and Immunity Crosstalk and Human Epithelial to Mesenchymal Transition RT² Profiler PCR Arrays were used to identify top deregulated inflammatory and EMT-related genes. Their mRNA expression and DNA methylation were quantified by qRT-PCR and pyrosequencing. BxPC-3 and SU.86.86 cell lines were the most sensitive to hypoxia and inflammation. Although the methylation of gene promoters correlated with gene expression negatively, it was not significantly influenced by experimental conditions. However, DNA methyltransferase inhibitor decitabine efficiently decreased DNA methylation up to 53% and reactivated all silenced genes. These results confirm the role of DNA methylation in EMT-related gene regulation and uncover possible new targets involved in PDAC progression.
Collapse
Affiliation(s)
- Maria Urbanova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (M.U.); (V.B.); (L.T.); (V.H.K.); (M.T.); (P.D.); (J.B.); (S.C.)
| | - Verona Buocikova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (M.U.); (V.B.); (L.T.); (V.H.K.); (M.T.); (P.D.); (J.B.); (S.C.)
| | - Lenka Trnkova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (M.U.); (V.B.); (L.T.); (V.H.K.); (M.T.); (P.D.); (J.B.); (S.C.)
| | - Sabina Strapcova
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (S.S.); (E.S.)
| | - Viera Horvathova Kajabova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (M.U.); (V.B.); (L.T.); (V.H.K.); (M.T.); (P.D.); (J.B.); (S.C.)
| | - Emma Barreto Melian
- Molecular Epidemiology and Predictive Tumor Markers Group, Ramón y Cajal Health Research Institute (IRYCIS), Biomedical Research Network in Cancer (CIBERONC), Carretera Colmenar Km 9,100, 28034 Madrid, Spain; (E.B.M.); (J.E.)
| | - Maria Novisedlakova
- Oncology Outpatient Clinic, Hospital of the Hospitaller Order of Saint John of God, 814 65 Bratislava, Slovakia;
| | - Miroslav Tomas
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (M.U.); (V.B.); (L.T.); (V.H.K.); (M.T.); (P.D.); (J.B.); (S.C.)
- Department of Surgical Oncology, National Cancer Institute, Slovak Medical University, Klenova 1, 833 10 Bratislava, Slovakia
| | - Peter Dubovan
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (M.U.); (V.B.); (L.T.); (V.H.K.); (M.T.); (P.D.); (J.B.); (S.C.)
- Department of Surgical Oncology, National Cancer Institute, Slovak Medical University, Klenova 1, 833 10 Bratislava, Slovakia
| | - Julie Earl
- Molecular Epidemiology and Predictive Tumor Markers Group, Ramón y Cajal Health Research Institute (IRYCIS), Biomedical Research Network in Cancer (CIBERONC), Carretera Colmenar Km 9,100, 28034 Madrid, Spain; (E.B.M.); (J.E.)
| | - Jozef Bizik
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (M.U.); (V.B.); (L.T.); (V.H.K.); (M.T.); (P.D.); (J.B.); (S.C.)
| | - Eliska Svastova
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (S.S.); (E.S.)
| | - Sona Ciernikova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (M.U.); (V.B.); (L.T.); (V.H.K.); (M.T.); (P.D.); (J.B.); (S.C.)
| | - Bozena Smolkova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (M.U.); (V.B.); (L.T.); (V.H.K.); (M.T.); (P.D.); (J.B.); (S.C.)
| |
Collapse
|
|
11
|
Min J, Ma J, Wang Q, Yu D. Long non-coding RNA SNHG1 promotes bladder cancer progression by upregulating EZH2 and repressing KLF2 transcription. Clinics (Sao Paulo) 2022; 77:100081. [PMID: 36087568 PMCID: PMC9468346 DOI: 10.1016/j.clinsp.2022.100081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 06/02/2022] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVE Long Non-Coding RNAs (LncRNAs) act as an indispensable role in cancer development. The study aimed to investigate the role and mechanism of lncRNA Small Nucleolar RNA Host Gene 1 (SNHG1) in Bladder Cancer (BC) progression. METHOD The expression, prognostic value, diagnostic value, and correlation of SNHG1, Enhancer of Zeste 2 polycomb repressive complex 2 subunit (EZH2), and Kruppel Like Factor 2 (KLF2) were analyzed through bioinformatics analysis. The expression was also validated in BC tissues and cell lines. Besides, their regulation and binding were tested via qPCR, Western blot, Dual-Luciferase Reporter Assay (DLRA), Argonaute RISC catalytic component 2-RNA Immunoprecipitation (AGO2-RIP), and Chromatin Immunoprecipitation (ChIP). A xenograft model in nude mice was also established. RESULTS SNHG1 was significantly overexpressed in BC tissues and cells. Importantly, SNHG1 was associated with poor survival, and ROC curves revealed high diagnostic values. Moreover, by CCK8, wound healing, transwell, and Western blot analysis, SNHG1 knockdown significantly inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition of BC cells. Additionally, in vivo experiments showed that silencing SNHG1 hindered tumorigenesis and tumor growth. Regarding mechanism, the results of AGO2-RIP, ChIP or DLRA showed that SNHG1 played different roles at diverse subcellular sites. In the cytoplasm, SNHG1 acted as a competing endogenous RNA for miR-137-3p to promote EZH2 expression. In the nucleus, SNHG1 could interact with EZH2 to inhibit KLF2 transcription. CONCLUSION Our study elucidated that SNHG1 formed a regulatory network and played an oncogenic role in BC, which provided a novel therapeutic target for BC treatment.
Collapse
Affiliation(s)
- Jie Min
- Department of Urology, The Second Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Jiaxing Ma
- Department of Urology, The Second Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Qi Wang
- Department of Urology, The Second Hospital of Anhui Medical University, Hefei, Anhui, China.
| | - Dexin Yu
- Department of Urology, The Second Hospital of Anhui Medical University, Hefei, Anhui, China.
| |
Collapse
|
|
12
|
Identification of Differentially Expressed Genes Reveals BGN Predicting Overall Survival and Tumor Immune Infiltration of Gastric Cancer. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2021; 2021:5494840. [PMID: 34868341 PMCID: PMC8641985 DOI: 10.1155/2021/5494840] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/06/2021] [Accepted: 10/11/2021] [Indexed: 01/12/2023]
Abstract
Gastric cancer (GC) is one of the most widely occurring malignancies worldwide. Although the diagnosis and treatment strategies of GC have been greatly improved in the past few decades, the morbidity and lethality rates of GC are still rising due to lacking early diagnosis strategies and powerful treatments. In this study, a total of 37 differentially expressed genes were identified in GC by analyzing TCGA, GSE118897, GSE19826, and GSE54129. Using the PPI database, we identified 17 hub genes in GC. By analyzing the expression of hub genes and OS, MFAP2, BGN, and TREM1 were related to the prognosis of GC. In addition, our results showed that higher levels of BGN exhibited a significant correlation with shorter OS time in GC. Nomogram analysis showed that the dysregulation of BGN could predict the prognosis of GC. Moreover, we revealed that BGN had a markedly negative correlation with B cells but had positive correlations with CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells in GC samples. The pan-cancer analysis demonstrated that BGN was differentially expressed and related to tumor-infiltrating immune cells across human cancers. This study for the first time comprehensively revealed that BGN was a potential biomarker for the prediction of GC prognosis and tumor immune infiltration.
Collapse
|