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Treviño-Juarez AS, Gonzalez-Gonzalez JG, Rodriguez-Gutierrez R, Sanchez-Garcia A, Gonzalez-Velazquez CD. Integrative bioinformatic analysis identifies differentially expressed gene targets as potential biomarkers for anaplastic thyroid cancer. J Egypt Natl Canc Inst 2025; 37:16. [PMID: 40350533 DOI: 10.1186/s43046-025-00282-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 03/25/2025] [Indexed: 05/14/2025] Open
Abstract
BACKGROUND Anaplastic thyroid carcinoma (ATC) is among the most lethal thyroid malignancies, with poor clinical outcomes and limited treatment strategies. To gain insights into the molecular mechanisms involved in its progression, we performed an integrative bioinformatic analysis. METHODS We analyzed five microarray datasets from the GEO database to compare gene expression profiles between ATC samples and normal thyroid tissues. Differentially expressed genes (DEGs) were identified using GEO2R, and overlapping genes across datasets were detected through Venn diagram analysis. Functional enrichment was performed using DAVID and Metascape. A protein-protein interaction (PPI) network was constructed with STRING, and significant gene modules were identified using the MCODE plugin in Cytoscape. Co-expression analysis was further explored with GeneMANIA. RESULTS We identified 7532 DEGs, of which 3509 were upregulated and 4023 were downregulated. Upregulated genes were mainly involved in cell division and mitotic control, while downregulated genes were related to thyroid hormone production and gland development. Six hub genes stood out for their centrality in the network: TPX2, MAD2L1, CDC20, CDKN3, CENPF, and NEK2. CONCLUSION Our findings shed light on key genes and pathways that may contribute to ATC pathogenesis. These results provide a foundation for identifying potential diagnostic biomarkers and therapeutic targets for this aggressive cancer.
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Affiliation(s)
- Angel Sebastian Treviño-Juarez
- Endocrinology Division, Department of Internal Medicine, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey, México.
| | - Jose Gerardo Gonzalez-Gonzalez
- Endocrinology Division, Department of Internal Medicine, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey, México
- Plataforma INVEST-Medicina UANL KER Unit, Universidad Autónoma de Nuevo León, Monterrey, 64460, México
| | - Rene Rodriguez-Gutierrez
- Endocrinology Division, Department of Internal Medicine, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey, México
- Plataforma INVEST-Medicina UANL KER Unit, Universidad Autónoma de Nuevo León, Monterrey, 64460, México
| | - Adriana Sanchez-Garcia
- Endocrinology Division, Department of Internal Medicine, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey, México
- Plataforma INVEST-Medicina UANL KER Unit, Universidad Autónoma de Nuevo León, Monterrey, 64460, México
| | - Camilo Daniel Gonzalez-Velazquez
- Endocrinology Division, Department of Internal Medicine, University Hospital "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey, México
- Thyroid, Head and Neck Cancer (THANC) Foundation, 10 Union Square East, Suite 5B, New York, NY, 10003, USA
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Raman R, Debata S, Govindarajan T, Kumar P. Targeting Triple-Negative Breast Cancer: Resistance Mechanisms and Therapeutic Advancements. Cancer Med 2025; 14:e70803. [PMID: 40318146 PMCID: PMC12048392 DOI: 10.1002/cam4.70803] [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: 07/10/2024] [Revised: 02/12/2025] [Accepted: 03/11/2025] [Indexed: 05/07/2025] Open
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is one of the most heterogeneous and menacing forms of breast cancer, with no sustainable cure available in the current treatment landscape. Its lack of targets makes it highly unresponsive to various treatment modalities, which is why chemotherapy continues to be the primary form of treatment, despite the high rates of patients developing chemoresistance. In recent years, however, there has been significant progress in identifying and understanding the role of several aspects that might contribute to genomic instability and other hallmarks of cancer, including cellular proteins, immune targets, and epigenetic mechanisms, which are desirable as they permit reversibility easier than the often-adamant genetic changes. METHODS A literature review was conducted on the role of various TNBC associated biomarkers, their therapeutic applications, and their role in tumorigenesis and tumor maintenance, with a focus on linking both the driving biological mechanisms and emerging treatment options for TNBC. CONCLUSIONS Shifting the focus of treatment to identify crucial tumor cell subpopulations and associated biomarkers, such as local immune cell populations and cancer stem cells, could potentially solve or simplify decades' worth of problems that are associated with TNBC, bolstering early detection and the evolution of precision medicine and treatment. The techniques that can be used here are epigenetic analysis and RNA sequencing. Biomarkers, such as PD-L1, survivin, and ABC transporters, are implicated in several crucial processes that maintain tumors, such as cell proliferation, metastasis, immunosuppression, and stemness. Complex treatment options such as, immunotherapy, pathway inhibition, PARP inhibition, virotherapy, and RNA targeting have been considered for TNBC. Phytochemicals are also being considered as a treatment modality for TNBC, as a supplement to chemotherapy and radiation therapy, or as sole treatment.
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Affiliation(s)
- Rachana Raman
- Photoceutics and Regeneration Laboratory, Department of Biotechnology, Centre for Microfluidics, Biomarkers, Photoceutics and Sensors (μBioPS), Manipal Institute of TechnologyManipal Academy of Higher EducationManipalKarnatakaIndia
- Innotech Manipal, Manipal Institute of TechnologyManipal Academy of Higher EducationManipalKarnatakaIndia
| | - Shristi Debata
- Department of Biotechnology, Manipal Institute of TechnologyManipal Academy of Higher EducationManipalKarnatakaIndia
| | | | - Praveen Kumar
- Photoceutics and Regeneration Laboratory, Department of Biotechnology, Centre for Microfluidics, Biomarkers, Photoceutics and Sensors (μBioPS), Manipal Institute of TechnologyManipal Academy of Higher EducationManipalKarnatakaIndia
- Innotech Manipal, Manipal Institute of TechnologyManipal Academy of Higher EducationManipalKarnatakaIndia
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Zhou Y, Zeng H, Ye L, Wang J, Feng G, Chen Y, Fang D, Lu J, Lu G. The role of cyclin dependent kinase molecules in the pathogenesis and immune cell infiltration of TNBC in silicosis: Based on core stem cell related genes TPX2 and CCNA2. Int J Biol Macromol 2025; 306:141683. [PMID: 40037461 DOI: 10.1016/j.ijbiomac.2025.141683] [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: 01/14/2025] [Revised: 02/19/2025] [Accepted: 03/01/2025] [Indexed: 03/06/2025]
Abstract
Silicosis is a pulmonary fibrotic disease caused by long-term inhalation of silica dust. CDKs regulate the process of cell cycle by binding with cyclin. This study revealed the role of cyclin-dependent kinase molecules in the pathogenesis of TNBC in silicosis and analyzed its influence on immune cell infiltration. By retrospective analysis of clinical samples from silicosis patients and TNBC patients, we evaluated the expression level of CDKs molecules. Then, the effect of silica dust exposure on breast cancer cell cycle was simulated using in vitro cell culture technology, and the expression changes of TPX2 and CCNA2 genes were observed. Immunohistochemical techniques were used to detect the infiltration of immune cells in silicosis and TNBC tissue samples, and to analyze its correlation with the expression of CDKs. The findings from the conducted research indicated that there was a significant elevation in the expression levels of cyclin-dependent kinases, or CDKs, in patients diagnosed with silicosis as well as those with triple-negative breast cancer, or TNBC. Through immunohistochemical analysis, it was further revealed that there was an increased infiltration of immune cells within the tissues of both silicosis and TNBC patients. Interestingly, this infiltration of immune cells was found to be positively correlated with the expression levels of CDK molecules. The up-regulated expression of the TPX2 and CCNA2 genes is believed to be associated with abnormal regulation of the cell cycle, which in turn affects the infiltration patterns of immune cells within the affected tissues.
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Affiliation(s)
- Yu Zhou
- Department of Breast and Thyroid Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Key Laloratory of Molecular Pathology in Tumors of Baise, Baise 533000, Guangxi, PR China; Department of Breast and Thyroid Surgery, The Third People's Hospital of Hechi, Hechi 547000, Guangxi, PR China
| | - Huifang Zeng
- Department of Breast and Thyroid Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Key Laloratory of Molecular Pathology in Tumors of Baise, Baise 533000, Guangxi, PR China
| | - Li Ye
- Department of Breast and Thyroid Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Key Laloratory of Molecular Pathology in Tumors of Baise, Baise 533000, Guangxi, PR China
| | - Jin Wang
- Department of Breast and Thyroid Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Key Laloratory of Molecular Pathology in Tumors of Baise, Baise 533000, Guangxi, PR China
| | - Guangqing Feng
- Department of Breast and Thyroid Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Key Laloratory of Molecular Pathology in Tumors of Baise, Baise 533000, Guangxi, PR China
| | - Yongcheng Chen
- Department of Breast and Thyroid Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Key Laloratory of Molecular Pathology in Tumors of Baise, Baise 533000, Guangxi, PR China
| | - Dalang Fang
- Department of Breast and Thyroid Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Key Laloratory of Molecular Pathology in Tumors of Baise, Baise 533000, Guangxi, PR China.
| | - Jinlan Lu
- Department of Stomatology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, Guangxi, PR China.
| | - Guanming Lu
- Department of Breast and Thyroid Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Key Laloratory of Molecular Pathology in Tumors of Baise, Baise 533000, Guangxi, PR China; Department of Oncology-Pathology, Karolinska Institutet, Stockholm SE-17176, Sweden.
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Ding Z, Ying W, Yan Y, Zhao Y, Liu C, Ma L. TPX2 promotes papillary renal cell carcinoma progression by forming a ceRNA with LINC00894. BMC Med Genomics 2025; 18:80. [PMID: 40289117 PMCID: PMC12036302 DOI: 10.1186/s12920-025-02120-9] [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] [Received: 04/22/2024] [Accepted: 03/05/2025] [Indexed: 04/30/2025] Open
Abstract
PURPOSE Papillary renal cell carcinoma (pRCC), particularly type 2, is associated with a poor prognosis. This study aimed to identify molecular mechanisms underlying pRCC progression and explore potential therapeutic targets to improve patient outcomes. METHODS TPX2 expression was analyzed in tumor samples from patients with type 2 pRCC. In vitro experiments were conducted to assess the effects of TPX2 and LINC00894 knockdown and overexpression on the proliferation and migration of Caki-2 and ACHN cells. Immunohistochemical analysis of tissue microarrays was performed to evaluate the associations between TPX2 expression and clinicopathological characteristics in type 2 pRCC patients. RESULTS Elevated TPX2 expression was significantly associated with a worse prognosis in type 2 pRCC patients and served as an independent risk factor for overall survival. Knockdown of TPX2 in Caki-2 and ACHN cells significantly reduced cell proliferation and migration. Additionally, LINC00894 was highly expressed in type 2 pRCC and correlated with poor prognosis. Mechanistically, miR-660-5p targeted the TPX2 3' UTR, promoting TPX2 degradation, while LINC00894 competitively bound to miR-660-5p, protecting TPX2 from miRNA-mediated degradation and exerting a pro-oncogenic effect. Immunohistochemical analysis revealed significant correlations between TPX2 expression and clinicopathological features, including tumor thrombus volume, tumor diameter, pathological TNM stage, and Fuhrman grade. CONCLUSION This study underscores the critical role of TPX2 in type 2 pRCC progression and highlights its potential as a prognostic biomarker and therapeutic target. The TPX2/LINC00894/miR-660-5p regulatory axis provides novel insights into the molecular mechanisms driving pRCC and offers a promising avenue for improving patient prognosis.
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Affiliation(s)
- Zhenshan Ding
- Department of Urology, China-Japan Friendship Hospital, Beijing, 100029, China
- Department of Urology, Peking University Third Hospital, Haidian District, 49 Huayuan North Road, Beijing, 100191, China
| | - Wenwei Ying
- Department of Urology, Peking University First Hospital, Beijing, 100034, China
| | - Ye Yan
- Department of Urology, Peking University Third Hospital, Haidian District, 49 Huayuan North Road, Beijing, 100191, China
| | - Ying Zhao
- Department of Urology, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Cheng Liu
- Department of Urology, Peking University Third Hospital, Haidian District, 49 Huayuan North Road, Beijing, 100191, China
| | - Lulin Ma
- Department of Urology, Peking University Third Hospital, Haidian District, 49 Huayuan North Road, Beijing, 100191, China.
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Dong Y, Sheng G, Chen W. TPX2 knockdown mediates p53 activation to induce autophagy and apoptosis for anti-colorectal cancer effects. J Recept Signal Transduct Res 2025:1-13. [PMID: 40116489 DOI: 10.1080/10799893.2025.2470180] [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: 07/22/2024] [Revised: 02/10/2025] [Accepted: 02/16/2025] [Indexed: 03/23/2025]
Abstract
Colorectal cancer (CRC) exhibits high morbidity and mortality worldwide. Targeting protein for Xenopus kinesin-like protein 2 (TPX2) impacts various cancers; however, mechanism of TPX2 in CRC remains unclear. Xenograft nude mouse models were constructed by subcutaneous injection of HCT116 cells with sh-NC, sh-TPX2, OE-NC, and OE-TPX2 transfection. Following the test of tumor growth, immunohistochemistry and TUNEL staining were done. In vitro, HCT116, RKO, and SW480 cells were divided into sh-NC, sh-TPX2, and sh-TPX2 + 3-methyladenine (3-MA, autophagy inhibitor) groups. Further, sh-p53 and rapamycin (RA, autophagy agonist) were added in HCT116 cells. EdU staining, flow cytometry, transparent electron microscopy, and Western blot were performed. Comparing with sh-NC group, sh-TPX2 inhibited tumor growth and Ki67 expression, and increased LC3-II expression and apoptosis, whereas OE-TPX2 group presented an opposite trend. In vitro, HCT116 and RKO cells in sh-TPX2 group enhanced apoptosis and LC3 II/LC3 I expression, and inhibited proliferation and P62 expression, which were reversed after further 3-MA intervention. The above results were not found in SW480 cells. Moreover, compared to sh-TPX2 group, sh-TPX2 + RA group enhanced apoptosis and autophagy, and suppressed the proliferation of HCT116 cells, which were reversed following further sh-p53 intervention. Therefore, sh-TPX2 mediated p53 activation to induce autophagy for anti-CRC effects, providing new ideas for CRC treatment.
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Affiliation(s)
- Yunfei Dong
- Department of Anorectal, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Guixian Sheng
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wenbin Chen
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Li XQ, Cao ZR, Deng M, Qing Y, Sun L, Wu ZJ. E2F8-TPX2 axis regulates glycolysis and angiogenesis to promote progression and reduce chemosensitivity of liver cancer. Cytotechnology 2024; 76:817-832. [PMID: 39435417 PMCID: PMC11490592 DOI: 10.1007/s10616-024-00655-w] [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: 06/04/2024] [Accepted: 09/11/2024] [Indexed: 10/23/2024] Open
Abstract
Liver cancer (LC) is a global health concern, marked by its high prevalence and mortality rates and known for its resistance to chemotherapy. The treatment of LC patients is facing great challenges. Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a LC marker that has been discovered in recent years, and there are sporadic data suggesting that it has an impact on the level of chemoresistance, but the exact mechanism remains to be deciphered. Our investigation, grounded in bioinformatics strategies including the TCGA database, GEO database, K-M plot database, GSEA, Pearson correlation analysis, and detection of clinical samples, led to the identification of TPX2 and its upstream transcription factor E2F8 as differentially expressed elements in LC tissues. We also probed the role of the axis in glycolysis, angiogenesis, tumor progression, and chemoresistance in LC cells. This was achieved by a battery of molecular and cellular experiments, such as qRT-PCR, CCK-8, Transwell, flow cytometry, and angiogenesis assays. Both TPX2 and E2F8 were upregulated in LC tissues and cells with E2F8 being responsible for the upregulation of TPX2. Through bioinformatics analysis, we observed a significant enrichment of TPX2 in the glycolysis and angiogenesis pathways. Cell-based experiments corroborated these findings, demonstrating that TPX2 knockdown led to significant inhibition of glycolysis and angiogenesis, along with a suppression of the malignant progression of LC cells. This was mirrored by a reduction in the IC50 values for cisplatin and apatinib to 0.8257 µM and 10.79 µM, respectively. In contrast, E2F8 overexpression reversed these effects in LC cells, increasing the IC50 values to 3.375 and 16.06 µM, respectively. The E2F8-TPX2 axis promotes glycolysis and angiogenesis in LC cells, which in turn accelerates cancer progression and reduces chemosensitivity. Supplementary Information The online version contains supplementary material available at 10.1007/s10616-024-00655-w.
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Affiliation(s)
- Xiao-Qing Li
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016 China
- Department of Oncology, Bishan Hospital of Chongqing Medical University, Chongqing, 402760 China
| | - Zhen-Rui Cao
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016 China
| | - Min Deng
- Department of Oncology, Bishan Hospital of Chongqing Medical University, Chongqing, 402760 China
| | - Yun Qing
- Department of Oncology, Bishan Hospital of Chongqing Medical University, Chongqing, 402760 China
| | - Lan Sun
- Department of Oncology, Bishan Hospital of Chongqing Medical University, Chongqing, 402760 China
| | - Zhong-Jun Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016 China
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Marugán C, Sanz‐Gómez N, Ortigosa B, Monfort‐Vengut A, Bertinetti C, Teijo A, González M, Alonso de la Vega A, Lallena MJ, Moreno‐Bueno G, de Cárcer G. TPX2 overexpression promotes sensitivity to dasatinib in breast cancer by activating YAP transcriptional signaling. Mol Oncol 2024; 18:1531-1551. [PMID: 38357786 PMCID: PMC11161735 DOI: 10.1002/1878-0261.13602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 01/03/2024] [Accepted: 01/26/2024] [Indexed: 02/16/2024] Open
Abstract
Chromosomal instability (CIN) is a hallmark of cancer aggressiveness, providing genetic plasticity and tumor heterogeneity that allows the tumor to evolve and adapt to stress conditions. CIN is considered a cancer therapeutic biomarker because healthy cells do not exhibit CIN. Despite recent efforts to identify therapeutic strategies related to CIN, the results obtained have been very limited. CIN is characterized by a genetic signature where a collection of genes, mostly mitotic regulators, are overexpressed in CIN-positive tumors, providing aggressiveness and poor prognosis. We attempted to identify new therapeutic strategies related to CIN genes by performing a drug screen, using cells that individually express CIN-associated genes in an inducible manner. We find that the overexpression of targeting protein for Xklp2 (TPX2) enhances sensitivity to the proto-oncogene c-Src (SRC) inhibitor dasatinib due to activation of the Yes-associated protein 1 (YAP) pathway. Furthermore, using breast cancer data from The Cancer Genome Atlas (TCGA) and a cohort of cancer-derived patient samples, we find that both TPX2 overexpression and YAP activation are present in a significant percentage of cancer tumor samples and are associated with poor prognosis; therefore, they are putative biomarkers for selection for dasatinib therapy.
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Grants
- 2018-20I114 Spanish National Research Council (CSIC)
- 2021-AEP035 Spanish National Research Council (CSIC)
- 2022-20I018 Spanish National Research Council (CSIC)
- FJC2020-044620-I Ministerio de Ciencia, Innovación, Agencia Estatal de Investigación MCIN/AEI/FEDER
- PID2019-104644RB-I00 Ministerio de Ciencia, Innovación, Agencia Estatal de Investigación MCIN/AEI/FEDER
- PID2021-125705OB-I00 Ministerio de Ciencia, Innovación, Agencia Estatal de Investigación MCIN/AEI/FEDER
- PID2022-136854OB-I00 Ministerio de Ciencia, Innovación, Agencia Estatal de Investigación MCIN/AEI/FEDER
- RTI2018-095496-B-I00 Ministerio de Ciencia, Innovación, Agencia Estatal de Investigación MCIN/AEI/FEDER
- CB16/12/00295 Instituto de Salud Carlos III - CIBERONC
- LABAE16017DECA Spanish Association Against Cancer (AECC) Scientific Foundation
- POSTD234371SANZ Spanish Association Against Cancer (AECC) Scientific Foundation
- PROYE19036MOR Spanish Association Against Cancer (AECC) Scientific Foundation
- Spanish National Research Council (CSIC)
- Spanish Association Against Cancer (AECC) Scientific Foundation
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Affiliation(s)
- Carlos Marugán
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
- Discovery Chemistry Research and TechnologyEli Lilly and CompanyMadridSpain
| | - Natalia Sanz‐Gómez
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
| | - Beatriz Ortigosa
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
- Translational Cancer Research Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Alberto Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
| | - Ana Monfort‐Vengut
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
| | - Cristina Bertinetti
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
| | - Ana Teijo
- Pathology DepartmentMD Anderson Cancer CenterMadridSpain
| | - Marta González
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
| | - Alicia Alonso de la Vega
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
| | - María José Lallena
- Discovery Chemistry Research and TechnologyEli Lilly and CompanyMadridSpain
| | - Gema Moreno‐Bueno
- Translational Cancer Research Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Alberto Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
- MD Anderson International FoundationMadridSpain
- Biomedical Cancer Research Network (CIBERONC)MadridSpain
- CSIC Conexión‐Cáncer Hub (https://conexion‐cancer.csic.es)
| | - Guillermo de Cárcer
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
- CSIC Conexión‐Cáncer Hub (https://conexion‐cancer.csic.es)
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Zhao X, Du M, Wu S, Du Z, Liu S, Yang L, Ma H, Zhang L, Song L, Bai C, Su G, Li G. High histone crotonylation modification in bovine fibroblasts promotes cell proliferation and the developmental efficiency of preimplantation nuclear transfer embryos. Sci Rep 2024; 14:10295. [PMID: 38704415 PMCID: PMC11069573 DOI: 10.1038/s41598-024-61148-6] [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: 01/17/2024] [Accepted: 05/02/2024] [Indexed: 05/06/2024] Open
Abstract
Lysine crotonylation (Kcr) is a recently discovered histone acylation modification that is closely associated with gene expression, cell proliferation, and the maintenance of stem cell pluripotency and indicates the transcriptional activity of genes and the regulation of various biological processes. During cell culture, the introduction of exogenous croconic acid disodium salt (Nacr) has been shown to modulate intracellular Kcr levels. Although research on Kcr has increased, its role in cell growth and proliferation and its potential regulatory mechanisms remain unclear compared to those of histone methylation and acetylation. Our investigation demonstrated that the addition of 5 mM Nacr to cultured bovine fibroblasts increased the expression of genes associated with Kcr modification, ultimately promoting cell growth and stimulating cell proliferation. Somatic cell nuclear transfer of donor cells cultured in 5 mM Nacr resulted in 38.1% blastocyst development, which was significantly greater than that in the control group (25.2%). This research is important for elucidating the crotonylation modification mechanism in fibroblast proliferation to promote the efficacy of somatic cell nuclear transfer.
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Affiliation(s)
- Xiaoyu Zhao
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (R2BGL), Inner Mongolia University, 24 Zhaojun Rd., Hohhot, 010070, China
- College of Life Sciences, Inner Mongolia University, 24 Zhaojun Rd., Hohhot, 010070, China
| | - Mengxin Du
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (R2BGL), Inner Mongolia University, 24 Zhaojun Rd., Hohhot, 010070, China
- College of Life Sciences, Inner Mongolia University, 24 Zhaojun Rd., Hohhot, 010070, China
| | - Shanshan Wu
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (R2BGL), Inner Mongolia University, 24 Zhaojun Rd., Hohhot, 010070, China
- Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, 518000, China
| | - Zhiwen Du
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (R2BGL), Inner Mongolia University, 24 Zhaojun Rd., Hohhot, 010070, China
- College of Life Sciences, Inner Mongolia University, 24 Zhaojun Rd., Hohhot, 010070, China
| | - Shuqin Liu
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (R2BGL), Inner Mongolia University, 24 Zhaojun Rd., Hohhot, 010070, China
- College of Life Sciences, Inner Mongolia University, 24 Zhaojun Rd., Hohhot, 010070, China
| | - Lei Yang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (R2BGL), Inner Mongolia University, 24 Zhaojun Rd., Hohhot, 010070, China
- College of Life Sciences, Inner Mongolia University, 24 Zhaojun Rd., Hohhot, 010070, China
| | - Haoran Ma
- Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Liguo Zhang
- Ulanqab Agriculture and Animal Husbandry Bureau, Ulanqab Animal Husbandry Workstation, Ulanqab, 012000, Inner Mongolia, China
| | - Lishuang Song
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (R2BGL), Inner Mongolia University, 24 Zhaojun Rd., Hohhot, 010070, China
- College of Life Sciences, Inner Mongolia University, 24 Zhaojun Rd., Hohhot, 010070, China
| | - Chunling Bai
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (R2BGL), Inner Mongolia University, 24 Zhaojun Rd., Hohhot, 010070, China
- College of Life Sciences, Inner Mongolia University, 24 Zhaojun Rd., Hohhot, 010070, China
| | - Guanghua Su
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (R2BGL), Inner Mongolia University, 24 Zhaojun Rd., Hohhot, 010070, China.
- College of Life Sciences, Inner Mongolia University, 24 Zhaojun Rd., Hohhot, 010070, China.
| | - Guangpeng Li
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock (R2BGL), Inner Mongolia University, 24 Zhaojun Rd., Hohhot, 010070, China.
- College of Life Sciences, Inner Mongolia University, 24 Zhaojun Rd., Hohhot, 010070, China.
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Yang M, Mao X, Li L, Yang J, Xing H, Jiang C. High TPX2 expression results in poor prognosis, and Sp1 mediates the coupling of the CX3CR1/CXCL10 chemokine pathway to the PI3K/Akt pathway through targeted inhibition of TPX2 in endometrial cancer. Cancer Med 2024; 13:e6958. [PMID: 38466034 PMCID: PMC10926884 DOI: 10.1002/cam4.6958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 06/19/2023] [Accepted: 07/25/2023] [Indexed: 03/12/2024] Open
Abstract
INTRODUCTION Approximately 30% of individuals with advanced EC have unsatisfactory prognosis. Evidence suggests that TPX2 is frequently upregulated in malignancies and related to cancer progression. Its role and pathological mechanism in EC need further research. METHODS GSEA and TPX2 expression, GO, KEGG, and prognostic analyses were performed with TCGA data by bioinformatic approaches. Relationships between TPX2 expression and clinicopathological parameters were investigated immunohistochemically and statistically. shRNA and overexpression plasmids were constructed and transfected into AN3CA and Ishikawa cells to evaluate phenotypic changes and injected into nude mouse axillae. Coimmunoprecipitation and chromatin immunoprecipitation were used to identify interacting proteins and promoter-binding sequences. Changes in TPX2 expression were identified by Western blotting and RT-qPCR. RESULTS TPX2 expression was significantly higher in EC tissues than in normal tissues in TCGA and in-house specimens (all p < 0.001). In survival analysis, high TPX2 expression was associated with poor prognosis (p = 0.003). TPX2 overexpression stimulated cancer cell proliferation, promoted the G0-G1-to-G2/M transition, enhanced invasion and migration, and accelerated tumor growth in nude mice. TPX2 regulated the CX3CR1/CXCL10 chemokine pathway and activated the PI3K/Akt signaling pathway. Sp1 negatively regulated TPX2 expression, affecting the malignant progression of endometrial cancer cells by coupling the CX3CR1/CXCL10 chemokine pathway to the PI3K/Akt signaling pathway. CONCLUSION TPX2 could be a prognostic biomarker for EC and play an important role in the CX3CR1/CXCL10 chemokine pathway and PI3K/Akt pathway via Sp1.
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Affiliation(s)
- Mei Yang
- Department of Obstetrics and GynecologyXiangyang Central Hospital, Affiliated Hospital of Hubei, University of Arts and ScienceXiangyangChina
- Institute of Maternity DiseaseXiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and ScienceXiangyangChina
| | - Xiaogang Mao
- Department of Obstetrics and GynecologyXiangyang Central Hospital, Affiliated Hospital of Hubei, University of Arts and ScienceXiangyangChina
| | - Lin Li
- Department of Obstetrics and GynecologyXiangyang Central Hospital, Affiliated Hospital of Hubei, University of Arts and ScienceXiangyangChina
| | - Jiang Yang
- Department of Obstetrics and GynecologyXiangyang Central Hospital, Affiliated Hospital of Hubei, University of Arts and ScienceXiangyangChina
| | - Hui Xing
- Department of Obstetrics and GynecologyXiangyang Central Hospital, Affiliated Hospital of Hubei, University of Arts and ScienceXiangyangChina
- Institute of Maternity DiseaseXiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and ScienceXiangyangChina
| | - Chunfan Jiang
- Institute of Maternity DiseaseXiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and ScienceXiangyangChina
- Department of PathologyXiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and ScienceXiangyangHubeiChina
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Rong Y, Tang MZ, Liu SH, Li XF, Cai H. Comprehensive analysis of the potential pathogenesis of COVID-19 infection and liver cancer. World J Gastrointest Oncol 2024; 16:436-457. [PMID: 38425388 PMCID: PMC10900145 DOI: 10.4251/wjgo.v16.i2.436] [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: 08/19/2023] [Revised: 12/13/2023] [Accepted: 01/09/2024] [Indexed: 02/02/2024] Open
Abstract
BACKGROUND A growing number of clinical examples suggest that coronavirus disease 2019 (COVID-19) appears to have an impact on the treatment of patients with liver cancer compared to the normal population, and the prevalence of COVID-19 is significantly higher in patients with liver cancer. However, this mechanism of action has not been clarified. AIM To investigate the disease relevance of COVID-19 in liver cancer. METHODS Gene sets for COVID-19 (GSE180226) and liver cancer (GSE87630) were obtained from the Gene Expression Omnibus database. After identifying the common differentially expressed genes (DEGs) of COVID-19 and liver cancer, functional enrichment analysis, protein-protein interaction network construction and screening and analysis of hub genes were performed. Subsequently, the validation of the differential expression of hub genes in the disease was performed and the regulatory network of transcription factors and hub genes was constructed. RESULTS Of 518 common DEGs were obtained by screening for functional analysis. Fifteen hub genes including aurora kinase B, cyclin B2, cell division cycle 20, cell division cycle associated 8, nucleolar and spindle associated protein 1, etc., were further identified from DEGs using the "cytoHubba" plugin. Functional enrichment analysis of hub genes showed that these hub genes are associated with P53 signalling pathway regulation, cell cycle and other functions, and they may serve as potential molecular markers for COVID-19 and liver cancer. Finally, we selected 10 of the hub genes for in vitro expression validation in liver cancer cells. CONCLUSION Our study reveals a common pathogenesis of liver cancer and COVID-19. These common pathways and key genes may provide new ideas for further mechanistic studies.
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Affiliation(s)
- Yao Rong
- First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
- General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Ming-Zheng Tang
- First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
- General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Song-Hua Liu
- First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
- General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Xiao-Feng Li
- First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Hui Cai
- General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
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Zhu M, Wang X, Zhang Q, Xie C, Wang T, Shen K, Zhang L, Zhou X. Integrative analysis confirms TPX2 as a novel biomarker for clinical implication, tumor microenvironment, and immunotherapy response across human solid tumors. Aging (Albany NY) 2024; 16:2563-2590. [PMID: 38315450 PMCID: PMC10911359 DOI: 10.18632/aging.205498] [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: 06/27/2023] [Accepted: 12/01/2023] [Indexed: 02/07/2024]
Abstract
Targeting Protein for Xenopus Kinesin Like Protein 2 (TPX2) serves as a microtubule associated protein for the regulation of spindle assembly and tumorigenesis. We aim to investigate the prognostic and immunological role of TPX2 in pan-cancer. TCGA database, Tumor Immune Single-cell Hub (TISCH), and Human Protein Atlas (HPA) were retrieved to evaluate the expression pattern of TPX2 as well as its diagnostic and prognostic value in solid tumors. Genomic alterations of TPX2 were assessed with cBioPortal database. In vitro experiments in lung adenocarcinoma (LUAD) were performed to confirm the potential role of TPX2. Overexpression of TPX2 was found in 22 types of cancers, and was positively related with copy number variations (CNV) and negative with methylation. Up-regulated TPX2 could predict worse outcomes in the majority of cancers. Single-cell analysis revealed that TPX2 was mainly distributed in malignant cells (especially in glioma) and proliferating T cells. Genomic alteration of TPX2 was common in different types of tumors, while with prognostic value in two types of cancers. Additionally, significant correlations were found between TPX2 expression and tumor microenvironment (including stromal cells and immune cells) as well as immune related genes across cancer types. Drug sensitivity analysis revealed that TPX2 could predict response to chemotherapy and immunotherapy. Functional analyses demonstrated close relationship of TPX2 with immune function and malignant phenotypes. Finally, it was confirmed that knockdown of TPX2 could reduce proliferation and migration ability of LUAD cells. In summary, TPX2 could serve as a diagnostic and prognostic biomarker and a potential immunotherapy marker.
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Affiliation(s)
- Mingxia Zhu
- Department of Radiation Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Xiaping Wang
- Department of Pathology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210000, China
| | - Qing Zhang
- Department of Neurosurgery, Xinghua People’s Hospital, Xinghua 225700, China
| | - Chen Xie
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Tongshan Wang
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Kai Shen
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Lan Zhang
- Department of Radiation Oncology, Shanghai Tenth People’s Hospital of Tongji University, Shanghai 200072, China
| | - Xin Zhou
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
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Krivec N, Ghosh MS, Spits C. Gains of 20q11.21 in human pluripotent stem cells: Insights from cancer research. Stem Cell Reports 2024; 19:11-27. [PMID: 38157850 PMCID: PMC10828824 DOI: 10.1016/j.stemcr.2023.11.013] [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: 09/08/2023] [Revised: 11/28/2023] [Accepted: 11/28/2023] [Indexed: 01/03/2024] Open
Abstract
The genetic abnormalities observed in hPSC cultures worldwide have been suggested to pose an important hurdle in their safe use in regenerative medicine due to the possibility of oncogenic transformation by mutant cells in the patient posttransplantation. One of the best-characterized genetic lesions in hPSCs is the gain of 20q11.21, found in 20% of hPSC lines worldwide, and strikingly, also amplified in 20% of human cancers. In this review, we have curated the existing knowledge on the incidence of this mutation in hPSCs and cancer, explored the significance of chromosome 20q11.21 amplification in cancer progression, and reviewed the oncogenic role of the genes in the smallest common region of gain, to shed light on the significance of this mutation in hPSC-based cell therapy. Lastly, we discuss the state-of-the-art strategies devised to detect aneuploidies in hPSC cultures, avoid genetic changes in vitro cultures of hPSCs, and strategies to eliminate genetically abnormal cells from culture.
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Affiliation(s)
- Nuša Krivec
- Research Group Reproduction and Genetics, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Manjusha S Ghosh
- Research Group Reproduction and Genetics, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Claudia Spits
- Research Group Reproduction and Genetics, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Laarbeeklaan 103, 1090 Brussels, Belgium.
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13
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Ulaganathan K, Puranam K, Mukta S, Hanumanth SR. Expression profiling of luminal B breast tumor in Indian women. J Cancer Res Clin Oncol 2023; 149:13645-13664. [PMID: 37516983 DOI: 10.1007/s00432-023-05195-y] [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: 07/12/2023] [Accepted: 07/17/2023] [Indexed: 08/01/2023]
Abstract
PURPOSE In this study, we aimed at profiling of luminal B breast cancer specific gene expression pattern in Indian women using mRNA-seq and validation based on TCGA expression data. METHODS RNA isolated from luminal B tumor and adjacent normal tissues was used for library construction and sequencing. Reference-based assemblies of these reads were used for differential gene expression analysis using DeSeq2. The DEGs were evaluated using TCGA expression data. Kaplan-Meier survival method was used to evaluate association between genes showing luminal B specific differential expression pattern and breast cancer prognosis and statistical significance was assessed using log-rank test. Alternate splicing analysis was done using rmats. RESULTS Differential expression analysis identified 2371 differentially expressed genes (DEGs) in luminal B breast tumors in comparison with adjacent normal tissues of Indian Women. Of them, 1692 DEGs were validated using TCGA luminal B paired samples. Integration of this data with the DEGs obtained by comparative analysis of unpaired luminal B with luminal A unpaired samples from TCGA resulted in 291 DEGs showing luminal B specific expression pattern. Further, 26 genes of prognostic value were identified. Differential splicing analysis between luminal B tumors and adjacent normal tissues in our cohort led to the identification of 687 genes showing significant differential alternate splicing events. CONCLUSION This study profiled gene expression pattern of luminal B tumors of Indian women and identified 26 key genes of prognostic value for luminal B breast cancer. This study also profiled differential alternate splicing and identified important alternate splicing events in luminal B breast cancer.
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Affiliation(s)
| | - Kaushik Puranam
- Department of Genetics, Osmania University, Hyderabad, Telangana, 500007, India
| | - Srinivasulu Mukta
- Department of Surgical Oncology, MNJ Institute of Oncology and RCC, Hyderabad, Telangana, India
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Huang M, Yang S, Tai WCS, Zhang L, Zhou Y, Cho WCS, Chan LWC, Wong SCC. Bioinformatics Identification of Regulatory Genes and Mechanism Related to Hypoxia-Induced PD-L1 Inhibitor Resistance in Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:8720. [PMID: 37240068 PMCID: PMC10218698 DOI: 10.3390/ijms24108720] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 04/28/2023] [Accepted: 05/04/2023] [Indexed: 05/28/2023] Open
Abstract
The combination of a PD-L1 inhibitor and an anti-angiogenic agent has become the new reference standard in the first-line treatment of non-excisable hepatocellular carcinoma (HCC) due to the survival advantage, but its objective response rate remains low at 36%. Evidence shows that PD-L1 inhibitor resistance is attributed to hypoxic tumor microenvironment. In this study, we performed bioinformatics analysis to identify genes and the underlying mechanisms that improve the efficacy of PD-L1 inhibition. Two public datasets of gene expression profiles, (1) HCC tumor versus adjacent normal tissue (N = 214) and (2) normoxia versus anoxia of HepG2 cells (N = 6), were collected from Gene Expression Omnibus (GEO) database. We identified HCC-signature and hypoxia-related genes, using differential expression analysis, and their 52 overlapping genes. Of these 52 genes, 14 PD-L1 regulator genes were further identified through the multiple regression analysis of TCGA-LIHC dataset (N = 371), and 10 hub genes were indicated in the protein-protein interaction (PPI) network. It was found that POLE2, GABARAPL1, PIK3R1, NDC80, and TPX2 play critical roles in the response and overall survival in cancer patients under PD-L1 inhibitor treatment. Our study provides new insights and potential biomarkers to enhance the immunotherapeutic role of PD-L1 inhibitors in HCC, which can help in exploring new therapeutic strategies.
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Affiliation(s)
- Mohan Huang
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Sijun Yang
- Department of endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - William Chi Shing Tai
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Lingfeng Zhang
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Yinuo Zhou
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | | | - Lawrence Wing Chi Chan
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Sze Chuen Cesar Wong
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
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15
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Alwadi D, Felty Q, Yoo C, Roy D, Deoraj A. Endocrine Disrupting Chemicals Influence Hub Genes Associated with Aggressive Prostate Cancer. Int J Mol Sci 2023; 24:ijms24043191. [PMID: 36834602 PMCID: PMC9959535 DOI: 10.3390/ijms24043191] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/25/2023] [Accepted: 01/30/2023] [Indexed: 02/08/2023] Open
Abstract
Prostate cancer (PCa) is one of the most frequently diagnosed cancers among men in the world. Its prevention has been limited because of an incomplete understanding of how environmental exposures to chemicals contribute to the molecular pathogenesis of aggressive PCa. Environmental exposures to endocrine-disrupting chemicals (EDCs) may mimic hormones involved in PCa development. This research aims to identify EDCs associated with PCa hub genes and/or transcription factors (TF) of these hub genes in addition to their protein-protein interaction (PPI) network. We are expanding upon the scope of our previous work, using six PCa microarray datasets, namely, GSE46602, GSE38241, GSE69223, GSE32571, GSE55945, and GSE26126, from the NCBI/GEO, to select differentially expressed genes based on |log2FC| (fold change) ≥ 1 and an adjusted p-value < 0.05. An integrated bioinformatics analysis was used for enrichment analysis (using DAVID.6.8, GO, KEGG, STRING, MCODE, CytoHubba, and GeneMANIA). Next, we validated the association of these PCa hub genes in RNA-seq PCa cases and controls from TCGA. The influence of environmental chemical exposures, including EDCs, was extrapolated using the chemical toxicogenomic database (CTD). A total of 369 overlapping DEGs were identified associated with biological processes, such as cancer pathways, cell division, response to estradiol, peptide hormone processing, and the p53 signaling pathway. Enrichment analysis revealed five up-regulated (NCAPG, MKI67, TPX2, CCNA2, CCNB1) and seven down-regulated (CDK1, CCNB2, AURKA, UBE2C, BUB1B, CENPF, RRM2) hub gene expressions. Expression levels of these hub genes were significant in PCa tissues with high Gleason scores ≥ 7. These identified hub genes influenced disease-free survival and overall survival of patients 60-80 years of age. The CTD studies showed 17 recognized EDCs that affect TFs (NFY, CETS1P54, OLF1, SRF, COMP1) that are known to bind to our PCa hub genes, namely, NCAPG, MKI67, CCNA2, CDK1, UBE2C, and CENPF. These validated differentially expressed hub genes can be potentially developed as molecular biomarkers with a systems perspective for risk assessment of a wide-ranging list of EDCs that may play overlapping and important role(s) in the prognosis of aggressive PCa.
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Affiliation(s)
- Diaaidden Alwadi
- Department of Environmental Health Sciences, Florida International University, Miami, FL 33199, USA
| | - Quentin Felty
- Department of Environmental Health Sciences, Florida International University, Miami, FL 33199, USA
| | - Changwon Yoo
- Department of Biostatistics, Florida International University, Miami, FL 33199, USA
| | - Deodutta Roy
- Department of Environmental Health Sciences, Florida International University, Miami, FL 33199, USA
| | - Alok Deoraj
- Department of Environmental Health Sciences, Florida International University, Miami, FL 33199, USA
- Correspondence:
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Fatty acid transport proteins (FATPs) in cancer. Chem Phys Lipids 2023; 250:105269. [PMID: 36462545 DOI: 10.1016/j.chemphyslip.2022.105269] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 11/12/2022] [Accepted: 11/27/2022] [Indexed: 12/03/2022]
Abstract
Lipids play pivotal roles in cancer biology. Lipids have a wide range of biological roles, especially in cell membrane synthesis, serve as energetic molecules in regulating energy-demanding processes; and they play a significant role as signalling molecules and modulators of numerous cellular functions. Lipids may participate in the development of cancer through the fatty acid signalling pathway. Lipids consumed in the diet act as a key source of extracellular pools of fatty acids transported into the cellular system. Increased availability of lipids to cancer cells is due to increased uptake of fatty acids from adipose tissues. Lipids serve as a source of energy for rapidly dividing cancerous cells. Surviving requires the swift synthesis of biomass and membrane matrix to perform exclusive functions such as cell proliferation, growth, invasion, and angiogenesis. FATPs (fatty acid transport proteins) are a group of proteins involved in fatty acid uptake, mainly localized within cells and the cellular membrane, and have a key role in long-chain fatty acid transport. FATPs are composed of six isoforms that are tissue-specific and encoded by a specific gene. Previous studies have reported that FATPs can alter fatty acid metabolism, cell growth, and cell proliferation and are involved in the development of various cancers. They have shown increased expression in most cancers, such as melanoma, breast cancer, prostate cancer, renal cell carcinoma, hepatocellular carcinoma, bladder cancer, and lung cancer. This review introduces a variety of FATP isoforms and summarises their functions and their possible roles in the development of cancer.
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Comprehensive Analysis of the Oncogenic Role of Targeting Protein for Xklp2 (TPX2) in Human Malignancies. DISEASE MARKERS 2022; 2022:7571066. [PMID: 36304254 PMCID: PMC9596273 DOI: 10.1155/2022/7571066] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 09/21/2022] [Accepted: 10/05/2022] [Indexed: 11/17/2022]
Abstract
Mitosis and spindle assembly require the microtubule-associated protein Xenopus kinesin-like protein 2 (TPX2). Although TPX2 is highly expressed in several malignant tumor forms, little is known about its role in cancer. In this study, we performed the gene set enrichment analysis of TPX2 in 33 types of cancers and an extensive pan-cancer bioinformatic analysis using prognosis, tumor mutational burdens, microsatellite instability, tumor microenvironment, and immune cell infiltration data. According to the differential expression study, TPX2 was found to be overexpressed across all studied cancer types. Based on the survival analysis, increased TPX2 expression was associated with a poor prognosis for most cancers. The TPX2 expression level was confirmed to correlate with the clinical stage, microsatellite instability, and tumor mutational burden across all cancer types. Furthermore, TPX2 expression has been linked to tumor microenvironments and immune cell infiltration, particularly in bladder urothelial carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, stomach adenocarcinoma, and uterine corpus endometrial carcinoma. Finally, the gene set enrichment analysis implicated TPX2 in the regulation of aminoacyl tRNA biosynthesis, which is the most important tumor cell cycle signaling pathway. This comprehensive pan-cancer analysis shows that TPX2 is a prognostic molecular biomarker for most cancers and suggests its potential as an effective therapeutic target for the treatment of these diseases.
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Cheng X, Li J, Feng L, Feng S, Wu X, Li Y. The role of hypoxia-related genes in TACE-refractory hepatocellular carcinoma: Exploration of prognosis, immunological characteristics and drug resistance based on onco-multi-OMICS approach. Front Pharmacol 2022; 13:1011033. [PMID: 36225568 PMCID: PMC9549174 DOI: 10.3389/fphar.2022.1011033] [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: 08/03/2022] [Accepted: 08/22/2022] [Indexed: 11/21/2022] Open
Abstract
Transcatheter arterial chemoembolization (TACE) is an effective treatment for hepatocellular carcinoma (HCC). During TACE, chemotherapeutic agents are locally infused into the tumor and simultaneously cause hypoxia in tumor cells. Importantly, the poor effect of TACE in some HCC patients has been shown to be related to dysregulated expression of hypoxia-related genes (HRGs). Therefore, we identified 33 HRGs associated with TACE (HRGTs) by differential analysis and characterized the mutational landscape of HRGTs. Among 586 HCC patients, two molecular subtypes reflecting survival status were identified by consistent clustering analysis based on 24 prognosis-associated HRGs. Comparing the transcriptomic difference of the above molecular subtypes, three molecular subtypes that could reflect changes in the immune microenvironment were then identified. Ultimately, four HRGTs (CTSO, MMP1, SPP1, TPX2) were identified based on machine learning approachs. Importantly, risk assessment can be performed for each patient by these genes. Based on the parameters of the risk model, we determined that high-risk patients have a more active immune microenvironment, indicating “hot tumor” status. And the Tumor Immune Dysfunction and Exclusion (TIDE), the Cancer Immunome Atlas (TCIA), and Genome of Drug Sensitivity in Cancer (GDSC) databases further demonstrated that high-risk patients have a positive response to immunotherapy and have lower IC50 values for drugs targeting cell cycle, PI3K/mTOR, WNT, and RTK related signaling pathways. Finally, single-cell level analysis revealed significant overexpression of CTSO, MMP1, SPP1, and TPX2 in malignant cell after PD-L1/CTLA-4 treatment. In conclusion, Onco-Multi-OMICS analysis showed that HRGs are potential biomarkers for patients with refractory TACE, and it provides a novel immunological perspective for developing personalized therapies.
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Affiliation(s)
- Xuelian Cheng
- School of Medicine and Holistic Integrative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jingjing Li
- School of Medicine and Holistic Integrative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, China
| | - Limei Feng
- School of Medicine and Holistic Integrative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, China
| | - Songwei Feng
- School of Medicine, Southeast University, Nanjing, China
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China
| | - Xiao Wu
- School of Medicine and Holistic Integrative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Xiao Wu, ; Yongming Li,
| | - Yongming Li
- School of Medicine and Holistic Integrative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Xiao Wu, ; Yongming Li,
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Target Protein for Xklp2 Functions as Coactivator of Androgen Receptor and Promotes the Proliferation of Prostate Carcinoma Cells. JOURNAL OF ONCOLOGY 2022; 2022:6085948. [PMID: 35444697 PMCID: PMC9015851 DOI: 10.1155/2022/6085948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 02/05/2022] [Accepted: 02/12/2022] [Indexed: 11/18/2022]
Abstract
The activation of the androgen receptor (AR) pathway is crucial in the progression of human prostate cancer. Results of the present study indicated that the target protein xenopus kinesin-like protein (TPX2) enhanced the transcription activation of AR and promoted the proliferation of LNCaP (ligand-dependent prostate carcinoma) cells. The protein-protein interaction between AR and TPX2 was investigated using coimmunoprecipitation assays. Results of the present study further demonstrated that TPX2 enhanced the transcription factor activation of AR and enhanced the expression levels of the downstream gene prostate-specific antigen (PSA). TPX2 did this by promoting the accumulation of AR in the nucleus and also promoting the recruitment of AR to the androgen response element, located in the promoter region of the PSA gene. Overexpression of TPX2 enhanced both the in vitro and in vivo proliferation of LNCaP cells. By revealing a novel role of TPX2 in the AR signaling pathway, the present study indicated that TPX2 may be an activator of AR and thus exhibits potential as a novel target for prostate carcinoma treatment.
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Gao F, Wang J, Li C, Xie C, Su M, Zou C, Xie X, Zhao D. Risk-Related Genes and Associated Signaling Pathways of Gastrointestinal Stromal Tumors. Int J Gen Med 2022; 15:3839-3849. [PMID: 35431569 PMCID: PMC9005359 DOI: 10.2147/ijgm.s357224] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/28/2022] [Indexed: 12/27/2022] Open
Abstract
Purpose Knowledge on the potential association between differential gene expression and risk of gastrointestinal stromal tumors (GISTs) is currently limited. We used bioinformatics tools to identify differentially expressed genes in GIST samples and the related signaling pathways of these genes. Patients and Methods The GSE136755 dataset was obtained from the GEO database and differentially expressed genes (CENPA, CDK1, TPX2, CCNB1, CCNA2, BUB1, AURKA, KIF11, NDC80) were screened using String and Cytoscape bioinformatics tools. Then, three groups of eight patients at high, intermediate and low risk of GIST were selected from patients diagnosed with GIST by immunohistochemistry in our hospital from October 2020 to March 2021. Differential expression of CDK1 and BUB1 was verified by comparing the amount of expressed p21-Activated kinase 4 (PAK4) protein in pathological sections. Results SPSS26.0 analysis showed that the expression level of PAK4 in GISTs was significantly higher than in normal tissues and paratumoral tissues and there was significant difference among the three groups of patients (P < 0.01). PAK4 levels in paratumoral and normal tissues were negligible with no significant difference between the tissues. Conclusion CENPA, CDK1, TPX2, CCNB1, CCNA2, BUB1, AURKA, KIF11 and NDC80 gene expression can be used as biomarkers to assess the risk of gastrointestinal stromal tumors whereby expression increases gradually with the increased risk of GIST formation. The genes encode proteins that regulate the division, proliferation and apoptosis of gastrointestinal stromal tumors mainly through PI3K/AKT, MARK, P53, WNT and other signaling pathways.
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Affiliation(s)
- Fulai Gao
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China
- Department of Gastroenterology, The First Hospital of Qinhuangdao, Qinhuangdao, 066000, People’s Republic of China
| | - Jiaqi Wang
- Basic Medical College, Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China
| | - Changjuan Li
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China
| | - Changshun Xie
- Department of Gastroenterology, The First Hospital of Qinhuangdao, Qinhuangdao, 066000, People’s Republic of China
| | - Miao Su
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China
| | - Chunyan Zou
- Department of Gastroenterology, The First Hospital of Qinhuangdao, Qinhuangdao, 066000, People’s Republic of China
| | - Xiaoli Xie
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China
| | - Dongqiang Zhao
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China
- Correspondence: Dongqiang Zhao, Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 215, He Ping West Road, Xinhua District, Shijiazhuang, 050000, People’s Republic of China, Tel +86 0311 66636179, Email
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Zhu D, Xu X, Zhang M, Wang T. TPX2 regulated by miR‑29c‑3p induces cell proliferation in osteosarcoma via the AKT signaling pathway. Oncol Lett 2022; 23:143. [PMID: 35340555 PMCID: PMC8931832 DOI: 10.3892/ol.2022.13262] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 02/25/2022] [Indexed: 12/02/2022] Open
Abstract
The present study aimed to investigate the significance of targeting protein for Xenopus kinesin-like protein 2 (TPX2) expression in osteosarcoma. First, the TPX2 expression and survival analysis data were evaluated from The Cancer Genome Atlas (TCGA) database. Next, reverse transcription-quantitative PCR was used to explore the expression of TPX2 in osteosarcoma tissues. The observed potential target relationship between TPX2 and microRNA (miR)-29c-3p was verified using TargetScan and luciferase reporter assays. Kaplan-Meier survival analysis was used to determine associations between TPX2 expression levels and survival prognosis. TPX2 small interfering RNA was successfully constructed and transfected into osteosarcoma cell lines. The effects of TPX2 on osteosarcoma cell proliferation were then detected by MTT assay. In addition, the expression levels of AKT signaling pathway-associated proteins were identified by western blot analysis. The expression of TPX2 was upregulated and the expression of miR-29c-3p was downregulated in osteosarcoma. High expression of TPX2 was linked to a poor prognosis. Using luciferase assay and the miRNA mimic and inhibitors, miR-29c-3p was able to target and repress TPX2, and siRNA knockdown of TPX2 resulted in the inhibition of osteosarcoma cell proliferation by affecting the AKT pathway. Overall, the study showed that miR-29c-3p could inhibit the proliferation of osteosarcoma cells via TPX2 downregulation, and that TPX2 and miR-29c-3p may serve as promising prognostic indicators.
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Affiliation(s)
- Dongsheng Zhu
- Department of Pediatric Surgery, The First People's Hospital of Lianyungang Affiliated to Xuzhou Medical University, Lianyungang, Jiangsu 222000, P.R. China
| | - Xiangfei Xu
- Department of Pediatric Surgery, The First People's Hospital of Lianyungang Affiliated to Xuzhou Medical University, Lianyungang, Jiangsu 222000, P.R. China
| | - Ming Zhang
- Department of Pediatric Surgery, The First People's Hospital of Lianyungang Affiliated to Xuzhou Medical University, Lianyungang, Jiangsu 222000, P.R. China
| | - Tong Wang
- Department of Pediatric Surgery, The First People's Hospital of Lianyungang Affiliated to Xuzhou Medical University, Lianyungang, Jiangsu 222000, P.R. China
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Geng QS, Yang MJ, Li LF, Shen ZB, Wang LH, Zheng YY, Xue WH, Zhao J. Over-Expression and Prognostic Significance of FATP5, as a New Biomarker, in Colorectal Carcinoma. Front Mol Biosci 2022; 8:770624. [PMID: 35155561 PMCID: PMC8829069 DOI: 10.3389/fmolb.2021.770624] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 12/13/2021] [Indexed: 12/24/2022] Open
Abstract
Background: Fatty acid transporters (FATPs) family play an important role in the uptake and metabolism regulation of long-chain fatty acids, which influence the occurrence and developing of multiple tumors. Fatty acid transporter 5(FATP5), a member of FATPs family, participates in fatty acid transport and lipid metabolism and is related to tumor development, whose mechanism in colorectal cancer (CRC) remains unclear.Methods: In this study, we comprehensively utilized a range of relevant bioinformatic tools along with multiple databases to analyze the expression of FATPs family and investigate the biological function and prognostic value of FATP5 in CRC. Besides, cell proliferation and cell cycle distribution analysis, western blotting and immunohistochemistry (IHC) further validated the conclusion of bioinformatics analysis.Results: FATP5 is the only member of FATPs family which was overexpressed in CRC. In the survival analysis based on the GSE39582 databases, the low expression of FATP5 predicts poor prognosis in CRC. Similar results were also observed in GSE17536, GSE28814 and TCGA colon cohorts. The potential function of DNA methylation regulated the abnormal expression of FATP5 in CRC. In addition, enrichment analysis indicated that FATP5 also participates in the regulation of cell cycle. Furthermore, Gene Set Enrichment Analysis (GSEA) showed a strong negative correlation between FATP5 and cell growth, implying that it may participate in regulating cancer cell proliferation by the regulation of cell cycle G2/M transition. At last, we identified that FATP5 was overexpressed in colorectal carcinoma tissues through immunohistochemistry staining, and played an important role in cell cycle by cell proliferation and cell cycle distribution analysis.Conclusion: This study suggested that FATP5 was overexpression in colorectal carcinoma and predicted favorable prognosis, indicating it as a novel appealing prognostic marker for CRC.
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Affiliation(s)
- Qi-Shun Geng
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mei-Jia Yang
- Internet Medical and System Applications of National Engineering Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Li-Feng Li
- Internet Medical and System Applications of National Engineering Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhi-Bo Shen
- Internet Medical and System Applications of National Engineering Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Long-Hao Wang
- Internet Medical and System Applications of National Engineering Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuan-Yuan Zheng
- Internet Medical and System Applications of National Engineering Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wen-Hua Xue
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jie Zhao
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Internet Medical and System Applications of National Engineering Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Jie Zhao,
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Cancer Grade Model: a multi-gene machine learning-based risk classification for improving prognosis in breast cancer. Br J Cancer 2021; 125:748-758. [PMID: 34131308 PMCID: PMC8405688 DOI: 10.1038/s41416-021-01455-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 04/29/2021] [Accepted: 05/28/2021] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Prognostic stratification of breast cancers remains a challenge to improve clinical decision making. We employ machine learning on breast cancer transcriptomics from multiple studies to link the expression of specific genes to histological grade and classify tumours into a more or less aggressive prognostic type. MATERIALS AND METHODS Microarray data of 5031 untreated breast tumours spanning 33 published datasets and corresponding clinical data were integrated. A machine learning model based on gradient boosted trees was trained on histological grade-1 and grade-3 samples. The resulting predictive model (Cancer Grade Model, CGM) was applied on samples of grade-2 and unknown-grade (3029) for prognostic risk classification. RESULTS A 70-gene signature for assessing clinical risk was identified and was shown to be 90% accurate when tested on known histological-grade samples. The predictive framework was validated through survival analysis and showed robust prognostic performance. CGM was cross-referenced with existing genomic tests and demonstrated the competitive predictive power of tumour risk. CONCLUSIONS CGM is able to classify tumours into better-defined prognostic categories without employing information on tumour size, stage, or subgroups. The model offers means to improve prognosis and support the clinical decision and precision treatments, thereby potentially contributing to preventing underdiagnosis of high-risk tumours and minimising over-treatment of low-risk disease.
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24
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Chen B, Xie X, Lan F, Liu W. Identification of prognostic markers by weighted gene co-expression network analysis in non-small cell lung cancer. Bioengineered 2021; 12:4924-4935. [PMID: 34369264 PMCID: PMC8806742 DOI: 10.1080/21655979.2021.1960764] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is one of the fatal tumors and is associated with a poor prognosis. Cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) was used to quantify the proportions of 22 types of immune cells. Weighted gene co-expression network analysis (WGCNA) was established from the GSE37745 data, and key modules correlating most with CD8+ T cell infiltration were determined. Genes that manifested a high module connectivity in the key module were identified as hub genes. Three bioinformatics online databases were used to evaluate hub gene expression levels in tumor and normal tissues. Finally, survival analysis was conducted for these hub genes. In this study, we chose four hub genes (AURKB, CDC20, TPX2 and KIF2C) based on the comprehensive bioinformatics analyses. All hub genes were overexpressed in tumor tissue, and high expression of AURKB, CDC20, TPX2, and KIF2C correlated with the poor prognosis of these patients. In vitro experiments confirmed that CDC20 knockdown inhibited cell proliferation and growth. The above results indicated that AURKB, CDC20, TPX2, and KIF2C are potential CD8+ T cell infiltration-related biomarkers and therapeutic targets.
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Affiliation(s)
- Binglin Chen
- Department of Radiation Oncology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiaowei Xie
- Department of Radiation Oncology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Feifeng Lan
- Department of Radiation Oncology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Wenqi Liu
- Department of Radiation Oncology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
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Meng Z, Wu J, Liu X, Zhou W, Ni M, Liu S, Guo S, Jia S, Zhang J. Identification of potential hub genes associated with the pathogenesis and prognosis of hepatocellular carcinoma via integrated bioinformatics analysis. J Int Med Res 2021; 48:300060520910019. [PMID: 32722976 PMCID: PMC7391448 DOI: 10.1177/0300060520910019] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Objective The objective was to identify potential hub genes associated with the pathogenesis and prognosis of hepatocellular carcinoma (HCC). Methods Gene expression profile datasets were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between HCC and normal samples were identified via an integrated analysis. A protein–protein interaction network was constructed and analyzed using the STRING database and Cytoscape software, and enrichment analyses were carried out through DAVID. Gene Expression Profiling Interactive Analysis and Kaplan–Meier plotter were used to determine expression and prognostic values of hub genes. Results We identified 11 hub genes (CDK1, CCNB2, CDC20, CCNB1, TOP2A, CCNA2, MELK, PBK, TPX2, KIF20A, and AURKA) that might be closely related to the pathogenesis and prognosis of HCC. Enrichment analyses indicated that the DEGs were significantly enriched in metabolism-associated pathways, and hub genes and module 1 were highly associated with cell cycle pathway. Conclusions In this study, we identified key genes of HCC, which indicated directions for further research into diagnostic and prognostic biomarkers that could facilitate targeted molecular therapy for HCC.
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Affiliation(s)
- Ziqi Meng
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jiarui Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xinkui Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Wei Zhou
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Mengwei Ni
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Shuyu Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Siyu Guo
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Shanshan Jia
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jingyuan Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
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Sanchez-Lopez JM, Mandujano-Tinoco EA, Garcia-Venzor A, Lozada-Rodriguez LF, Zampedri C, Uribe-Carvajal S, Melendez-Zajgla J, Maldonado V, Lizarraga F. Integrative analysis of transcriptional profile reveals LINC00052 as a suppressor of breast cancer cell migration. Cancer Biomark 2021; 30:365-379. [PMID: 33361583 DOI: 10.3233/cbm-200337] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Long-non-coding RNAs, a class of transcripts with lengths > 200 nt, play key roles in tumour progression. Previous reports revealed that LINC00052 (long intergenic non-coding RNA 00052) was strongly downregulated during breast cancer multicellular spheroids formation and suggested a role in cell migration and oxidative metabolism. OBJECTIVE To examine the function of LINC00052 in MCF-7 breast cancer cells. METHODS Loss-of-function studies were performed to evaluate LINC00052 role on MCF-7 breast cancer cells. Microarray expression assays were performed to determine genes and cellular functions modified after LINC00052 knockdown. Next, the impact of LINC00052 depletion on MCF-7 cell respiration and migration was evaluated. RESULTS 1,081 genes were differentially expressed upon LINC00052 inhibition. Gene set enrichment analysis, Gene Ontology and Key Pathway Advisor analysis showed that signalling networks related to cell migration and oxidative phosphorylation were enriched. However, whereas LINC00052 knockdown in MCF-7 cells revealed marginal difference in oxygen consumption rates when compared with control cells, LINC00052 inhibition enhanced cell migration in vitro and in vivo, as observed using a Zebrafish embryo xenotransplant model. CONCLUSION Our data show that LINC00052 modulates MCF-7 cell migration. Genome-wide microarray experiments suggest that cancer cell migration is affected by LINC00052 through cytoskeleton modulation and Notch/β-catenin/NF-κB signalling pathways.
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Affiliation(s)
- Jose Manuel Sanchez-Lopez
- Epigenetics Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, Mexico.,Postgraduate Program in Biological Sciences, Faculty of Medicine, Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Edna Ayerim Mandujano-Tinoco
- Epigenetics Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, Mexico.,Laboratory of Connective Tissue, Centro Nacional de Investigación y Atención de Quemados, Instituto Nacional de Rehabilitación Luís Guillermo Ibarra Ibarra, Mexico City, Mexico
| | - Alfredo Garcia-Venzor
- Epigenetics Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | | | - Cecilia Zampedri
- Epigenetics Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Salvador Uribe-Carvajal
- Department of Molecular Genetics, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Jorge Melendez-Zajgla
- Functional Genomics Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Vilma Maldonado
- Epigenetics Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Floria Lizarraga
- Epigenetics Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
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Matson DR, Denu RA, Zasadil LM, Burkard ME, Weaver BA, Flynn C, Stukenberg PT. High nuclear TPX2 expression correlates with TP53 mutation and poor clinical behavior in a large breast cancer cohort, but is not an independent predictor of chromosomal instability. BMC Cancer 2021; 21:186. [PMID: 33622270 PMCID: PMC7901195 DOI: 10.1186/s12885-021-07893-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 02/08/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Targeting Protein for Xenopus Kinesin Like Protein 2 (TPX2) is a microtubule associated protein that functions in mitotic spindle assembly. TPX2 also localizes to the nucleus where it functions in DNA damage repair during S-phase. We and others have previously shown that TPX2 RNA levels are strongly associated with chromosomal instability (CIN) in breast and other cancers, and TPX2 RNA levels have been demonstrated to correlate with aggressive behavior and poor clinical outcome across a range of solid malignancies, including breast cancer. METHODS We perform TPX2 IHC on a cohort of 253 primary breast cancers and adopt a clinically amenable scoring system to separate tumors into low, intermediate, or high TPX2 expression. We then correlate TPX2 expression against diverse pathologic parameters and important measures of clinical outcome, including disease-specific and overall survival. We link TPX2 expression to TP53 mutation and evaluate whether TPX2 is an independent predictor of chromosomal instability (CIN). RESULTS We find that TPX2 nuclear expression strongly correlates with high grade morphology, elevated clinical stage, negative ER and PR status, and both disease-specific and overall survival. We also show that increased TPX2 nuclear expression correlates with elevated ploidy, supernumerary centrosomes, and TP53 mutation. TPX2 nuclear expression correlates with CIN via univariate analyses but is not independently predictive when compared to ploidy, Ki67, TP53 mutational status, centrosome number, and patient age. CONCLUSIONS Our findings demonstrate a strong correlation between TPX2 nuclear expression and aggressive tumor behavior, and show that TPX2 overexpression frequently occurs in the setting of TP53 mutation and elevated ploidy. However, TPX2 expression is not an independent predictor of CIN where it fails to outperform existing clinical and pathologic metrics.
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Affiliation(s)
- Daniel R Matson
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, 600 Highland Ave, Madison, WI, 53792, USA.
| | - Ryan A Denu
- Department of Medicine, University of Wisconsin Hospitals and Clinics, Madison, WI, USA
| | - Lauren M Zasadil
- Molecular and Cellular Pharmacology Training Program, University of Wisconsin-Madison, Madison, WI, USA
| | - Mark E Burkard
- Department of Medicine, University of Wisconsin Hospitals and Clinics, Madison, WI, USA
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
- Department of Oncology/McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA
| | - Beth A Weaver
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
- Department of Oncology/McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, USA
| | - Christopher Flynn
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, 600 Highland Ave, Madison, WI, 53792, USA
| | - P Todd Stukenberg
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA
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Zhang B, Zhang M, Li Q, Yang Y, Shang Z, Luo J. TPX2 mediates prostate cancer epithelial-mesenchymal transition through CDK1 regulated phosphorylation of ERK/GSK3β/SNAIL pathway. Biochem Biophys Res Commun 2021; 546:1-6. [PMID: 33556637 DOI: 10.1016/j.bbrc.2021.01.106] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 01/28/2021] [Indexed: 02/07/2023]
Abstract
Prostate cancer with high Gleason grade is prone to metastasis, which is one of the factors that seriously threaten the survival of patients, and it is also a treatment difficulty. In this study, we first revealed the potential connection between TPX2 and prostate cancer metastasis. We found that TPX2 is highly expressed in high-grade prostate cancer and is significantly related to poor prognosis. Depletion of TPX2 can significantly inhibit cell activity and migration, and in vivo experiments show that knockdown of TPX2 can significantly inhibit tumor growth. In terms of mechanism, we found that knocking down TPX2 can inhibit the expression of CDK1, repress the phosphorylation of ERK/GSK3β/SNAIL signaling pathway, and thereby inhibit tumor epithelial-mesenchymal transition. Subsequently, we found that after rescuing TPX2, all related proteins and phenotype changes were restored, and this effect can be inhibited by CDK1 inhibitor, RO-3306. Our findings suggest the potential of TPX2 as an important target in anti-tumor metastasis therapy, which is conducive to precision medicine for prostate cancer.
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Affiliation(s)
- Boya Zhang
- Tianjin Institute of Urology, the Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Mingpeng Zhang
- Tianjin Institute of Urology, the Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Qi Li
- Tianjin Institute of Urology, the Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Yanjie Yang
- Tianjin Institute of Urology, the Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Zhiqun Shang
- Tianjin Institute of Urology, the Second Hospital of Tianjin Medical University, Tianjin, 300211, China.
| | - Jun Luo
- Tianjin Institute of Urology, the Second Hospital of Tianjin Medical University, Tianjin, 300211, China.
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Upregulated LEPRE1 correlates with poor outcome and its knockdown attenuates cells proliferation, migration and invasion in osteosarcoma. Anticancer Drugs 2021; 31:326-332. [PMID: 32197005 DOI: 10.1097/cad.0000000000000851] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Leucine proline-enriched proteoglycan 1 has been extensively explored because of its protective function in cell homeostasis and correlation with osteogenesis imperfect. Human osteosarcoma is the most common primary malignant tumor of bone with multiple and complex genomic aberrations. However, the functional role of leucine proline-enriched proteoglycan 1 is still unknown in osteosarcoma. Thus we performed this study to explain the leucine proline-enriched proteoglycan 1 effect in osteosarcoma. Gene arrays of human osteosarcoma were downloaded from the Gene Expression Omnibus database. Quantitative real-time PCR was conducted to assess the expression of leucine proline-enriched proteoglycan 1 in osteosarcoma cell lines. Then we attenuated leucine proline-enriched proteoglycan 1 expression in MG63 cells by siRNA strategy and assessed the effect of leucine proline-enriched proteoglycan 1 on cell proliferation, migration and invasion through in-vitro experiments. Additionally, we detected the role of leucine proline-enriched proteoglycan 1 knockdown on PI3K/AKT pathway-related proteins using western blotting. Leucine proline-enriched proteoglycan 1 was increased in osteosarcoma tissues and cells. The overall survival curve demonstrated that high-regulated leucine proline-enriched proteoglycan 1 was linked with poor prognosis of patients with osteosarcoma. The capabilities of proliferation, migration and invasion were all inhibited in MG63 cell because of the downregulation of leucine proline-enriched proteoglycan 1. Furthermore, the expression of phosphorylated PI3K and AKT was impaired after knockdown the leucine proline-enriched proteoglycan 1 as well as P70S6K. In conclusion, leucine proline-enriched proteoglycan 1 might function as an important therapeutic factor in human osteosarcoma through regulating the PI3K/AKT signaling pathway.
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A 23-gene prognostic classifier for prediction of recurrence and survival for Asian breast cancer patients. Biosci Rep 2020; 40:227018. [PMID: 33226082 PMCID: PMC7711061 DOI: 10.1042/bsr20202794] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 11/18/2020] [Accepted: 11/20/2020] [Indexed: 11/17/2022] Open
Abstract
We report a 23- gene-classifier profiled from Asian women, with the primary purpose of assessing its clinical utility towards improved risk stratification for relapse for breast cancer patients from Asian cohorts within 10 years’ following mastectomy. Four hundred and twenty-two breast cancer patients underwent mastectomy and were used to train the classifier on a logistic regression model. A subset of 197 patients were chosen to be entered into the follow-up studies post mastectomy who were examined to determine the patterns of recurrence and survival analysis based on gene expression of the gene classifier, age at diagnosis, tumor stage and lymph node status, over a 5 and 10 years follow-up period. Metastasis to lymph node (N2-N3) with N0 as the reference (N2 vs. N0 hazard ratio: 2.02 (1.05–8.70), N3 vs. N0 hazard ratio: 4.32 (1.41–13.22) for 5 years) and gene expression of the 23-gene panel (P=0.06, 5 years and 0.02, 10 years, log-rank test) were found to have significant discriminatory effects on the risk of relapse (HR (95%CI):2.50 (0.95–6.50)). Furthermore, survival curves for subgroup analysis with N0-N1 and T1-T2 predicted patients with higher risk scores. The study provides robust evidence of the effectiveness of the 23-gene-classifier and could be used to determine the risk of relapse event (locoregional and distant recurrence) in Asian patients, leading to a meaningful reduction in chemotherapy recommendations.
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Zhu H, Liu J, Feng J, Zhang Q, Bian T, Li X, Sun H, Zhang J, Liu Y. Overexpression of TPX2 predicts poor clinical outcome and is associated with immune infiltration in hepatic cell cancer. Medicine (Baltimore) 2020; 99:e23554. [PMID: 33285774 PMCID: PMC7717782 DOI: 10.1097/md.0000000000023554] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Targeting protein for Xenopus kinesin-like protein 2 (TPX2) has been identified as an oncogene in multiple cancers. However, the associations among TPX2 expression, prognosis, and tumor immunity in hepatic cell cancer (HCC) have not been explored. We analyzed TPX2 expression by multiple gene expression databases, including Oncomine, TIMER, and UALCAN. The prognosis effect of TPX2 was analyzed by Kaplan--Meier plotter. The coexpressed genes with TPX2 were analyzed using Linked Omics. The association among TPX2 and immune infiltrates and immune checkpoints was determined by TIMER. It was found that TPX2 expression was notably upregulated in multiple HCC tissues. Overexpression of TPX2 has associations with race, age, weight, clinical stage and tumor grade, as well as poor prognosis in overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), and disease-specific survival (DSS). In addition, TPX2 expression has a positive association with the infiltration of immune cells and the expression of immune checkpoint molecules. Coexpressed genes and functional network analysis suggested several potential mechanisms of TPX2 affecting HCC progression. The findings reveal that TPX2 has associations with prognosis and infiltration of immune cells in HCC patients, which has laid a basis for in-depth study of TPX2 role in HCC.
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Affiliation(s)
- Hongjun Zhu
- Departments of Pathology, Affiliated Hospital of Nantong University
- Department of Oncology, The Third People's Hospital of Nantong
| | - Jian Liu
- Departments of Chemotherapy, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
| | - Jia Feng
- Departments of Pathology, Affiliated Hospital of Nantong University
| | - Qing Zhang
- Departments of Pathology, Affiliated Hospital of Nantong University
| | - Tingting Bian
- Departments of Pathology, Affiliated Hospital of Nantong University
| | - Xiaoli Li
- Departments of Pathology, Affiliated Hospital of Nantong University
| | - Hui Sun
- Departments of Pathology, Affiliated Hospital of Nantong University
| | - Jianguo Zhang
- Departments of Pathology, Affiliated Hospital of Nantong University
| | - Yifei Liu
- Departments of Pathology, Affiliated Hospital of Nantong University
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32
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He L, Wang X, Cheng D, Xiong Z, Liu X. Ginsenoside Rg1 improves pathological damages by activating the p21‑p53‑STK pathway in ovary and Bax‑Bcl2 in the uterus in premature ovarian insufficiency mouse models. Mol Med Rep 2020; 23:37. [PMID: 33179093 PMCID: PMC7684879 DOI: 10.3892/mmr.2020.11675] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 08/25/2020] [Indexed: 01/02/2023] Open
Abstract
The aim of the present study was to investigate the effects of the ginsenoside Rg1 on D-galactose (D-gal)-induced mouse models of premature ovarian insufficiency (POI) and the related mechanisms. C57BL/6 female mice were randomly grouped into the following: i) D-gal [subcutaneously (s.c.) 200 mg/kg/d D-gal for 42 days]; ii) Rg1 [intraperitoneally (i.p.) 20 mg/kg/d Rg1 for 28 days]; iii) D-gal + Rg1 (s.c. 200 mg/kg/d D-gal for 42 days followed by i.p. 20 mg/kg/d Rg1 for 28 days); and iv) saline groups (equivalent volume of saline s.c. and i.p.). Hematoxylin and eosin staining and electron microscopy were used to analyze uterine and ovarian morphology. Expression levels of senescence factors (p21, p53 and serine/threonine kinase), secretion of pro-inflammatory cytokines [interleukin (IL)-6, tumor necrosis factor (TNF)-α and IL-1β] and the activities of oxidation biomarkers [superoxide dismutase (T-SOD), malondialdehyde (MDA) and glutathione peroxidase (GSH-px)] were analyzed. The results showed that mice in the Rg1 + D-gal group had significantly higher uterine and ovarian weight compared with those in the D-gal group. Uterus morphology was also improved, based on the comparison between the D-gal group and the Rg1 + D-gal group. In addition, the Rg1 treatment after D-gal administration significantly decreased the expression of senescence-associated factors, enhanced the activities of anti-oxidant enzymes total T-SOD and GSH-px in addition to reducing TNF-α, IL-1β, MDA and IL-6 (based on the comparison between the D-gal group and the Rg1 + D-gal group). In conclusion, the present study suggested that the ginsenoside Rg1 improved pathological damages in the ovary and uterus by increasing anti-oxidant and anti-inflammatory abilities whilst reducing the expression of senescence signaling pathways in POI mouse models.
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Affiliation(s)
- Lianli He
- Department of Gynecology and Obstetrics, The First People's Hospital of Zunyi and Third Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Xiaojuan Wang
- Department of Gynecology and Obstetrics, The First People's Hospital of Zunyi and Third Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Daigang Cheng
- Department of Gynecology and Obstetrics, The First People's Hospital of Zunyi and Third Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Zhengai Xiong
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, P.R. China
| | - Xiaoyun Liu
- Department of Gynecology and Obstetrics, The First People's Hospital of Zunyi and Third Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
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Coexpression Network Analysis of Genes Related to the Characteristics of Tumor Stemness in Triple-Negative Breast Cancer. BIOMED RESEARCH INTERNATIONAL 2020; 2020:7575862. [PMID: 32766313 PMCID: PMC7374213 DOI: 10.1155/2020/7575862] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 05/25/2020] [Accepted: 06/08/2020] [Indexed: 02/07/2023]
Abstract
Cancer stem cells (CSCs) are subsets of cells with the ability of self-renewal and differentiation in neoplasm, which are considered to be related to tumor heterogeneity. It has been reported that CSCs act on tumorigenesis and tumor biology of triple-negative breast cancer (TNBC). However, the key genes that cause TNBC showing stem cell characteristics are still unclear. We combined the RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA) database and mRNA expression-based stemness index (mRNAsi) to further analyze mRNAsi with regard to molecular subtypes, tumor depth, and pathological staging characteristics of breast cancer (BC). Secondly, we extract the differential gene expression of tumor vs. normal group and TNBC vs. other subtypes of BC group, respectively, and intersect them to achieve precise results. We used a weighted gene coexpression network analysis (WGCNA) to screen significant gene modules and the functions of selected genes including BIRC5, CDC25A, KIF18B, KIF2C, ORC1, RAD54L, and TPX2 were carried out through gene ontology (GO) functional annotation. The Oncomine, bc-GenExMiner v4.4, GeneMANIA, Kaplan-Meier Plotter (KM-plotter), and GEPIA were used to verify the expression level and functions of key genes. In this study, we found that TNBC had the highest stem cell characteristics in BC compared with other subtypes. The lower the mRNAsi score, the better the overall survival and treatment outcome. Seven key genes of TNBC were screened and functional annotation indicated that there were strong correlations between them, relating to nuclear division, organelle fission, mitotic nuclear division, and other events that determine cell fate. Among these genes, we found four genes that were highly associated with adverse survival events. Seven key genes identified in this study were found to be closely related to the maintenance of TNBC stemness, and the overexpression of four showed earlier recurrence. The overall survival (OS) curves of all key genes between differential expression level crossed at around nine-year follow-up, which was consistent with the trend of the OS curve related to mRNAsi. These findings may provide new ideas for screening therapeutic targets in order to depress TNBC stemness.
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Jiang N, Dai Q, Su X, Fu J, Feng X, Peng J. Role of PI3K/AKT pathway in cancer: the framework of malignant behavior. Mol Biol Rep 2020; 47:4587-4629. [PMID: 32333246 PMCID: PMC7295848 DOI: 10.1007/s11033-020-05435-1] [Citation(s) in RCA: 373] [Impact Index Per Article: 74.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 04/03/2020] [Indexed: 12/12/2022]
Abstract
Given that the PI3K/AKT pathway has manifested its compelling influence on multiple cellular process, we further review the roles of hyperactivation of PI3K/AKT pathway in various human cancers. We state the abnormalities of PI3K/AKT pathway in different cancers, which are closely related with tumorigenesis, proliferation, growth, apoptosis, invasion, metastasis, epithelial-mesenchymal transition, stem-like phenotype, immune microenvironment and drug resistance of cancer cells. In addition, we investigated the current clinical trials of inhibitors against PI3K/AKT pathway in cancers and found that the clinical efficacy of these inhibitors as monotherapy has so far been limited despite of the promising preclinical activity, which means combinations of targeted therapy may achieve better efficacies in cancers. In short, we hope to feature PI3K/AKT pathway in cancers to the clinic and bring the new promising to patients for targeted therapies.
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Affiliation(s)
- Ningni Jiang
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, 63 Duobao Road, Guangzhou, 510150 China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, 510150 China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, 510150 China
| | - Qijie Dai
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, 63 Duobao Road, Guangzhou, 510150 China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, 510150 China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, 510150 China
| | - Xiaorui Su
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, 63 Duobao Road, Guangzhou, 510150 China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, 510150 China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, 510150 China
| | - Jianjiang Fu
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, 63 Duobao Road, Guangzhou, 510150 China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, 510150 China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, 510150 China
| | - Xuancheng Feng
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, 63 Duobao Road, Guangzhou, 510150 China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, 510150 China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, 510150 China
| | - Juan Peng
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, 63 Duobao Road, Guangzhou, 510150 China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, 510150 China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, 510150 China
- Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
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35
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Fu T, Liang A, Liu Y. [Role of P21 in Resistance of Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2020; 23:597-602. [PMID: 32434295 PMCID: PMC7406443 DOI: 10.3779/j.issn.1009-3419.2020.101.16] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Lung cancer is the most common malignant tumor in the world with the highest incidence of deaths. In recent years, the treatment of lung cancer has made a significant breakthrough. However, as the tumor progresses, lung cancer cells inevitably acquire resistance and the efficacy of the treatment are greatly reduced. P21 protein plays a dual role in tumors, which not only regulates the cell cycle, induces apoptosis, inhibits cell proliferation, but also protects cells against apoptosis and promotes tumor cell resistance. This article reviews the research on P21 and lung cancer resistance, to provide new ideas for individualized treatment of lung cancer and overcoming lung cancer resistance.
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Affiliation(s)
- Tian Fu
- Medical Molecular Diagnostics Key Laboratory of Guangdong, Dongguan 523808, China.,Department of Biochemistry and Molecular Biology and Department of Clinical Biochemistry in Guangdong Medical University, Dongguan 523808, China
| | - Ailing Liang
- Medical Molecular Diagnostics Key Laboratory of Guangdong, Dongguan 523808, China.,Department of Clinical Laboratory Biochemistry of Guangdong Medical University, Dongguan 523808, China
| | - Yongjun Liu
- Medical Molecular Diagnostics Key Laboratory of Guangdong, Dongguan 523808, China.,Department of Biochemistry and Molecular Biology and Department of Clinical Biochemistry in Guangdong Medical University, Dongguan 523808, China
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36
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Ye Z, Zeng Z, Wang D, Lei S, Shen Y, Chen Z. Identification of key genes associated with the progression of intrahepatic cholangiocarcinoma using weighted gene co-expression network analysis. Oncol Lett 2020; 20:483-494. [PMID: 32565973 PMCID: PMC7286119 DOI: 10.3892/ol.2020.11600] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Accepted: 10/22/2019] [Indexed: 12/16/2022] Open
Abstract
The present study aimed to identify the key genes that are associated with the progression of intrahepatic cholangiocarcinoma through weighted gene co-expression network analysis (WGCNA). A total of three gene datasets were downloaded from the Gene Expression Omnibus database, including GSE107943, GSE119336 and GSE26566. Differentially expressed genes (DEGs) between intrahepatic cholangiocarcinoma tissues and adjacent liver tissues were identified using GSE107943, while tissue specific genes between bile duct and liver tissues were identified using GSE26566. Following the removal of tissue-specific genes, real DEGs were used to construct the WGCNA to investigate the association between gene modules and clinical traits. Following functional analysis, pathway enrichment analysis and the construction of a protein-protein interaction (PPI) network were performed, hub genes were selected and their diagnostic value was verified in GSE119336 using a receiver operating characteristic curve. Finally, the protein levels of the hub genes were also verified in intrahepatic cholangiocarcinoma tissues. A total of 1,643 real DEGs were identified and used to construct the WGCNA. Additionally, a total of seven co-expressed gene modules were identified following WGCNA, while genes in brown and yellow modules were identified to be associated with multiple clinical traits (the number of clinical traits >3) and used as key modules. A total of 63 core key module genes were subsequently identified, and it was indicated that these genes were most enriched in the nucleus (Gene Ontology term) and the cell cycle pathway (Kyoto Encyclopedia of Genes and Genomes term). Finally, a total of eight genes, including cyclin B1, cell division cycle 20, cell division cycle associated 8, cyclin dependent kinase 1, centrosomal protein 55, kinesin family member 2C, DNA topoisomerase IIα and TPX2 microtubule nucleation factor, exhibited the highest score in PPI analysis and had a high diagnostic value for intrahepatic cholangiocarcinoma. In addition, the protein levels of these genes were also revealed to be increased in most intrahepatic cholangiocarcinoma tissues. These eight genes may be used as novel biomarkers for the diagnosis of intrahepatic cholangiocarcinoma.
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Affiliation(s)
- Zi Ye
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.,Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Zhirui Zeng
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China.,Department of Physiology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China
| | - Da Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430060, P.R. China
| | - Shan Lei
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China.,Department of Physiology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China
| | - Yiyi Shen
- Department of Liver-Biliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China
| | - Zubing Chen
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.,Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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37
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Wang Y, Wang J, Yan K, Lin J, Zheng Z, Bi J. Identification of core genes associated with prostate cancer progression and outcome via bioinformatics analysis in multiple databases. PeerJ 2020; 8:e8786. [PMID: 32266115 PMCID: PMC7120053 DOI: 10.7717/peerj.8786] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 02/23/2020] [Indexed: 12/27/2022] Open
Abstract
Abstract The morbidity and mortality of prostate carcinoma has increased in recent years and has become the second most common ale malignant carcinoma worldwide. The interaction mechanisms between different genes and signaling pathways, however, are still unclear. Methods Variation analysis of GSE38241, GSE69223, GSE46602 and GSE104749 were realized by GEO2R in Gene Expression Omnibus database. Function enrichment was analyzed by DAVID.6.8. Furthermore, the PPI network and the significant module were analyzed by Cytoscape, STRING and MCODE.GO. Pathway analysis showed that the 20 candidate genes were closely related to mitosis, cell division, cell cycle phases and the p53 signaling pathway. A total of six independent prognostic factors were identified in GSE21032 and TCGA PRAD. Oncomine database and The Human Protein Atlas were applied to explicit that six core genes were over expression in prostate cancer compared to normal prostate tissue in the process of transcriptional and translational. Finally, gene set enrichment were performed to identified the related pathway of core genes involved in prostate cancer. Result Hierarchical clustering analysis revealed that these 20 core genes were mostly related to carcinogenesis and development. CKS2, TK1, MKI67, TOP2A, CCNB1 and RRM2 directly related to the recurrence and prognosis of prostate cancer. This result was verified by TCGA database and GSE21032. Conclusion These core genes play a crucial role in tumor carcinogenesis, development, recurrence, metastasis and progression. Identifying these genes could help us to understand the molecular mechanisms and provide potential biomarkers for the diagnosis and treatment of prostate cancer.
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Affiliation(s)
- Yutao Wang
- Department of Urology, The First Hospital of China Medical University, Shenyang, China
| | - Jianfeng Wang
- Department of Urology, The First Hospital of China Medical University, Shenyang, China
| | - Kexin Yan
- Department of Dermatology, The First Hospital of China Medical University, Shenyang, China
| | - Jiaxing Lin
- Department of Urology, The First Hospital of China Medical University, Shenyang, China
| | - Zhenhua Zheng
- Department of Urology, The First Hospital of China Medical University, Shenyang, China
| | - Jianbin Bi
- Department of Urology, The First Hospital of China Medical University, Shenyang, China
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Ohshima K, Fujiya K, Nagashima T, Ohnami S, Hatakeyama K, Urakami K, Naruoka A, Watanabe Y, Moromizato S, Shimoda Y, Ohnami S, Serizawa M, Akiyama Y, Kusuhara M, Mochizuki T, Sugino T, Shiomi A, Tsubosa Y, Uesaka K, Terashima M, Yamaguchi K. Driver gene alterations and activated signaling pathways toward malignant progression of gastrointestinal stromal tumors. Cancer Sci 2019; 110:3821-3833. [PMID: 31553483 PMCID: PMC6890443 DOI: 10.1111/cas.14202] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 09/17/2019] [Accepted: 09/22/2019] [Indexed: 12/28/2022] Open
Abstract
Mutually exclusive KIT and PDGFRA mutations are considered to be the earliest events in gastrointestinal stromal tumors (GIST), but insufficient for their malignant progression. Herein, we aimed to identify driver genes and signaling pathways relevant to GIST progression. We investigated genetic profiles of 707 driver genes, including mutations, gene fusions, copy number gain or loss, and gene expression for 65 clinical specimens of surgically dissected GIST, consisting of six metastatic tumors and 59 primary tumors from stomach, small intestine, rectum, and esophagus. Genetic alterations included oncogenic mutations and amplification‐dependent expression enhancement for oncogenes (OG), and loss of heterozygosity (LOH) and expression reduction for tumor suppressor genes (TSG). We assigned activated OG and inactivated TSG to 27 signaling pathways, the activation of which was compared between malignant GIST (metastasis and high‐risk GIST) and less malignant GIST (low‐ and very low‐risk GIST). Integrative molecular profiling indicated that a greater incidence of genetic alterations of driver genes was detected in malignant GIST (96%, 22 of 23) than in less malignant GIST (73%, 24 of 33). Malignant GIST samples groups showed mutations, LOH, and aberrant expression dominantly in driver genes associated with signaling pathways of PI3K (PIK3CA, AKT1, and PTEN) and the cell cycle (RB1, CDK4, and CDKN1B). Additionally, we identified potential PI3K‐related genes, the expression of which was upregulated (SNAI1 and TPX2) or downregulated (BANK1) in malignant GIST. Based on our observations, we propose that inhibition of PI3K pathway signals might potentially be an effective therapeutic strategy against malignant progression of GIST.
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Affiliation(s)
- Keiichi Ohshima
- Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.,Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Keiichi Fujiya
- Division of Gastric Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Takeshi Nagashima
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.,SRL, Inc., Tokyo, Japan
| | - Sumiko Ohnami
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Keiichi Hatakeyama
- Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Kenichi Urakami
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.,Region Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Akane Naruoka
- Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Yuko Watanabe
- Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Sachi Moromizato
- Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Yuji Shimoda
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.,SRL, Inc., Tokyo, Japan
| | - Shumpei Ohnami
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Masakuni Serizawa
- Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Yasuto Akiyama
- Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Masatoshi Kusuhara
- Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.,Region Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Tohru Mochizuki
- Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Takashi Sugino
- Division of Pathology, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Akio Shiomi
- Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Yasuhiro Tsubosa
- Division of Esophageal Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Katsuhiko Uesaka
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Masanori Terashima
- Division of Gastric Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Ken Yamaguchi
- Shizuoka Cancer Center Hospital and Research Institute, Shizuoka, Japan
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Huang DH, Jian J, Li S, Zhang Y, Liu LZ. TPX2 silencing exerts anti‑tumor effects on hepatocellular carcinoma by regulating the PI3K/AKT signaling pathway. Int J Mol Med 2019; 44:2113-2122. [PMID: 31638175 PMCID: PMC6844623 DOI: 10.3892/ijmm.2019.4371] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 09/11/2019] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the primary causes of cancer-associated deaths worldwide. Current treatment methods include surgical resection, chemotherapy and radiotherapy; however the curative rate remains low, thus novel treatments are required. The aim of the present study was to investigate the role of targeting protein for Xenopus kinesin-like protein 2 (TPX2) in the growth of HCC and its underlying molecular mechanism. Immunohistochemistry staining, reverse transcription-quantitative (RT-q)PCR and western blotting were used to detect the expression of TPX2 mRNA and protein in liver cancer tissue samples, adjacent normal liver tissue samples, and the HCC cell lines Huh7, Hep3B, PLC/PRF/5 and MHCC97-H. The recombinant plasmid pMagic4.1-shRNA-TPX2 was constructed and transfected into Huh7 and Hep3B HCC cells to silence TPX2 expression. The proliferation, apoptosis, migration and invasion of Huh7 cells and Hep3B cells were evaluated before and after TPX2 silencing. The mRNA and protein expression levels of multiple signaling pathway-associated genes were detected by RT-qPCR and western blotting. The expression levels of TPX2 mRNA and protein were significantly higher in HCC tissue samples compared with adjacent normal liver tissue sample. TPX2 mRNA and protein expression levels were detected in the different HCC cell lines. The recombinant plasmid pMagic4.1-shRNA-TPX2 was successfully transfected into Huh7 and Hep3B cells, resulting in TPX2 silencing. TPX2 knockdown significantly reduced cell proliferation, cell migration and cell invasion of Huh7 and Hep3B cells, whilst also increasing the rate of apoptosis in these cells. Following TPX2 silencing, the expression levels of PI3K, phospho-AKT, Bcl-2, c-Myc and Cyclin D1 were significantly decreased, whereas the expression levels of P21 and P27 were significantly increased. In conclusion, TPX2 may suppress the growth of HCC by regulating the PI3K/AKT signaling pathway and thus, TPX2 may be a potential target for the treatment of liver cancer.
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Affiliation(s)
- Dan-Hong Huang
- Department of Clinical Laboratory, Jiading District Central Hospital of Shanghai University of Medicine and Health Sciences, Shanghai 201800, P.R. China
| | - Jie Jian
- Department of Gastroenterology, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Shuang Li
- Department of Gastroenterology, Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Yan Zhang
- Department of Oncology, Jiading District Central Hospital of Shanghai University of Medicine and Health Sciences, Shanghai 201800, P.R. China
| | - Li-Zhen Liu
- Department of Oncology, Jiading District Central Hospital of Shanghai University of Medicine and Health Sciences, Shanghai 201800, P.R. China
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40
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He R, Zuo S. A Robust 8-Gene Prognostic Signature for Early-Stage Non-small Cell Lung Cancer. Front Oncol 2019; 9:693. [PMID: 31417870 PMCID: PMC6684755 DOI: 10.3389/fonc.2019.00693] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 07/12/2019] [Indexed: 12/24/2022] Open
Abstract
Background: The current staging system is imprecise for prognostic prediction of early-stage non-small cell lung cancer (NSCLC). This study aimed to develop a robust prognostic signature for early-stage NSCLC, allowing classification of patients with a high risk of poor outcome and specific treatment decision. Method: In the present study, a comprehensive genome-wide profiling analysis was conducted using a retrospective pool of early-stage NSCLC patient data from the previous datasets of Gene Expression Omnibus (GEO) including GSE31210, GSE37745, and GSE50081 and The Cancer Genome Atlas (TCGA). Cox proportional hazards models were implemented to determine the association between gene expression levels and overall patient survival in each dataset. The common genes among all datasets were selected as candidate prognostic genes. A risk score model was developed and validated using four independent datasets and the entire cohort. The Kaplan-Meier with log-rank test was used to assess survival difference. Results: A univariate Cox proportional hazards regression analysis for each dataset showed that a total of 2280 genes in GSE31210, 762 genes in GSE37745, 871 genes in GSE50081, and 666 genes in TCGA were identified as candidate protective genes, while overall 2131 genes in GSE31210, 913 in GSE37745, 1107 in GSE50081, and 997 in TCGA were identified as candidate risky genes. There were 8 common genes associated with overall survival, including 7 mRNA and 1 lncRNA. By using the Step-wise multivariate Cox analysis, an 8-gene prognostic signature (CDCP1, HMMR, TPX2, CIRBP, HLF, KBTBD7, SEC24B-AS1, and SH2B1) for early-stage NSCLC was developed. Patients in the high-risk group had shorter overall survival than those in the low-risk group. Multivariate regression and stratified analysis suggested that the prognostic power of the 8-gene signature was independent of other clinical factors. Furthermore, the 8-gene signature achieved AUC values of 0.726, 0.701, 0.725 and 0.650 in GSE31210, GSE37745, GSE50081 and TCGA, respectively. Moreover, the combination of the 8-gene signature and the stage resulted to a better patient classification for survival prediction and treatment decision. Conclusion: This study developed a robust gene signature with great value for prognostic prediction in early-stage NSCLC, which may contribute to patient classification and personalized treatment decisions.
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Affiliation(s)
- Ru He
- Center for Translational Medicine, Huaihe Hospital of Henan University, Kaifeng, China
| | - Shuguang Zuo
- Center for Translational Medicine, Huaihe Hospital of Henan University, Kaifeng, China.,Institute of Infection and Immunity, Huaihe Hospital of Henan University, Kaifeng, China
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Cai Y, Mei J, Xiao Z, Xu B, Jiang X, Zhang Y, Zhu Y. Identification of five hub genes as monitoring biomarkers for breast cancer metastasis in silico. Hereditas 2019; 156:20. [PMID: 31285741 PMCID: PMC6588910 DOI: 10.1186/s41065-019-0096-6] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Accepted: 06/12/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Breast cancer is one of the most common endocrine cancers among females worldwide. Distant metastasis of breast cancer is causing an increasing number of breast cancer-related deaths. However, the potential mechanisms of metastasis and candidate biomarkers remain to be further explored. RESULTS The gene expression profiles of GSE102484 were downloaded from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was used to screen for the most potent gene modules associated with the metastatic risk of breast cancer, and a total of 12 modules were identified based on the analysis. In the most significant module (R2 = 0.68), 21 network hub genes (MM > 0.90) were retained for further analyses. Next, protein-protein interaction (PPI) networks were used to further explore the biomarkers with the most interactions in gene modules. According to the PPI networks, five hub genes (TPX2, KIF2C, CDCA8, BUB1B, and CCNA2) were identified as key genes associated with breast cancer progression. Furthermore, the prognostic value and differential expression of these genes were validated based on data from The Cancer Genome Atlas (TCGA) and Kaplan-Meier (KM) Plotter. Receiver operating characteristic (ROC) curve analysis revealed that the mRNA expression levels of these five hub genes showed excellent diagnostic value for breast cancer and adjacent tissues. Moreover, these five hub genes were significantly associated with worse distant metastasis-free survival (DMFS) in the patient cohort based on KM Plotter. CONCLUSION Five hub genes (TPX2, KIF2C, CDCA8, BUB1B, and CCNA2) associated with the risk of distant metastasis were extracted for further research, which might be used as biomarkers to predict distant metastasis of breast cancer.
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Affiliation(s)
- Yun Cai
- Department of Physiology, Nanjing Medical University, Nanjing, 211166 China
- Department of Bioinformatics, Nanjing Medical University, Nanjing, 211166 China
| | - Jie Mei
- Department of Physiology, Nanjing Medical University, Nanjing, 211166 China
| | - Zhuang Xiao
- Department of Physiology, Nanjing Medical University, Nanjing, 211166 China
| | - Bujie Xu
- Department of Physiology, Nanjing Medical University, Nanjing, 211166 China
| | - Xiaozheng Jiang
- Department of Physiology, Nanjing Medical University, Nanjing, 211166 China
| | - Yongjie Zhang
- Department of Human Anatomy, Nanjing Medical University, Nanjing, 211166 China
- Key Laboratory for Aging & Diseases of Nanjing Medical University, Nanjing Medical University, Nanjing, 211166 China
| | - Yichao Zhu
- Department of Physiology, Nanjing Medical University, Nanjing, 211166 China
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166 China
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