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Koch MS, Deo M, Schmitt LM, Hoetker MS, Turcan Ş. GSK3 acts as a switch for transcriptional programs in a model of low-grade gliomagenesis. Acta Neuropathol Commun 2025; 13:87. [PMID: 40307935 PMCID: PMC12042597 DOI: 10.1186/s40478-025-02006-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Accepted: 04/13/2025] [Indexed: 05/02/2025] Open
Abstract
Mutations in isocitrate dehydrogenase (IDH)1/2 are defining drivers of low-grade gliomagenesis. However, mutant IDH alone is not sufficient for malignant transformation, and additional events are required for the development of low-grade glioma. While specific genetic lesions have been identified to contribute to low-grade gliomagenesis, less is known about the signaling pathways involved in the acquisition of malignancy. To identify prerequisites of IDH mutant tumorigenesis, we modulated pathways previously implicated in glioma initiation using a tractable in vitro model system for early IDH1R132H-dependent gliomagenesis. Through the use of chemical compounds, we targeted WNT/GSK3, TGF-β and NOTCH-signaling, assessing their functional, transcriptional, and translational impacts. Expression of LGG-related marker L1CAM was affected by perturbation of all pathways, though only modulation of WNT/GSK3-signaling resulted in profound molecular transformation, including glioma-associated genes and programs regulating cellular architecture and cell replication. This was accompanied by altered cell morphology, migration capacity, and enhanced proliferation. Transcription factor RUNX2 was identified as a potential downstream effector, whose inhibition abrogated cell proliferation. Disrupted WNT/GSK3 signaling in a model system of early low-grade gliomagenesis fundamentally impacted cell fate, as demonstrated by a reshaped transcriptional landscape, aberrant transcription factor activity, extracellular matrix restructuring, and altered proliferation capacity. Our data suggests that GSK3 may play a central role during low-grade gliomagenesis, warranting further investigation.
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Affiliation(s)
- Marilin S Koch
- Clinical Cooperation Unit Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Neurology and Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany
| | - Minh Deo
- Clinical Cooperation Unit Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Neurology and Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany
| | - Lena-Marie Schmitt
- Clinical Cooperation Unit Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Neurology and Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany
| | - Michael S Hoetker
- Department of Internal Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Şevin Turcan
- Clinical Cooperation Unit Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Department of Neurology and Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
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Chen J, Ji Z, Wu D, Wei S, Zhu W, Peng G, Hu M, Zhao Y, Wu H. MYBL2 promotes cell proliferation and inhibits cell apoptosis via PI3K/AKT and BCL2/BAX/Cleaved-caspase-3 signaling pathway in gastric cancer cells. Sci Rep 2025; 15:9148. [PMID: 40097530 PMCID: PMC11914465 DOI: 10.1038/s41598-025-93022-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 03/04/2025] [Indexed: 03/19/2025] Open
Abstract
The transcription factor MYB proto-oncogene like 2 (MYBL2) has been reported to be involved in the occurrence and development of various tumors, however, its role in gastric cancer (GC) remains to be elucidated. In this study, the Kaplan-Meier plotter was used to evaluate the prognostic value of different MYBL2 expression levels in GC patients. The UALCAN database were applied to analyze the relationships between MYBL2 and clinicopathological characteristics of GC. GC cell proliferation, cell cycle and apoptosis were determined by CCK-8 and flow cytometry assays, and proteins were examined by Western blot analysis. Next, signaling pathway enrichment analysis of MYBL2-related genes and protein expression were analyzed by Gene Set Enrichment Analysis (GSEA) and Western blot assays. The results found that MYBL2 expression was significantly upregulated in GC compared with adjacent non-malignant tissues and associated with poor patient survival, tumor, stages and lymph node metastasis. Forced expression of MYBL2 could promote cell proliferation, resulting in an accelerated S phase progression and inhibiting cell apoptosis in GC cells. Conversely, MYBL2 silencing inhibited cell proliferation, induced G2/M phase arrest and promoted cell apoptosis in GC cells. Mechanistically, Western blot analysis showed that MYBL2 silencing decreased the expression of BCL2 and upregulated the expression of Cleaved-caspase-3 and BAX in HGC-27 cells. Conversely, MYBL2 overexpression in AGS cells resulted in the opposite effects. Furthermore, enforced expression of MYBL2 activated the PI3K/AKT signaling pathway, especially AKT phosphorylation. Additionally, the AKT inhibitor MK2206 significantly reversed the proliferation capacity of GC cells induced by MYBL2 overexpression. Therefore, these results suggest that upregulated expression of MYBL2 contributes to GC cell growth and inhibits cell apoptosis by regulating the PI3K/AKT and BCL2/BAX/Cleaved-caspase-3 signaling pathways in GC cells indicating that MYBL2 may be a new therapeutic target and prognostic marker for GC.
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Affiliation(s)
- Jingya Chen
- School of Public Health, Bengbu Medical University, Bengbu, China
| | - Zhenglei Ji
- School of Public Health, Bengbu Medical University, Bengbu, China
| | - Di Wu
- School of Life Science, Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu Medical University, Bengbu, China
| | - Siyang Wei
- School of Public Health, Bengbu Medical University, Bengbu, China
| | - Wanjing Zhu
- School of Life Science, Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu Medical University, Bengbu, China
| | - Guisen Peng
- School of Life Science, Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu Medical University, Bengbu, China
| | - Mingjie Hu
- School of Life Science, Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu Medical University, Bengbu, China.
| | - Yunli Zhao
- School of Public Health, Bengbu Medical University, Bengbu, China.
| | - Huazhang Wu
- School of Life Science, Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu Medical University, Bengbu, China.
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Yan Z, Liu Y, Yuan Y. The plasticity of epithelial cells and its potential in the induced differentiation of gastric cancer. Cell Death Discov 2024; 10:512. [PMID: 39719478 DOI: 10.1038/s41420-024-02275-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 12/05/2024] [Accepted: 12/13/2024] [Indexed: 12/26/2024] Open
Abstract
Cell plasticity refers to the deviation of cells from normal terminal differentiation states when faced with environmental and genetic toxic stresses, resulting in the phenomenon of transforming into other cell or tissue phenotypes. Unlocking phenotype plasticity has been defined as a hallmark of malignant tumors. The stomach is one of the organs in the body with the highest degree of self-renewal and exhibits significant cell plasticity. In this paper, based on the review of the characteristics of normal differentiation of gastric epithelial cells and their markers, the four main phenotypes of gastric epithelial cell remodeling and their relationship with gastric cancer (GC) are drawn. Furthermore, we summarize the regulatory factors and mechanisms that affect gastric epithelial cell plasticity and outline the current status of research and future prospection for the treatment targeting gastric epithelial cell plasticity. This study has important theoretical reference value for the in-depth exploration of epithelial cell plasticity and the tumor heterogeneity caused by it, as well as for the precise treatment of GC.
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Affiliation(s)
- Ziwei Yan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Yingnan Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China.
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4
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Liu Y, Chen J, Li A, Wu Y, Ge J, Yuan M, Xu B, Zheng X, Chen L, Jiang J. Novel biomarkers: the RUNX family as prognostic predictors in colorectal cancer. Front Immunol 2024; 15:1430136. [PMID: 39822248 PMCID: PMC11736411 DOI: 10.3389/fimmu.2024.1430136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 11/21/2024] [Indexed: 01/30/2025] Open
Abstract
While biomarkers have been shown to enhance the prognosis of patients with colorectal cancer (CRC) compared to conventional treatments, there is a pressing need to discover novel biomarkers that can assist in assessing the prognostic impact of immunotherapy and in formulating individualized treatment plans. The RUNX family, consisting of RUNX1, RUNX2, and RUNX3, has been recognized as crucial regulators in developmental processes, with dysregulation of these genes also being implicated in tumorigenesis and cancer progression. In our present study, we demonstrated a crucial regulatory role of RUNX in CD8+T and CD103+CD8+T cell-mediated anti-tumor response within the tumor microenvironment (TME) of human CRC. Specifically, RUNXs were significantly differentially expressed between tumor and normal tissues in CRC. Patients with a greater proportion of infiltrating CD8+RUNX1+, CD103+CD8+RUNX1+, CD8+RUNX2+, CD103+CD8+RUNX2+, CD8+RUNX3+, or CD103+CD8+RUNX3+ T cells demonstrated improved outcomes compared to those with lower proportions. Additionally, the proportions of infiltrating CD8+RUNX1+T and CD8+RUNX3+T cells may serve as valuable prognostic predictors for CRC patients, independent of other clinicopathological factors. Moreover, further bioinformatic analysis conducted utilizing the TISIDB and TIMER platforms demonstrated significant associations between the members of the RUNX family and immune-infiltrating cells, specifically diverse subpopulations of CD8+TILs. Our study of human colorectal cancer tissue microarray (TMA) also revealed positive and statistically significant correlations between the expressions of RUNX1, RUNX2, and RUNX3 in both CD8+T cells and CD103+CD8+T cells. Our study comprehensively revealed the varied expressions and prognostic importance of the RUNX family in human colorectal cancer tissues. It underscored their potential as vital biomarkers for prognostic evaluation in colorectal cancer patients and as promising targets for immunotherapy in treating this disease.
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Affiliation(s)
- Yingting Liu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, China
- Institute of Cell Therapy, Soochow University, Changzhou, Jiangsu, China
| | - Junjun Chen
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, China
- Institute of Cell Therapy, Soochow University, Changzhou, Jiangsu, China
| | - An Li
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, China
- Institute of Cell Therapy, Soochow University, Changzhou, Jiangsu, China
| | - Yue Wu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, China
- Institute of Cell Therapy, Soochow University, Changzhou, Jiangsu, China
| | - Junwei Ge
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, China
- Institute of Cell Therapy, Soochow University, Changzhou, Jiangsu, China
| | - Maoling Yuan
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, China
- Institute of Cell Therapy, Soochow University, Changzhou, Jiangsu, China
| | - Bin Xu
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, China
- Institute of Cell Therapy, Soochow University, Changzhou, Jiangsu, China
| | - Xiao Zheng
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, China
- Institute of Cell Therapy, Soochow University, Changzhou, Jiangsu, China
| | - Lujun Chen
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, China
- Institute of Cell Therapy, Soochow University, Changzhou, Jiangsu, China
| | - Jingting Jiang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, China
- Institute of Cell Therapy, Soochow University, Changzhou, Jiangsu, China
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Torres M, Kirchner M, Marks CG, Mertins P, Kramer A. Proteomic insights into circadian transcription regulation: novel E-box interactors revealed by proximity labeling. Genes Dev 2024; 38:1020-1032. [PMID: 39562139 PMCID: PMC11610934 DOI: 10.1101/gad.351836.124] [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: 04/18/2024] [Accepted: 10/23/2024] [Indexed: 11/21/2024]
Abstract
Circadian clocks (∼24 h) are responsible for daily physiological, metabolic, and behavioral changes. Central to these oscillations is the regulation of gene transcription. Previous research has identified clock protein complexes that interact with the transcriptional machinery to orchestrate circadian transcription, but technological constraints have limited the identification of de novo proteins. Here we use a novel genomic locus-specific quantitative proteomics approach to provide a new perspective on time of day-dependent protein binding at a critical chromatin locus involved in circadian transcription: the E-box. Using proximity labeling proteomics at the E-box of the clock-controlled Dbp gene in mouse fibroblasts, we identified 69 proteins at this locus at the time of BMAL1 binding. This method successfully enriched BMAL1 as well as HDAC3 and HISTONE H2A.V/Z, known circadian regulators. New E-box proteins include the MINK1 kinase and the transporters XPO7 and APPL1, whose depletion in human U-2 OS cells results in disrupted circadian rhythms, suggesting a role in the circadian transcriptional machinery. Overall, our approach uncovers novel circadian modulators and provides a new strategy to obtain a complete temporal picture of circadian transcriptional regulation.
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Affiliation(s)
- Manon Torres
- Laboratory of Chronobiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
| | - Marieluise Kirchner
- Core Unit Proteomics, Berlin Institute of Health at Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
| | - Caroline G Marks
- Laboratory of Chronobiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
| | - Philipp Mertins
- Core Unit Proteomics, Berlin Institute of Health at Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
| | - Achim Kramer
- Laboratory of Chronobiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany;
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Ou YC, Yu TM, Li JR, Wu CC, Wang JD, Liao SL, Chen WY, Kuan YH, Chen CJ. Runx2 silencing sensitized human renal cell carcinoma cells to ABT-737 apoptosis. Arch Biochem Biophys 2024; 761:110173. [PMID: 39369835 DOI: 10.1016/j.abb.2024.110173] [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: 06/26/2024] [Revised: 09/17/2024] [Accepted: 10/03/2024] [Indexed: 10/08/2024]
Abstract
The prognostic value of Runt-related transcription factor 2 (Runx2) and its involvement in cell growth and motility have been reported in patients diagnosed with renal cell carcinoma (RCC). Since Runx2 may have the potential to be a target for the purpose of antitumor intervention, there is an urgent need to gain insight into its oncogenic properties. Using human 786-O, Caki-1 and ACHN RCC cells as models, the silencing of cellular Runx2 expression brought about a reduction in cyclin D1 and β-catenin expression, cell growth and migration without any significant cell death. Runx2-silenced cells turned into apoptosis vulnerable in the presence of ABT-737, a BH3 mimetic Bcl-2 inhibitor. Data from biochemical and molecular studies have revealed a positive correlation between Runx2 expression and Akt phosphorylation, Mcl-1 expression, and fibronectin expression. Results of genetic silencing studies have indicated the potential involvement of Mcl-1 and fibronectin in the decision of RCC cell ABT-737 resistance and sensitivity. The regulatory roles of the PI3K/Akt axis in the expression of Mcl-1 and fibronectin were suggested by means of the results taken from experiments involving pharmacological study of the PI3K/Akt. Since overexpression and prognostic roles of Runx2, activated Akt, Mcl-1, fibronectin, cyclin D1, and β-catenin have been revealed in RCC, it is important to explore the precise mechanisms underlying Runx2 oncogenic effects. Although the linking details between Runx2 and PI3K/Akt have yet to be identified, our findings suggest that Mcl-1 and fibronectin are downstream effectors of Runx2 via a regulatory axis of the PI3K/Akt and their promotion of cell growth, migration, and ABT-737 resistance in RCC cells.
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Affiliation(s)
- Yen-Chuan Ou
- Department of Urology, Tungs' Taichung MetroHarbor Hospital, Taichung City, 433, Taiwan.
| | - Tung-Min Yu
- Division of Nephrology, Taichung Veterans General Hospital, Taichung City, 407, Taiwan.
| | - Jian-Ri Li
- Division of Urology, Taichung Veterans General Hospital, Taichung City, 407, Taiwan.
| | - Chih-Cheng Wu
- Department of Anesthesiology, Taichung Veterans General Hospital, Taichung City, 407, Taiwan; Department of Financial Engineering, Providence University, Taichung City, 433, Taiwan; Department of Data Science and Big Data Analytics, Providence University, Taichung City, 433, Taiwan.
| | - Jiaan-Der Wang
- Children's Medical Center, Taichung Veterans General Hospital, Taichung City, 407, Taiwan.
| | - Su-Lan Liao
- Department of Medical Research, Taichung Veterans General Hospital, Taichung City, 407, Taiwan.
| | - Wen-Ying Chen
- Department of Veterinary Medicine, National Chung Hsing University, Taichung City, 402, Taiwan.
| | - Yu-Hsiang Kuan
- Department of Pharmacology, Chung Shan Medical University, Taichung City, 402, Taiwan.
| | - Chun-Jung Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung City, 407, Taiwan; Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung City, 404, Taiwan.
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Fu J, Liu W, Liu S, Zhao R, Hayashi T, Zhao H, Xiang Y, Mizuno K, Hattori S, Fujisaki H, Ikejima T. Inhibition of YAP/TAZ pathway contributes to the cytotoxicity of silibinin in MCF-7 and MDA-MB-231 human breast cancer cells. Cell Signal 2024; 119:111186. [PMID: 38643945 DOI: 10.1016/j.cellsig.2024.111186] [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: 01/29/2024] [Revised: 04/14/2024] [Accepted: 04/18/2024] [Indexed: 04/23/2024]
Abstract
Breast cancer is one of the most common cancers threatening women's health. Our previous study found that silibinin induced the death of MCF-7 and MDA-MB-231 human breast cancer cells. We noticed that silibinin-induced cell damage was accompanied by morphological changes, including the increased cell aspect ratio (cell length/width) and decreased cell area. Besides, the cytoskeleton is also destroyed in cells treated with silibinin. YAP/TAZ, a mechanical signal sensor interacted with extracellular pressure, cell adhesion area and cytoskeleton, is also closely associated with cell survival, proliferation and migration. Thus, the involvement of YAP/TAZ in the cytotoxicity of silibinin in breast cancer cells has attracted our interests. Excitingly, we find that silibinin inhibits the nuclear translocation of YAP/TAZ in MCF-7 and MDA-MB-231 cells, and reduces the mRNA expressions of YAP/TAZ target genes, ACVR1, MnSOD and ANKRD. More importantly, expression of YAP1 gene is negatively correlated with the survival of the patients with breast cancers. Molecular docking analysis reveals high probabilities for binding of silibinin to the proteins in the YAP pathways. DARTS and CETSA results confirm the binding abilities of silibinin to YAP and LATS. Inhibiting YAP pathway either by addition of verteporfin, an inhibitor of YAP/TAZ-TEAD, or by transfection of si-RNAs targeting YAP or TAZ further enhances silibinin-induced cell damage. While enhancing YAP activity by silencing LATS1/2 or overexpressing YAPS127/397A, an active form of YAP, attenuates silibinin-induced cell damage. These findings demonstrate that inhibition of the YAP/TAZ pathway contributes to cytotoxicity of silibinin in breast cancers, shedding lights on YAP/TAZ-targeted cancer therapies.
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Affiliation(s)
- Jianing Fu
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Weiwei Liu
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Siyu Liu
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Ruxiao Zhao
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Toshihiko Hayashi
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China; Nippi Research Institute of Biomatrix, Toride, Ibaraki 302-0017, Japan
| | - Haina Zhao
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Yinlanqi Xiang
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Kazunori Mizuno
- Nippi Research Institute of Biomatrix, Toride, Ibaraki 302-0017, Japan
| | - Shunji Hattori
- Nippi Research Institute of Biomatrix, Toride, Ibaraki 302-0017, Japan
| | - Hitomi Fujisaki
- Nippi Research Institute of Biomatrix, Toride, Ibaraki 302-0017, Japan
| | - Takashi Ikejima
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China; Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning, China.
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Niu C, Ren D, Liu BL. Editorial: Novel therapeutic targets of gastric carcinogenesis: from basic research to drug development and clinical application. Front Oncol 2024; 14:1431520. [PMID: 38854722 PMCID: PMC11159047 DOI: 10.3389/fonc.2024.1431520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Accepted: 05/15/2024] [Indexed: 06/11/2024] Open
Affiliation(s)
- Chenchen Niu
- Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, United States
| | - Dong Ren
- Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, United States
| | - Bella Lingjia Liu
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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Zhou JW, Zhang YB, Huang ZY, Yuan YP, Jin J. Identification of differentially expressed mRNAs as novel predictive biomarkers for gastric cancer diagnosis and prognosis. World J Gastrointest Oncol 2024; 16:1947-1964. [PMID: 38764850 PMCID: PMC11099425 DOI: 10.4251/wjgo.v16.i5.1947] [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: 12/13/2023] [Revised: 01/04/2024] [Accepted: 03/14/2024] [Indexed: 05/09/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) has a high mortality rate worldwide. Despite significant progress in GC diagnosis and treatment, the prognosis for affected patients still remains unfavorable. AIM To identify important candidate genes related to the development of GC and identify potential pathogenic mechanisms through comprehensive bioinformatics analysis. METHODS The Gene Expression Omnibus database was used to obtain the GSE183136 dataset, which includes a total of 135 GC samples. The limma package in R software was employed to identify differentially expressed genes (DEGs). Thereafter, enrichment analyses of Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed for the gene modules using the clusterProfile package in R software. The protein-protein interaction (PPI) networks of target genes were constructed using STRING and visualized by Cytoscape software. The common hub genes that emerged in the cohort of DEGs that was retrieved from the GEPIA database were then screened using a Venn Diagram. The expression levels of these overlapping genes in stomach adenocarcinoma samples and non-tumor samples and their association with prognosis in GC patients were also obtained from the GEPIA database and Kaplan-Meier curves. Moreover, real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting were performed to determine the mRNA and protein levels of glutamic-pyruvic transaminase (GPT) in GC and normal immortalized cell lines. In addition, cell viability, cell cycle distribution, migration and invasion were evaluated by cell counting kit-8, flow cytometry and transwell assays. Furthermore, we also conducted a retrospective analysis on 70 GC patients diagnosed and surgically treated in Wenzhou Central Hospital, Dingli Clinical College of Wenzhou Medical University, The Second Affiliated Hospital of Shanghai University between January 2017 to December 2020. The tumor and adjacent normal samples were collected from the patients to determine the potential association between the expression level of GPT and the clinical as well as pathological features of GC patients. RESULTS We selected 19214 genes from the GSE183136 dataset, among which there were 250 downregulated genes and 401 upregulated genes in the tumor samples of stage III-IV in comparison to those in tumor samples of stage I-II with a P-value < 0.05. In addition, GO and KEGG results revealed that the various upregulated DEGs were mainly enriched in plasma membrane and neuroactive ligand-receptor interaction, whereas the downregulated DEGs were primarily enriched in cytosol and pancreatic secretion, vascular smooth muscle contraction and biosynthesis of the different cofactors. Furthermore, PPI networks were constructed based on the various upregulated and downregulated genes, and there were a total 15 upregulated and 10 downregulated hub genes. After a comprehensive analysis, several hub genes, including runt-related transcription factor 2 (RUNX2), salmonella pathogenicity island 1 (SPI1), lysyl oxidase (LOX), fibrillin 1 (FBN1) and GPT, displayed prognostic values. Interestingly, it was observed that GPT was downregulated in GC cells and its upregulation could suppress the malignant phenotypes of GC cells. Furthermore, the expression level of GPT was found to be associated with age, lymph node metastasis, pathological staging and distant metastasis (P < 0.05). CONCLUSION RUNX2, SPI1, LOX, FBN1 and GPT were identified key hub genes in GC by bioinformatics analysis. GPT was significantly associated with the prognosis of GC, and its upregulation can effectively inhibit the proliferative, migrative and invasive capabilities of GC cells.
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Affiliation(s)
- Jian-Wei Zhou
- Department of Gastroenterology, Wenzhou Central Hospital, Dingli Clinical College of Wenzhou Medical University, The Second Affiliated Hospital of Shanghai University, Wenzhou 325000, Zhejiang Province, China
| | - Yi-Bing Zhang
- Department of Gastroenterology, Wenzhou Central Hospital, Dingli Clinical College of Wenzhou Medical University, The Second Affiliated Hospital of Shanghai University, Wenzhou 325000, Zhejiang Province, China
| | - Zhi-Yang Huang
- Department of Gastroenterology, Wenzhou Central Hospital, Dingli Clinical College of Wenzhou Medical University, The Second Affiliated Hospital of Shanghai University, Wenzhou 325000, Zhejiang Province, China
| | - Yu-Ping Yuan
- Department of Gastroenterology, Wenzhou Central Hospital, Dingli Clinical College of Wenzhou Medical University, The Second Affiliated Hospital of Shanghai University, Wenzhou 325000, Zhejiang Province, China
| | - Jie Jin
- Department of Gastroenterology, Wenzhou Central Hospital, Dingli Clinical College of Wenzhou Medical University, The Second Affiliated Hospital of Shanghai University, Wenzhou 325000, Zhejiang Province, China
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10
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Zhou X, Shen K, Cao S, Li P, Xiao J, Dong J, Cheng Q, Hu L, Xu Z, Yang L. Polymorphism rs2327430 in TCF21 predicts the risk and prognosis of gastric cancer by affecting the binding between TFAP2A and TCF21. Cancer Cell Int 2024; 24:159. [PMID: 38714991 PMCID: PMC11075239 DOI: 10.1186/s12935-024-03343-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 04/24/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND Single nuclear polymorphisms (SNPs) have been published to be correlated with multiple diseases. Transcription Factor 21 (TCF21) is a critical transcription factor involved in various types of cancers. However, the association of TCF21 genetic polymorphisms with gastric cancer (GC) susceptibility and prognosis remains unclear. METHODS A case-control study comprising 890 patients diagnosed with GC and an equal number of cancer-free controls was conducted. After rigorous statistical analysis, molecular experiments were carried out to elucidate the functional significance of the SNPs in the context of GC. RESULTS TCF21 rs2327430 (OR = 0.78, P = 0.026) provides protection against GC, while rs4896011 (OR = 1.39, P = 0.005) exhibit significant associations with GC risk. Furthermore, patients with the (TC + CC) genotype of rs2327430 demonstrate a relatively favorable prognosis (OR = 0.47, P = 0.012). Mechanistically, chromatin immunoprecipitation assay and luciferase reporter assay revealed that the C allele of rs2327430 disrupts the binding of Transcription Factor AP-2 Alpha (TFAP2A) to the promoter region of TCF21, resulting in increased expression of TCF21 and inhibition of malignant behaviors in GC cells. CONCLUSION Our findings highlight the significant role of TCF21 SNPs in both the risk and prognosis of GC and provide valuable insights into the underlying molecular mechanisms. Specifically, the disruptive effect of rs2327430 on TCF21 expression and its ability to modulate malignant cell behaviors suggest that rs2327430 may serve as a potential predictive marker for GC risk and prognosis.
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Affiliation(s)
- Xinyi Zhou
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China
| | - Kuan Shen
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China
| | - Shuqing Cao
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China
| | - Pengyu Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China
| | - Jian Xiao
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China
| | - Jiacheng Dong
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China
| | - Quan Cheng
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China
| | - Li Hu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China
| | - Zekuan Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China
| | - Li Yang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China.
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11
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Chen X, Wang L, Yang M, Zhao W, Tu J, Liu B, Yuan X. RUNX transcription factors: biological functions and implications in cancer. Clin Exp Med 2024; 24:50. [PMID: 38430423 PMCID: PMC10908630 DOI: 10.1007/s10238-023-01281-0] [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: 09/30/2023] [Accepted: 11/10/2023] [Indexed: 03/03/2024]
Abstract
Runt-related transcription factors (RUNX) are a family of transcription factors that are essential for normal and malignant hematopoietic processes. Their most widely recognized role in malignancy is to promote the occurrence and development of acute myeloid leukemia. However, it is worth noting that during the last decade, studies of RUNX proteins in solid tumors have made considerable progress, suggesting that these proteins are directly involved in different stages of tumor development, including tumor initiation, progression, and invasion. RUNX proteins also play a role in tumor angiogenesis, the maintenance of tumor cell stemness, and resistance to antitumor drugs. These findings have led to the consideration of RUNX as a tumor biomarker. All RUNX proteins are involved in the occurrence and development of solid tumors, but the role of each RUNX protein in different tumors and the major signaling pathways involved are complicated by tumor heterogeneity and the interacting tumor microenvironment. Understanding how the dysregulation of RUNX in tumors affects normal biological processes is important to elucidate the molecular mechanisms by which RUNX affects malignant tumors.
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Affiliation(s)
- Xinyi Chen
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jie Fang Road 1095, Wuhan, Hubei Province, China
| | - Lu Wang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jie Fang Road 1095, Wuhan, Hubei Province, China
| | - Mu Yang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jie Fang Road 1095, Wuhan, Hubei Province, China
| | - Weiheng Zhao
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jie Fang Road 1095, Wuhan, Hubei Province, China
| | - Jingyao Tu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jie Fang Road 1095, Wuhan, Hubei Province, China.
| | - Bo Liu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jie Fang Road 1095, Wuhan, Hubei Province, China.
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jie Fang Road 1095, Wuhan, Hubei Province, China.
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12
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Ding W, Chen WW, Wang YQ, Xu XZ, Wang YB, Yan YM, Tan YL. Immune-related long noncoding RNA zinc finger protein 710-AS1-201 promotes the metastasis and invasion of gastric cancer cells. World J Gastrointest Oncol 2024; 16:458-474. [PMID: 38425400 PMCID: PMC10900153 DOI: 10.4251/wjgo.v16.i2.458] [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: 09/04/2023] [Revised: 12/02/2023] [Accepted: 12/20/2023] [Indexed: 02/02/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is a prevalent malignant tumor of the gastrointestinal system. ZNF710 is a transcription factor (TF), and zinc finger protein 710 (ZNF710)-AS1-201 is an immune-related long noncoding RNA (lncRNA) that is upregulated in GC cells. AIM To assess the correlation between ZNF710-AS1-201 and immune microenvironment features and to investigate the roles of ZNF710-AS1-201 in the invasion and metastasis processes of GC cells. METHODS We obtained data from The Cancer Genome Atlas and Wujin Hospital. We assessed cell growth, migration, invasion, and programmed cell death using cell counting kit-8, EdU, scratch, Transwell, and flow cytometry assays. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to identify the potential downstream targets of ZNF710-AS1-201. RESULTS In GC tissues with low ZNF710-AS1-201 expression, immunoassays detected significant infiltration of various antitumor immune cells, such as memory CD8 T cells and activated CD4 T cells. In the low-expression group, the half-maximal inhibitory concentrations (IC50s) of 5-fluorouracil, cisplatin, gemcitabine, and trametinib were lower, whereas the IC50s of dasatinib and vorinostat were higher. The malignant degree of GC was higher and the stage was later in the high-expression group. Additionally, patients with high expression of ZNF710-AS1-201 had lower overall survival and disease-free survival rates. In vitro, the overexpression of ZNF710-AS1-201 greatly enhanced growth, metastasis, and infiltration while suppressing cell death in HGC-27 cells. In contrast, the reduced expression of ZNF710-AS1-201 greatly hindered cell growth, enhanced apoptosis, and suppressed the metastasis and invasion of MKN-45 cells. The expression changes in ZNF710 were significant, but the corresponding changes in isocitrate dehydrogenase-2, Semaphorin 4B, ARHGAP10, RGMB, hsa-miR-93-5p, and ZNF710-AS1-202 were not consistent or statistically significant after overexpression or knockdown of ZNF710-AS1-201, as determined by qRT-PCR. CONCLUSION Immune-related lncRNA ZNF710-AS1-201 facilitates the metastasis and invasion of GC cells. It appears that ZNF710-AS1-201 and ZNF710 have potential as effective targets for therapeutic intervention in GC. Nevertheless, it is still necessary to determine the specific targets of the ZNF710 TF.
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Affiliation(s)
- Wei Ding
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213003, Jiangsu Province, China
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213017, Jiangsu Province, China
- Department of General Surgery, The Wujin Clinical College of Xuzhou Medical University, Changzhou 213003, Jiangsu Province, China
| | - Wei-Wei Chen
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213003, Jiangsu Province, China
| | - Yi-Qin Wang
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213003, Jiangsu Province, China
| | - Xue-Zhong Xu
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213003, Jiangsu Province, China
| | - Yi-Bo Wang
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213003, Jiangsu Province, China
| | - Yong-Min Yan
- Changzhou Medical Center, Nanjing Medical University, Changzhou 213017, Jiangsu Province, China
| | - Yu-Lin Tan
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213003, Jiangsu Province, China
- Department of General Surgery, The Wujin Clinical College of Xuzhou Medical University, Changzhou 213003, Jiangsu Province, China
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13
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Toner J, Gordon JAR, Greenyer H, Kaufman P, Stein JL, Stein GS, Lian JB. RUNX2 as a Prognostic Factor in Human Cancers. Crit Rev Eukaryot Gene Expr 2024; 34:51-66. [PMID: 39072409 DOI: 10.1615/critreveukaryotgeneexpr.2024054162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
The RUNX2 transcription factor was discovered as an essential transcriptional regulator for commitment to osteoblast lineage cells and bone formation. Expression of RUNX2 in other tissues, such as breast, prostate, and lung, has been linked to oncogenesis, cancer progression, and metastasis. In this study, we sought to determine the extent of RUNX2 involvement in other tumors using a pan-cancer analysis strategy. We correlated RUNX2 expression and clinical-pathological parameters in human cancers by interrogating publicly available multiparameter clinical data. Our analysis demonstrated that altered RUNX2 expression or function is associated with several cancer types from different tissues. We identified three tumor types associated with increased RUNX2 expression and four other tumor types associated with decreased RUNX2 expression. Our pan-cancer analysis for RUNX2 revealed numerous other discoveries for RUNX2 regulation of different cancers identified in each of the pan-cancer databases. Both up and down regulation of RUNX2 was observed during progression of specific types of cancers in promoting the distinct types of cancers.
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Affiliation(s)
- J Toner
- Department of Biochemistry, University of Vermont, Larner College of Medicine, Burlington, VT, 05405, USA
| | - Johnathan A R Gordon
- Department of Biochemistry, University of Vermont, Burlington, Vermont, USA; University of Vermont Cancer Center, Burlington, Vermont, USA
| | - H Greenyer
- Department of Biochemistry, University of Vermont, Larner College of Medicine, Burlington, VT, 05405, USA
| | - Peter Kaufman
- Hematology/Oncology Division, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA
| | - Janet L Stein
- Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT 05405; University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT 05405
| | - Gary S Stein
- Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT 05405; University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT 05405
| | - Jane B Lian
- Department of Biochemistry, University of Vermont Larner College of Medicine, Burlington, VT 05405; University of Vermont Cancer Center, University of Vermont Larner College of Medicine, Burlington, VT 05405
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14
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Tyagi K, Roy A, Mandal S. Pharmacological inhibition of protein kinase D suppresses epithelial ovarian cancer via MAPK/ERK1/2/Runx2 signalling axis. Cell Signal 2023; 110:110849. [PMID: 37562720 DOI: 10.1016/j.cellsig.2023.110849] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 08/04/2023] [Accepted: 08/06/2023] [Indexed: 08/12/2023]
Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy with poor prognosis and dismal patient survival. Although protein kinase D (PKD) isoforms, especially PKD2 and PKD3 are critical for many cellular and physiological functions involved in carcinogenesis including cell proliferation and angiogenesis, their role in human EOC remains unknown. Towards the goal to identify novel prognostic biomarker and therapeutic interventions against EOC, this study aimed to elucidate the molecular roles of PKD2, PKD3 and highly selective, pan-PKD inhibitor CRT0066101 in this lethal pathology. Our results indicated that inactivation of PKD2 and PKD3 by 1 μM CRT0066101 suppressed EOC cell proliferation, colony formation, cell migration and invasion. Moreover, CRT0066101 induced apoptosis and inhibited cell cycle at G2-M phase in EOC cells. Genetic knockdown of PKD2 and PKD3 confirmed the anti-carcinogenic effects of CRT0066101 against EOC. The anti-cancer phenotype of EOC cells resulted from CRT0066101-mediated PKD2 and PKD3 inactivation or genetic depletion was, in part, mediated by transcription factor Runx2 as abrogation of PKD2 and PKD3 caused downregulation of Runx2 and its downstream target genes including osteopontin, focal adhesion kinase and ERK1/2. Moreover, overexpression of a constitutively active PKD2 augmented the expression levels of phosphor-ERK1/2T202/Y204, Runx2 and its downstream targets. Mechanistically, PKD2 and PKD3 positively regulated Runx2 via MAPK/ERK1/2 pathway and promoted EOC. Taken together, our results indicated that PKD2/3/ERK1/2/Runx2 signalling axis might be a novel drug target against EOC and CRT0066101 could be developed as a promising therapeutic choice against this lethal pathology.
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Affiliation(s)
- Komal Tyagi
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University, Sector 125, Noida, Uttar Pradesh 201303, India
| | - Adhiraj Roy
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University, Sector 125, Noida, Uttar Pradesh 201303, India.
| | - Supratim Mandal
- Department of Microbiology, University of Kalyani, Kalyani, Nadia, West Bengal 741235, India
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15
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Roy A, Chauhan S, Bhattacharya S, Jakhmola V, Tyagi K, Sachdeva A, Wasai A, Mandal S. Runt-related transcription factors in human carcinogenesis: a friend or foe? J Cancer Res Clin Oncol 2023; 149:9409-9423. [PMID: 37081242 DOI: 10.1007/s00432-023-04769-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 04/08/2023] [Indexed: 04/22/2023]
Abstract
PURPOSE Cancer is one of the deadliest pathologies with more than 19 million new cases and 10 million cancer-related deaths across the globe. Despite development of advanced therapeutic interventions, cancer remains as a fatal pathology due to lack of early prognostic biomarkers, therapy resistance and requires identification of novel drug targets. METHODS Runt-related transcription factors (Runx) family controls several cellular and physiological functions including osteogenesis. Recent literatures from PubMed was mined and the review was written in comprehensive manner RESULTS: Recent literature suggests that aberrant expression of Runx contributes to tumorigenesis of many organs. Conversely, cell- and tissue-specific tumor suppressor roles of Runx are also reported. In this review, we have provided the structural/functional properties of Runx isoforms and its regulation in context of human cancer. Moreover, in an urgent need to discover novel therapeutic interventions against cancer, we comprehensively discussed the reported oncogenic and tumor suppressive roles of Runx isoforms in several tumor types and discussed the discrepancies that may have risen on Runx as a driver of malignant transformation. CONCLUSION Runx may be a novel therapeutic target against a battery of deadly human cancers.
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Affiliation(s)
- Adhiraj Roy
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University, Sector 125, Noida, Uttar Pradesh, 201303, India.
| | - Shivi Chauhan
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University, Sector 125, Noida, Uttar Pradesh, 201303, India
| | - Sujata Bhattacharya
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University, Sector 125, Noida, Uttar Pradesh, 201303, India
| | - Vibhuti Jakhmola
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University, Sector 125, Noida, Uttar Pradesh, 201303, India
| | - Komal Tyagi
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University, Sector 125, Noida, Uttar Pradesh, 201303, India
| | - Abha Sachdeva
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University, Sector 125, Noida, Uttar Pradesh, 201303, India
| | - Abdul Wasai
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University, Sector 125, Noida, Uttar Pradesh, 201303, India
| | - Supratim Mandal
- Department of Microbiology, University of Kalyani, Kalyani, Nadia, West Bengal, 741235, India
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16
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Wang Y, Tan Z, Li X, Zhang L, Pei X. RUNX2 promotes gastric cancer progression through the transcriptional activation of MGAT5 and MMP13. Front Oncol 2023; 13:1133476. [PMID: 37256183 PMCID: PMC10226684 DOI: 10.3389/fonc.2023.1133476] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 04/20/2023] [Indexed: 06/01/2023] Open
Abstract
Introduction RUNX2 is overexpressed in gastric cancer but the mechanism(s) through which it promotes tumor progression remain undefined. Here, we investigated the role of RUNX2 on gastric cancer pathogenesis at the molecular level. Methods The qRT-PCR and western bolt were utilized to examine the mRNA and protein levels. CCK-8, Transwell and wound healing assays were used to measure cell proliferation, invasion and migration. CHIP-PCR gel electrophoresis was used to verify RUNX2 as a transcription factor for MMP13 and MGAT5. The in vivo assay was utilized to assess tumor growth. In vivo assay was used to evaluate tumor growth, aberrant expression of RUNX2 and lung metastasis of gastric cancer. Results RUNX2 is overexpressed in MKN-45 and AGS cells. Genetic RUNX2 silencing reduced the proliferation, invasion and migration of MKN-45 and AGS cells. Analysis of the gastric cancer samples from the database revealed a significant positive correlation between MGAT5, MMP13, and RUNX2 expression. JASPAR analysis revealed that there was a potential binding site of RUNX2 in the promoter regions of MGAT5 and MMP13, and the experimental results confirmed that RUNX2 could regulate the expression of MGAT5 and MMP13 respectively. In vivo assays confirmed the aberrant expression of RUNX2 in mouse models of gastric cancer and reduced growth and lung metastasis in RUNX2 silenced xenograft tumors assessed. Conclusion Collectively, these data reveal that RUNX2 enhances MGAT5 and MMP13 expression in gastric cancer cells and represents a biomarker and potential therapeutic target for gastric cancer therapy.
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Affiliation(s)
- Ying Wang
- Department of Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Shenzhen, Guangdong, China
| | - Zhibo Tan
- Department of Radiation Oncology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Xiaoyu Li
- Department of Pathology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China
| | - Lili Zhang
- Department of Pathology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China
| | - Xiaojuan Pei
- Department of Pathology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China
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17
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Si W, Kan C, Zhang L, Li F. Role of RUNX2 in breast cancer development and drug resistance (Review). Oncol Lett 2023; 25:176. [PMID: 37033103 PMCID: PMC10079821 DOI: 10.3892/ol.2023.13762] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 03/02/2023] [Indexed: 03/17/2023] Open
Abstract
Breast cancer is the most common malignancy and ranks second among the causes of tumor-associated death in females. The recurrence and drug resistance of breast cancer are intractable due to the presence of breast cancer stem cells (BCSCs), which are adequate to initiate tumor formation and refractory to conventional remedies. Runt-related transcription factor 2 (RUNX2), a pivotal transcription factor in mammary gland and bone development, has also been related to metastatic cancer and BCSCs. State-of-the-art research has indicated the retention of RUNX2 expression in a more invasive subtype of breast cancer, and in particular, triple-negative breast cancer development and drug resistance are associated with estrogen receptor signaling pathways. The present review mainly focused on the latest updates on RUNX2 in BCSCs and their roles in breast cancer progression and drug resistance, providing insight that may aid the development of RUNX2-based diagnostics and treatments for breast cancer in clinical practice.
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Affiliation(s)
- Wentao Si
- Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Chen Kan
- Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Leisheng Zhang
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province and NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
- Key Laboratory of Radiation Technology and Biophysics, Hefei Institute of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, P.R. China
| | - Feifei Li
- Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
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18
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Cao Z, An L, Han Y, Jiao S, Zhou Z. The Hippo signaling pathway in gastric cancer. Acta Biochim Biophys Sin (Shanghai) 2023. [PMID: 36924251 DOI: 10.3724/abbs.2023038] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2023] Open
Abstract
Gastric cancer (GC) is an aggressive malignant disease which still lacks effective early diagnosis markers and targeted therapies, representing the fourth-leading cause of cancer-associated death worldwide. The Hippo signaling pathway plays crucial roles in organ size control and tissue homeostasis under physiological conditions, yet its aberrations have been closely associated with several hallmarks of cancer. The last decade witnessed a burst of investigations dissecting how Hippo dysregulation contributes to tumorigenesis, highlighting the therapeutic potential of targeting this pathway for tumor intervention. In this review, we systemically document studies on the Hippo pathway in the contexts of gastric tumor initiation, progression, metastasis, acquired drug resistance, and the emerging development of Hippo-targeting strategies. By summarizing major open questions in this field, we aim to inspire further in-depth understanding of Hippo signaling in GC development, as well as the translational implications of targeting Hippo for GC treatment.
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Affiliation(s)
- Zhifa Cao
- Department of Stomatology, Shanghai Tenth People's Hospital, Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai 200072, China.,CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Liwei An
- Department of Stomatology, Shanghai Tenth People's Hospital, Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai 200072, China
| | - Yi Han
- Department of Stomatology, Shanghai Tenth People's Hospital, Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai 200072, China
| | - Shi Jiao
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200438, China
| | - Zhaocai Zhou
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200438, China.,Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, China
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Wang P, Zhang J, Zhang H, Zhang F. The role of MACF1 on acute myeloid leukemia cell proliferation is involved in Runx2-targeted PI3K/Akt signaling. Mol Cell Biochem 2023; 478:433-441. [PMID: 35857251 DOI: 10.1007/s11010-022-04517-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 06/24/2022] [Indexed: 11/25/2022]
Abstract
Acute myeloid leukemia (AML) is a type of hematologic diseases, which is related to abnormal genes. The aberrant microtubule actin cross-linking factor 1 (MACF1) is associated with progression of multiple tumors by initiating cell proliferation. Nevertheless, the function and action mechanism of MACF1 in AML cell proliferation remain mostly unknown. Our study aimed to explore the influence of MACF1 on AML cell proliferation by CCK-8 and EdU staining assays. Moreover, we aimed to explore the effect of MACF1 on downstream Runx2 and the PI3K/Akt signaling. MACF1 expression in AML patients was predicted by bioinformatics analysis. Cells were transfected with si-con, si-MACF1 or Runx2 using Lipofectamine 2000. Upregulated MACF1 was found in AML patients and predicted worse overall survival. MACF1 expression was upregulated in AML cells compared with that in hematopoietic stem and progenitor cells. MACF1 silencing reduced AML cell proliferation. Runx2 level was increased in AML cells, and decreased by silencing MACF1. Runx2 upregulation rescued MACF1 silencing-mediated inhibition of proliferation. MACF1 downregulation inhibited activation of the PI3K/Akt pathway by decreasing Runx2. Activation of the PI3K/Akt pathway abrogated the suppressive role of MACF1 downregulation in AML cell proliferation. In conclusion, MACF1 knockdown decreased AML cell proliferation by reducing Runx2 and inactivating the PI3K/Akt signaling.
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Affiliation(s)
- Ping Wang
- Department of Hematology, People's Hospital of Chongqing Banan District (Banan Hospital of Chongqing Medical University), No.659, Yu'nan Avenue, Chongqing, 401320, People's Republic of China.
| | - Jiajia Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Henan Polytechnic University, Jiaozuo, 454000, Henan, People's Republic of China
| | - Hui Zhang
- Department of Endocrinology, The First Affiliated Hospital of Henan Polytechnic University, Jiaozuo, 454000, Henan, People's Republic of China
| | - Fang Zhang
- Department of Neurology, The First Affiliated Hospital of Henan Polytechnic University, Jiaozuo, 454000, Henan, People's Republic of China
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Li R, Huang W. Yes-Associated Protein and Transcriptional Coactivator with PDZ-Binding Motif in Cardiovascular Diseases. Int J Mol Sci 2023; 24:ijms24021666. [PMID: 36675179 PMCID: PMC9861006 DOI: 10.3390/ijms24021666] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/08/2023] [Accepted: 01/10/2023] [Indexed: 01/18/2023] Open
Abstract
Yes-associated protein (YAP, also known as YAP1) and its paralogue TAZ (with a PDZ-binding motif) are transcriptional coactivators that switch between the cytoplasm and nucleus and regulate the organ size and tissue homeostasis. This review focuses on the research progress on YAP/TAZ signaling proteins in myocardial infarction, cardiac remodeling, hypertension and coronary heart disease, cardiomyopathy, and aortic disease. Based on preclinical studies on YAP/TAZ signaling proteins in cellular/animal models and clinical patients, the potential roles of YAP/TAZ proteins in some cardiovascular diseases (CVDs) are summarized.
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21
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Messina B, Lo Sardo F, Scalera S, Memeo L, Colarossi C, Mare M, Blandino G, Ciliberto G, Maugeri-Saccà M, Bon G. Hippo pathway dysregulation in gastric cancer: from Helicobacter pylori infection to tumor promotion and progression. Cell Death Dis 2023; 14:21. [PMID: 36635265 PMCID: PMC9837097 DOI: 10.1038/s41419-023-05568-8] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 12/27/2022] [Accepted: 01/06/2023] [Indexed: 01/13/2023]
Abstract
The Hippo pathway plays a critical role for balancing proliferation and differentiation, thus regulating tissue homeostasis. The pathway acts through a kinase cascade whose final effectors are the Yes-associated protein (YAP) and its paralog transcriptional co‑activator with PDZ‑binding motif (TAZ). In response to a variety of upstream signals, YAP and TAZ activate a transcriptional program that modulates cellular proliferation, tissue repair after injury, stem cell fate decision, and cytoskeletal reorganization. Hippo pathway signaling is often dysregulated in gastric cancer and in Helicobacter pylori-induced infection, suggesting a putative role of its deregulation since the early stages of the disease. In this review, we summarize the architecture and regulation of the Hippo pathway and discuss how its dysregulation fuels the onset and progression of gastric cancer. In this setting, we also focus on the crosstalk between Hippo and other established oncogenic signaling pathways. Lastly, we provide insights into the therapeutic approaches targeting aberrant YAP/TAZ activation and discuss the related clinical perspectives and challenges.
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Affiliation(s)
- Beatrice Messina
- Clinical Trial Center, Biostatistics and Bioinformatics Unit, Department of Research, Diagnosis and Innovative Technologies, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Federica Lo Sardo
- Oncogenomic and Epigenetic Unit, Department of Research, Diagnosis and Innovative Technologies, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Stefano Scalera
- SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Lorenzo Memeo
- Pathology Unit, Mediterranean Institute of Oncology, Viagrande, Italy
| | | | - Marzia Mare
- Medical Oncology Unit, Mediterranean Institute of Oncology, Viagrande, Italy
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Messina, Italy
| | - Giovanni Blandino
- Oncogenomic and Epigenetic Unit, Department of Research, Diagnosis and Innovative Technologies, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Gennaro Ciliberto
- Scientific Directorate, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Marcello Maugeri-Saccà
- Clinical Trial Center, Biostatistics and Bioinformatics Unit, Department of Research, Diagnosis and Innovative Technologies, IRCCS Regina Elena National Cancer Institute, Rome, Italy
- Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Giulia Bon
- Cellular Network and Molecular Therapeutic Target Unit, Department of Research, Diagnosis and Innovative Technologies, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
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22
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Malpeli G, Barbi S, Innamorati G, Alloggio M, Filippini F, Decimo I, Castelli C, Perris R, Bencivenga M. Landscape of Druggable Molecular Pathways Downstream of Genomic CDH1/Cadherin-1 Alterations in Gastric Cancer. J Pers Med 2022; 12:jpm12122006. [PMID: 36556227 PMCID: PMC9784514 DOI: 10.3390/jpm12122006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/03/2022] [Accepted: 11/24/2022] [Indexed: 12/09/2022] Open
Abstract
Loss of CDH1/Cadherin-1 is a common step towards the acquisition of an abnormal epithelial phenotype. In gastric cancer (GC), mutation and/or downregulation of CDH1/Cadherin-1 is recurrent in sporadic and hereditary diffuse GC type. To approach the molecular events downstream of CDH1/Cadherin-1 alterations and their relevance in gastric carcinogenesis, we queried public databases for genetic and DNA methylation data in search of molecular signatures with a still-uncertain role in the pathological mechanism of GC. In all GC subtypes, modulated genes correlating with CDH1/Cadherin-1 aberrations are associated with stem cell and epithelial-to-mesenchymal transition pathways. A higher level of genes upregulated in CDH1-mutated GC cases is associated with reduced overall survival. In the diffuse GC (DGC) subtype, genes downregulated in CDH1-mutated compared to cases with wild type CDH1/Cadherin-1 resulted in being strongly intertwined with the DREAM complex. The inverse correlation between hypermethylated CpGs and CDH1/Cadherin-1 transcription in diverse subtypes implies a common epigenetic program. We identified nonredundant protein-encoding isoforms of 22 genes among those differentially expressed in GC compared to normal stomach. These unique proteins represent potential agents involved in cell transformation and candidate therapeutic targets. Meanwhile, drug-induced and CDH1/Cadherin-1 mutation-related gene expression comparison predicts FIT, GR-127935 hydrochloride, amiodarone hydrochloride in GC and BRD-K55722623, BRD-K13169950, and AY 9944 in DGC as the most effective treatments, providing cues for the design of combined pharmacological treatments. By integrating genetic and epigenetic aspects with their expected functional outcome, we unveiled promising targets for combinatorial pharmacological treatments of GC.
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Affiliation(s)
- Giorgio Malpeli
- Department of Surgical, Odontostomatologic, Maternal and Child Sciences, University of Verona, 37134 Verona, Italy
- Correspondence:
| | - Stefano Barbi
- Department of Diagnostics and Public Health, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Giulio Innamorati
- Department of Surgical, Odontostomatologic, Maternal and Child Sciences, University of Verona, 37134 Verona, Italy
| | - Mariella Alloggio
- General and Upper GI Surgery Division, Department and of Surgical, Odontostomatologic, Maternal and Child Sciences, University of Verona, 37134 Verona, Italy
| | - Federica Filippini
- General and Upper GI Surgery Division, Department and of Surgical, Odontostomatologic, Maternal and Child Sciences, University of Verona, 37134 Verona, Italy
| | - Ilaria Decimo
- Section of Pharmacology, Department of Diagnostic and Public Health, University of Verona, 37134 Verona, Italy
| | - Claudia Castelli
- Pathology Unit, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Roberto Perris
- Department of Biosciences, COMT-Centre for Molecular and Translational Oncology, University of Parma, 43124 Parma, Italy
| | - Maria Bencivenga
- General and Upper GI Surgery Division, Department and of Surgical, Odontostomatologic, Maternal and Child Sciences, University of Verona, 37134 Verona, Italy
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23
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RUNX Proteins as Epigenetic Modulators in Cancer. Cells 2022; 11:cells11223687. [PMID: 36429115 PMCID: PMC9688118 DOI: 10.3390/cells11223687] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/11/2022] [Accepted: 10/27/2022] [Indexed: 11/22/2022] Open
Abstract
RUNX proteins are highly conserved in metazoans and perform critical functions during development. Dysregulation of RUNX proteins through various molecular mechanisms facilitates the development and progression of various cancers, where different RUNX proteins show tumor type-specific functions and regulate different aspects of tumorigenesis by cross-talking with different signaling pathways such as Wnt, TGF-β, and Hippo. Molecularly, they could serve as transcription factors (TFs) to activate their direct target genes or interact with many other TFs to modulate chromatin architecture globally. Here, we review the current knowledge on the functions and regulations of RUNX proteins in different cancer types and highlight their potential role as epigenetic modulators in cancer.
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24
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Si W, Xu X, Wan L, Lv F, Wei W, Xu X, Li W, Huang D, Zhang L, Li F. RUNX2 facilitates aggressiveness and chemoresistance of triple negative breast cancer cells via activating MMP1. Front Oncol 2022; 12:996080. [PMID: 36483054 PMCID: PMC9724742 DOI: 10.3389/fonc.2022.996080] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 10/24/2022] [Indexed: 11/30/2023] Open
Abstract
Breast cancer remains the most common malignancy in women and constantly threatens the lives of patients worldwide. State-of-the-art renewal has indicated the involvement of RUNX-associated transcription factor 2 (RUNX2) in tumorigenesis and cancer progression, yet the detailed information during breast cancer is largely obscure. Herein, we took advantage of breast cancer cell lines and in vivo tumorigenicity test as well as multifaceted phenotypic analyses (e.g., RNA-sequencing, ChIP and qRT-PCR assay) to verify the pathogenic mechanism of RUNX2 in triple negative breast cancer aggressiveness and chemoresistance. Strikingly, the proliferation, migration, invasion and chemoresistance of resistant cell lines in triple negative breast cancer was effectively suppressed by RUNX2 silencing, and the in vivo tumorigenicity was significantly weakened as well. Furthermore, with the aid of transcriptomic and bioinformatic analyses, we found MMP1 was highly expressed in triple negative breast cancer (TNBC) and showed a strong correlation with the poor prognosis of the patients, which was consistent with the expression pattern of RUNX2. Finally, by conducting ChIP and qRT-PCR assessment, we verified that RUNX2 functioned via directly binding to the specific motifs in the promoter of MMP1 and thus activating the transcriptional process. Collectively, our data demonstrated the facilitating effect of RUNX2 during triple negative breast cancer progression by directly orchestrating the expression of MMP1, which supplied overwhelming new references for RUNX2-MMP1 axis serving as a novel candidate for breast cancer diagnosis and treatment.
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Affiliation(s)
- Wentao Si
- Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Xiaodan Xu
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Lijuan Wan
- Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Fengxu Lv
- Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Wei Wei
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiaojun Xu
- Department of Breast Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wei Li
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Dabing Huang
- Department of Oncology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Leisheng Zhang
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province & NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, China
- Key Laboratory of Radiation Technology and Biophysics, Hefei Institute of Physical Science, Chinese Academy of Sciences, Hefei, China
| | - Feifei Li
- Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
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25
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Zhang X, Ren Z, Liu B, Wei S. RUNX2 Mediates Renal Cell Carcinoma Invasion through Calpain2. Biol Pharm Bull 2022; 45:1653-1659. [DOI: 10.1248/bpb.b22-00451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Xiaoyu Zhang
- Department of Urology Surgery, The Fourth Hospital of Hebei Medical University
| | - Zongtao Ren
- Department of Urology Surgery, The Fourth Hospital of Hebei Medical University
| | - Bin Liu
- Department of Urology Surgery, The Fourth Hospital of Hebei Medical University
| | - Shufei Wei
- Department of Urology Surgery, The Fourth Hospital of Hebei Medical University
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26
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Xing F, Yin HM, Zhe M, Xie JC, Duan X, Xu JZ, Xiang Z, Li ZM. Nanotopographical 3D-Printed Poly(ε-caprolactone) Scaffolds Enhance Proliferation and Osteogenic Differentiation of Urine-Derived Stem Cells for Bone Regeneration. Pharmaceutics 2022; 14:pharmaceutics14071437. [PMID: 35890332 PMCID: PMC9317219 DOI: 10.3390/pharmaceutics14071437] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/02/2022] [Accepted: 07/06/2022] [Indexed: 02/05/2023] Open
Abstract
3D-printing technology can be used to construct personalized bone substitutes with customized shapes, but it cannot regulate the topological morphology of the scaffold surface, which plays a vital role in regulating the biological behaviors of stem cells. In addition, stem cells are able to sense the topographical and mechanical cues of surface of scaffolds by mechanosensing and mechanotransduction. In our study, we fabricated a 3D-printed poly(ε-caprolactone) (PCL) scaffold with a nanotopographical surface and loaded it with urine-derived stem cells (USCs) for application of bone regeneration. The topological 3D-printed PCL scaffolds (TPS) fabricated by surface epiphytic crystallization, possessed uniformly patterned nanoridges, of which the element composition and functional groups of nanoridges were the same as PCL. Compared with bare 3D-printed PCL scaffolds (BPS), TPS have a higher ability for protein adsorption and mineralization in vitro. The proliferation, cell length, and osteogenic gene expression of USCs on the surface of TPS were significantly higher than that of BPS. In addition, the TPS loaded with USCs exhibited a good ability for bone regeneration in cranial bone defects. Our study demonstrated that nanotopographical 3D-printed scaffolds loaded with USCs are a safe and effective therapeutic strategy for bone regeneration.
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Affiliation(s)
- Fei Xing
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, No. 37 Guoxue Lane, Chengdu 610041, China; (F.X.); (Z.X.)
| | - Hua-Mo Yin
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, China; (H.-M.Y.); (Z.-M.L.)
| | - Man Zhe
- Animal Experiment Center, West China Hospital, Sichuan University, Chengdu 610041, China;
| | - Ji-Chang Xie
- Laboratoire Roberval, FRE UTC-CNRS 2012, Sorbonne Universités, Université de Technologie de Compiègne, Centre de Recherche Royallieu, CS60319, CEDEX, 60203 Compiègne, France;
| | - Xin Duan
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, No. 37 Guoxue Lane, Chengdu 610041, China; (F.X.); (Z.X.)
- Correspondence: (X.D.); (J.-Z.X.)
| | - Jia-Zhuang Xu
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, China; (H.-M.Y.); (Z.-M.L.)
- Correspondence: (X.D.); (J.-Z.X.)
| | - Zhou Xiang
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, No. 37 Guoxue Lane, Chengdu 610041, China; (F.X.); (Z.X.)
| | - Zhong-Ming Li
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu 610065, China; (H.-M.Y.); (Z.-M.L.)
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27
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miR-218-5p/RUNX2 Axis Positively Regulates Proliferation and Is Associated with Poor Prognosis in Cervical Cancer. Int J Mol Sci 2022; 23:ijms23136993. [PMID: 35805994 PMCID: PMC9267020 DOI: 10.3390/ijms23136993] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/10/2022] [Accepted: 06/21/2022] [Indexed: 12/13/2022] Open
Abstract
The overexpression of miR-218-5p in cervical cancer (CC) cell lines decreases migration, invasion and proliferation. The objective was to identify target genes of miR-218-5p and the signaling pathways and cellular processes that they regulate. The relationship between the expression of miR-218-5p and RUNX2 and overall survival in CC as well as the effect of the exogenous overexpression of miR-218-5p on the level of RUNX2 were analyzed. The target gene prediction of miR-218-5p was performed in TargetScan, miRTarBase and miRDB. Predicted target genes were subjected to gene ontology (GO) and pathway enrichment analysis using the Kyoto Encyclopaedia of Genes and Genomes (KEGG). The miR-218-5p mimetic was transfected into C-33A and CaSki cells, and the miR-218-5p and RUNX2 levels were determined by RT–qPCR. Of the 118 predicted targets for miR-218-5p, 86 are involved in protein binding, and 10, including RUNX2, are involved in the upregulation of proliferation. Low miR-218-5p expression and a high level of RUNX2 are related to poor prognosis in CC. miR-218-5p overexpression is related to decreased RUNX2 expression in C-33A and CaSki cells. miR-218-5p may regulate RUNX2, and both molecules may be prognostic markers in CC.
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28
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Seeneevassen L, Dubus P, Gronnier C, Varon C. Hippo in Gastric Cancer: From Signalling to Therapy. Cancers (Basel) 2022; 14:cancers14092282. [PMID: 35565411 PMCID: PMC9105983 DOI: 10.3390/cancers14092282] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/12/2022] [Accepted: 04/20/2022] [Indexed: 12/12/2022] Open
Abstract
The Hippo pathway is one of the most important ones in mammals. Its key functions in cell proliferation, tissue growth, repair, and homeostasis make it the most crucial one to be controlled. Many means have been deployed for its regulation, since this pathway is not only composed of core regulatory components, but it also communicates with and regulates various other pathways, making this signalisation even more complex. Its role in cancer has been studied more and more over the past few years, and it presents YAP/TAZ as the major oncogenic actors. In this review, we relate how vital this pathway is for different organs, and how regulatory mechanisms have been bypassed to lead to cancerous states. Most studies present an upregulation status of YAP/TAZ, and urge the need to target them. A focus is made here on gastric carcinogenesis, its main dysregulations, and the major strategies adopted and tested to counteract Hippo pathway disbalance in this disease. Hippo pathway targeting can be achieved by various means, which are described in this review. Many studies have tested different potential molecules, which are detailed hereby. Though not all tested in gastric cancer, they could represent a real interest.
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Affiliation(s)
- Lornella Seeneevassen
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, F-33000 Bordeaux, France; (L.S.); (P.D.); (C.G.)
| | - Pierre Dubus
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, F-33000 Bordeaux, France; (L.S.); (P.D.); (C.G.)
- Department of Histology and Pathology, CHU Bordeaux, F-33000 Bordeaux, France
| | - Caroline Gronnier
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, F-33000 Bordeaux, France; (L.S.); (P.D.); (C.G.)
- Department of Digestive Surgery, Haut-Lévêque Hospital, CHU Bordeaux, F-33000 Bordeaux, France
| | - Christine Varon
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, F-33000 Bordeaux, France; (L.S.); (P.D.); (C.G.)
- Correspondence:
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29
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Chuang LSH, Ito Y. The Multiple Interactions of RUNX with the Hippo-YAP Pathway. Cells 2021; 10:2925. [PMID: 34831147 PMCID: PMC8616315 DOI: 10.3390/cells10112925] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/22/2021] [Accepted: 10/26/2021] [Indexed: 01/04/2023] Open
Abstract
The Hippo-YAP signaling pathway serves roles in cell proliferation, stem cell renewal/maintenance, differentiation and apoptosis. Many of its functions are central to early development, adult tissue repair/regeneration and not surprisingly, tumorigenesis and metastasis. The Hippo pathway represses the activity of YAP and paralog TAZ by modulating cell proliferation and promoting differentiation to maintain tissue homeostasis and proper organ size. Similarly, master regulators of development RUNX transcription factors have been shown to play critical roles in proliferation, differentiation, apoptosis and cell fate determination. In this review, we discuss the multiple interactions of RUNX with the Hippo-YAP pathway, their shared collaborators in Wnt, TGFβ, MYC and RB pathways, and their overlapping functions in development and tumorigenesis.
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Affiliation(s)
| | - Yoshiaki Ito
- NUS Centre for Cancer Research, Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, #12-01, Singapore 117599, Singapore
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30
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Guo Z, Zhou K, Wang Q, Huang Y, Ji J, Peng Y, Zhang X, Zheng T, Zhang Z, Chong D, Yang Z. The transcription factor RUNX2 fuels YAP1 signaling and gastric cancer tumorigenesis. Cancer Sci 2021; 112:3533-3544. [PMID: 34160112 PMCID: PMC8409423 DOI: 10.1111/cas.15045] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 12/12/2022] Open
Abstract
Despite considerable efforts in the detection and treatment of gastric cancer (GC), the underlying mechanism of the progression of GC remains unknown. Our previous work has demonstrated the remarkable role of Runt‐related transcription factor 2 (RUNX2), in fueling the invasion and metastasis of GC. The present study aimed to elucidate the role of RUNX2 in tumorigenesis of GC. We assessed Runx2 expression and its clinical significance via bioinformatic analysis of the Cancer Genome Atlas and Gene Expression Omnibus databases. Roles for Runx2 in self‐renewal and tumorigenesis were examined in vitro and in vivo. Further bioinformatic analysis was applied to study the mechanism of GC progression. We found that Runx2 was highly expressed in the early stage of GC and positively correlated with a poor clinical outcome of patients. Runx2 was also significantly correlated with clinicopathological features, such as Hp infection, new neoplastic events, primary therapeutic outcome, ethnicity, race, and tumor stage. Multivariate analysis revealed that together with Runx2, age, cancer status, M stage, and T stage were independent prognostic factors for the outcome of GC patients. RUNX2 overexpression induced increased anchorage‐independent colony formation, sphere formation, and tumorigenesis in GC cells in vitro and in vivo. Mechanistically, bioinformatic analysis indicated that yes1 associated transcriptional regulator (YAP1) might be a downstream target of RUNX2. Specific knockdown of YAP1 reduced the tumor‐initiating ability of GC cells induced by ectopic Runx2 expression. Our findings support the hypothesis that RUNX2 exerts oncogenic properties via YAP1 regulation, highlighting essential roles for RUNX2 and YAP1 in gastric carcinogenesis and suggesting potential therapeutic targets.
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Affiliation(s)
- Zhengjun Guo
- Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Kai Zhou
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Qiang Wang
- Pathology Department, Navy 971 Hospital of PLA, Qindao, China
| | - Yusheng Huang
- Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jia Ji
- Department of Neurosurgery, Chongqing University Cancer Hospital, Chongqing, China
| | - Yuan Peng
- Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoyue Zhang
- Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Taihao Zheng
- Department of Oncology, Yongchuan Hospital of Chongqing Medical University, Chongqing, China
| | - Zhen Zhang
- Department of Plastic and Aesthetic Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Daochen Chong
- Pathology Department, Navy 971 Hospital of PLA, Qindao, China
| | - Zhenzhou Yang
- Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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