|
1
|
Wang T, Zhang M, Gong X, Chen W, Peng Y, Liao C, Xu H, Li Q, Shen G, Ren H, Zhu Y, Zhang B, Mao J, Wei L, Chen Y, Yang X. Inhibition of Nogo-B reduces the progression of pancreatic cancer by regulation NF-κB/GLUT1 and SREBP1 pathways. iScience 2024; 27:109741. [PMID: 38706871 PMCID: PMC11068639 DOI: 10.1016/j.isci.2024.109741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 01/22/2024] [Accepted: 04/10/2024] [Indexed: 05/07/2024] Open
Abstract
Pancreatic cancer (PC) is a lethal disease and associated with metabolism dysregulation. Nogo-B is related to multiple metabolic related diseases and types of cancers. However, the role of Nogo-B in PC remains unknown. In vitro, we showed that cell viability and migration was largely reduced in Nogo-B knockout or knockdown cells, while enhanced by Nogo-B overexpression. Consistently, orthotopic tumor and metastasis was reduced in global Nogo knockout mice. Furthermore, we indicated that glucose enhanced cell proliferation was associated to the elevation expression of Nogo-B and nuclear factor κB (NF-κB). While, NF-κB, glucose transporter type 1 (GLUT1) and sterol regulatory element-binding protein 1 (SREBP1) expression was reduced in Nogo-B deficiency cells. In addition, we showed that GLUT1 and SREBP1 was downstream target of NF-κB. Therefore, we demonstrated that Nogo deficiency inhibited PC progression is regulated by the NF-κB/GLUT1 and SREBP1 pathways, and suggested that Nogo-B may be a target for PC therapy.
Collapse
Affiliation(s)
- Tianxiang Wang
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230000, China
| | - Min Zhang
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230000, China
| | - Xinyu Gong
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230000, China
| | - Wanjing Chen
- Department of General Surgery, The Second Affiliated Hospital, Anhui Medical University, Hefei 230000, China
| | - Ying Peng
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230000, China
| | - Chenzhong Liao
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230000, China
| | - Hongmei Xu
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230000, China
| | - Qingshan Li
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230000, China
| | - Guodong Shen
- Department of Geriatrics, The First Affiliated Hospital of University of Science and Technology of China, Gerontology Institute of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230000, China
| | - Huirong Ren
- Department of Geriatrics, The First Affiliated Hospital of University of Science and Technology of China, Gerontology Institute of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230000, China
| | - Yaxin Zhu
- Institute for International Health Professions Education and Research, China Medical University, Shenyang 110000, China
| | - Baotong Zhang
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, Shenzhen 518000, China
| | - Jiali Mao
- Department of Anesthesiology, The First Affiliated Hospital of University of Science and Technology of China, Hefei 230000, China
| | - Lingling Wei
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230000, China
| | - Yuanli Chen
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230000, China
| | - Xiaoxiao Yang
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230000, China
| |
Collapse
|
|
2
|
Ruiz CF, Garcia C, Jacox JB, Lawres L, Muzumdar MD. Decoding the obesity-cancer connection: lessons from preclinical models of pancreatic adenocarcinoma. Life Sci Alliance 2023; 6:e202302228. [PMID: 37648285 PMCID: PMC10474221 DOI: 10.26508/lsa.202302228] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/15/2023] [Accepted: 08/21/2023] [Indexed: 09/01/2023] Open
Abstract
Obesity is a metabolic state of energy excess and a risk factor for over a dozen cancer types. Because of the rising worldwide prevalence of obesity, decoding the mechanisms by which obesity promotes tumor initiation and early progression is a societal imperative and could broadly impact human health. Here, we review results from preclinical models that link obesity to cancer, using pancreatic adenocarcinoma as a paradigmatic example. We discuss how obesity drives cancer development by reprogramming the pretumor or tumor cell and its micro- and macro-environments. Specifically, we describe evidence for (1) altered cellular metabolism, (2) hormone dysregulation, (3) inflammation, and (4) microbial dysbiosis in obesity-driven pancreatic tumorigenesis, denoting variables that confound interpretation of these studies, and highlight remaining gaps in knowledge. Recent advances in preclinical modeling and emerging unbiased analytic approaches will aid in further unraveling the complex link between obesity and cancer, informing novel strategies for prevention, interception, and therapy in pancreatic adenocarcinoma and other obesity-associated cancers.
Collapse
Affiliation(s)
- Christian F Ruiz
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- Yale Cancer Biology Institute, Yale University, West Haven, CT, USA
| | - Cathy Garcia
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- Yale Cancer Biology Institute, Yale University, West Haven, CT, USA
| | - Jeremy B Jacox
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- Yale Cancer Biology Institute, Yale University, West Haven, CT, USA
- Department of Medicine (Section of Medical Oncology), Yale University School of Medicine, New Haven, CT, USA
| | - Lauren Lawres
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Mandar D Muzumdar
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- Yale Cancer Biology Institute, Yale University, West Haven, CT, USA
- Department of Medicine (Section of Medical Oncology), Yale University School of Medicine, New Haven, CT, USA
- Yale Cancer Center, Yale University, New Haven, CT, USA
| |
Collapse
|
|
3
|
Bocian-Jastrzębska A, Malczewska-Herman A, Rosiek V, Kos-Kudła B. Assessment of the Role of Leptin and Adiponectinas Biomarkers in Pancreatic Neuroendocrine Neoplasms. Cancers (Basel) 2023; 15:3517. [PMID: 37444627 DOI: 10.3390/cancers15133517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/23/2023] [Accepted: 07/04/2023] [Indexed: 07/15/2023] Open
Abstract
Data on the possible connection between circulating adipokines and PanNENs are limited. This novel study aimed to assess the serum levels of leptin and adiponectin and their ratio in patients with PanNENs and to evaluate the possible relationship between them and PanNEN's grade or stage, including the presence of metastases. The study group consisted of PanNENs (n = 83), and healthy controls (n = 39). Leptin and adiponectin measurement by an ELISA assay was undertaken in the entire cohort. The serum concentration of adiponectin was significantly higher in the control group compared to the study group (p < 0.001). The concentration of leptin and adiponectin was significantly higher in females than in males (p < 0.01). Anincreased leptin-adiponectin ratio was observed in well-differentiated PanNENs (G1) vs. moderatelydifferentiated PanNENs (G2) (p < 0.05). An increased leptin-adiponectin ratio was found in PanNENs with Ki-67 < 3% vs. Ki-67 ≥ 3% (p < 0.05). PanNENs with distal disease presented lower leptin levels (p < 0.001) and a decreased leptin-adiponectin ratio (p < 0.01) compared with the localized disease group. Leptin, adiponectin, and the leptin-adiponectin ratio may serve as potential diagnostic, prognostic, and predictive biomarkers for PanNENs. Leptin levels and the leptin-adiponectin ratio may play an important role as predictors of malignancy and metastasis in PanNENs.
Collapse
Affiliation(s)
- Agnes Bocian-Jastrzębska
- Department of Endocrinology and Neuroendocrine Tumors, Department of Pathophysiology and Endocrinogy, Medical University of Silesia, 40-514 Katowice, Poland
| | - Anna Malczewska-Herman
- Department of Endocrinology and Neuroendocrine Tumors, Department of Pathophysiology and Endocrinogy, Medical University of Silesia, 40-514 Katowice, Poland
| | - Violetta Rosiek
- Department of Endocrinology and Neuroendocrine Tumors, Department of Pathophysiology and Endocrinogy, Medical University of Silesia, 40-514 Katowice, Poland
| | - Beata Kos-Kudła
- Department of Endocrinology and Neuroendocrine Tumors, Department of Pathophysiology and Endocrinogy, Medical University of Silesia, 40-514 Katowice, Poland
| |
Collapse
|
|
4
|
The Expression and Role Analysis of Methylation-Regulated Differentially Expressed Gene UBE2C in Pan-Cancer, Especially for HGSOC. Cancers (Basel) 2022; 14:cancers14133121. [PMID: 35804892 PMCID: PMC9264902 DOI: 10.3390/cancers14133121] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 06/22/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary DNA methylation has attracted a great deal of scientific interest as an early biomarker and potential therapeutic target. HGSOC result in high mortality due to the absence of reliable biomarkers for early diagnosis and prognosis. In this study, we performed an integrated bioinformatic analysis and found that UBE2C was hypomethylation and overexpression in ovarian cancer, which was associated with advanced cancer stages and poor prognoses. Meantime, this finding was also confirmed in pan-cancer analysis. Furthermore, the experimental validation of the expression and role of UBE2C was performed on HGSOC tissues and cancer cell lines. Importantly, demethylation could upregulate the expression of UBE2C. Taken together, methylation-regulated UBE2C may be a novel biomarker for diagnosis and prognosis, not only for ovarian cancer but a variety of cancers. Abstract High-grade serous ovarian cancer (HGSOC) is the most fatal gynecological malignant tumor. DNA methylation is associated with the occurrence and development of a variety of tumor types, including HGSOC. However, the signatures regarding DNA methylation changes for HGSOC diagnosis and prognosis are less explored. Here, we screened differentially methylated genes and differentially expressed genes in HGSOC through the GEO database. We identified that UBE2C was hypomethylation and overexpression in ovarian cancer, which was associated with more advanced cancer stages and poor prognoses. Additionally, the pan-cancer analysis showed that UBE2C was overexpressed and hypomethylation in almost all cancer types and was related to poor prognoses for various cancers. Next, we established a risk or prognosis model related to UBE2C methylation sites and screened out the three sites (cg03969725, cg02838589, and cg00242976). Furthermore, we experimentally validated the overexpression of UBE2C in HGSOC clinical samples and ovarian cell lines using quantitative real-time PCR, Western blot, and immunohistochemistry. Importantly, we discovered that ovarian cancer cell lines had lower DNA methylation levels of UBE2C than IOSE-80 cells (normal ovarian epithelial cell line) by bisulfite sequencing PCR. Consistently, treatment with 5-Azacytidine (a methylation inhibitor) was able to restore the expression of UBE2C. Taken together, our study may help us to understand the underlying molecular mechanism of UBE2C in pan-cancer tumorigenesis; it may be a useful biomarker for diagnosis, treatment, and monitoring, not only of ovarian cancer but a variety of cancers.
Collapse
|
|
5
|
Xia T, Meng L, Zhao Z, Li Y, Wen H, Sun H, Zhang T, Wei J, Li F, Liu C. Bioinformatics prediction and experimental verification identify MAD2L1 and CCNB2 as diagnostic biomarkers of rhabdomyosarcoma. Cancer Cell Int 2021; 21:634. [PMID: 34838000 PMCID: PMC8626952 DOI: 10.1186/s12935-021-02347-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 11/16/2021] [Indexed: 12/19/2022] Open
Abstract
Background Rhabdomyosarcoma (RMS) is a malignant soft-tissue tumour. In recent years, the tumour microenvironment (TME) has been reported to be associated with the development of tumours. However, the relationship between the occurrence and development of RMS and TME is unclear. The purpose of this study is to identify potential tumor microenvironment-related biomarkers in rhabdomyosarcoma and analyze their molecular mechanisms, diagnostic and prognostic significance. Methods We first applied bioinformatics method to analyse the tumour samples of 125 patients with rhabdomyosarcoma (RMS) from the Gene Expression Omnibus database (GEO). Differential genes (DEGs) that significantly correlate with TME and the clinical staging of tumors were extracted. Immunohistochemistry (IHC) was applied to validate the expression of mitotic arrest deficient 2 like 1 (MAD2L1) and cyclin B2 (CCNB2) in RMS tissue. Then, we used cell function and molecular biology techniques to study the influence of MAD2L1 and CCNB2 expression levels on the progression of RMS. Results Bioinformatics results show that the RMS TME key genes were screened, and a TME-related tumour clinical staging model was constructed. The top 10 hub genes were screened through the establishment of a protein–protein interaction (PPI) network, and then Gene Expression Profiling Interactive Analysis (GEPIA) was conducted to measure the overall survival (OS) of the 10 hub genes in the sarcoma cases in The Cancer Genome Atlas (TCGA). Six DEGs of statistical significance were acquired. The relationship between these six differential genes and the clinical stage of RMS was analysed. Further analysis revealed that the OS of RMS patients with high expression of MAD2L1 and CCNB2 was worse and the expression of MAD2L1 and CCNB2 was related to the clinical stage of RMS patients. Gene set enrichment analysis (GSEA) revealed that the genes in MAD2L1 and CCNB2 groups with high expression were mainly related to the mechanism of tumour metastasis and recurrence. In the low-expression MAD2L1 and CCNB2 groups, the genes were enriched in the metabolic and immune pathways. Immunohistochemical results also confirmed that the expression levels of MAD2L1 (30/33, 87.5%) and CCNB2 (33/33, 100%) were remarkably higher in RMS group than in normal control group (0/11, 0%). Moreover, the expression of CCNB2 was related to tumour size. Downregulation of MAD2L1 and CCNB2 suppressed the growth, invasion, migration, and cell cycling of RMS cells and promoted their apoptosis. The CIBERSORT immune cell fraction analysis indicated that the expression levels of MAD2L1 and CCNB2 affected the immune status in the TME. Conclusions The expression levels of MAD2L1 and CCNB2 are potential indicators of TME status changes in RMS, which may help guide the prognosis of patients with RMS and the clinical staging of tumours.
Collapse
Affiliation(s)
- Tian Xia
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, 832002, China
| | - Lian Meng
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, 832002, China
| | - Zhijuan Zhao
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, 832002, China
| | - Yujun Li
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, 832002, China
| | - Hao Wen
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, 832002, China
| | - Hao Sun
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, 832002, China
| | - Tiantian Zhang
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, 832002, China
| | - Jingxian Wei
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, 832002, China
| | - Feng Li
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, 832002, China. .,Department of Pathology and Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China.
| | - Chunxia Liu
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, 832002, China. .,Department of Pathology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China.
| |
Collapse
|