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1
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Hu JJ, Zhang QY, Yang ZC. The correlation between obesity and the occurrence and development of breast cancer. Eur J Med Res 2025; 30:419. [PMID: 40414892 DOI: 10.1186/s40001-025-02659-4] [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: 03/01/2025] [Accepted: 05/04/2025] [Indexed: 05/27/2025] Open
Abstract
This study reviews the mechanisms by which obesity affects the development and progression of breast cancer (BC). The association between obesity and BC is mainly due to three aspects: disruption of glycolipid metabolism, abnormal cell function and imbalance of adipokine levels. The dysregulation of glycolipid metabolism caused by obesity, including the accumulation of cholesterol and fatty acids and the reprogramming of glucose metabolism, promotes the growth and invasion of tumour cells. Obesity triggers multiple cellular abnormalities, particularly in lipid-associated macrophages and cancer-associated adipocytes, which promote tumour progression and immunosuppression by secreting inflammatory factors and various fatty acids into the tumour microenvironment. Obesity leads to an imbalance in the expression of several adipokines. Leptin upregulation is closely associated with BC metastasis and resistance to endocrine therapy, while reduced adiponectin levels attenuate the protective effect. At the same time, chronic inflammation and insulin resistance not only further increase the risk of BC, but also exacerbate tumour resistance. In terms of treatment, weight-loss drugs and metformin can improve the efficacy of obesity-related BC treatment to some extent. Intervention strategies targeting adipose tissue remodelling, lipid metabolism and leptin regulation also show potential clinical value, but more research is needed to clarify their safety and efficacy. This review provides systematic ideas and references for research into the mechanisms and clinical management of obesity-related BC.
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Affiliation(s)
- Jun-Jie Hu
- Hunan University of Traditional Chinese Medicine, Changsha, 410078, China
| | - Qi-Yue Zhang
- Hunan University of Traditional Chinese Medicine, Changsha, 410078, China
| | - Zhi-Chun Yang
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.
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2
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Xu M, Pan G, Zhang Q, Huang J, Wu Y, Ashan Y. FOXM1 boosts glycolysis by upregulating SQLE to inhibit anoikis in breast cancer cells. J Cancer Res Clin Oncol 2025; 151:162. [PMID: 40360780 PMCID: PMC12075401 DOI: 10.1007/s00432-025-06174-1] [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: 12/03/2024] [Accepted: 03/15/2025] [Indexed: 05/15/2025]
Abstract
BACKGROUND Resisting anoikis is a prerequisite for cancer to spread and invade and a major cause of cancer-related deaths. Yet, the intricate mechanisms of how cancer cells evade anoikis remain largely unknown. There is a significant need to explore how these mechanisms play out in breast cancer (BC). METHODS Bioinformatics analysis revealed the expression levels of SQLE and FOXM1 in BC tissue, along with their correlation. The enrichment pathways of SQLE were also explored. qPCR detected the expression of SQLE and FOXM1 in BC cells. CCK-8 assessed cell viability, while flow cytometry measured anoikis. Western blot was employed to examine the protein expression of key genes in glycolytic metabolism and apoptosis-related proteins. Extracellular acidification rate was quantified, and corresponding kits evaluated glucose consumption, lactate production, and adenosine triphosphate levels in cells. Dual-luciferase reporter assays and chromatin immunoprecipitation tests unveiled the binding relationship between FOXM1 and SQLE. RESULTS SQLE was found to be highly expressed in BC and enriched in pathways associated with anoikis and glycolysis. SQLE curbed anoikis in BC via the aerobic glycolysis pathway. There was also a direct binding between FOXM1 and SQLE and a positive correlation between their expression. Recovery experiments substantiated that FOXM1 targeted SQLE to suppress anoikis in BC cells. CONCLUSION FOXM1 upregulates SQLE, which in turn mediates glycolysis to suppress anoikis in BC. The FOXM1/SQLE axis is a promising therapeutic target for BC treatment.
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Affiliation(s)
- Mei Xu
- Radiotherapy Department of Changji Hui Autonomous Prefecture People's Hospital, No. 303 Yan'an North Road, Changji City, Xinjiang Province, 831100, China.
| | - Guozhi Pan
- Cardiothoracic Surgery Department, Changji Hui Autonomous Prefecture People's Hospital, Changji, China
| | - Qian Zhang
- Radiotherapy Department of Changji Hui Autonomous Prefecture People's Hospital, No. 303 Yan'an North Road, Changji City, Xinjiang Province, 831100, China
| | - Jiangming Huang
- Department of Surgical Oncology, Changji People's Hospital, Changji, China
| | - Yehua Wu
- General Surgery Department of Changji Hui Autonomous Prefecture People's Hospital, Changji, China
| | - Yashengjiang Ashan
- Radiotherapy Department of Changji Hui Autonomous Prefecture People's Hospital, No. 303 Yan'an North Road, Changji City, Xinjiang Province, 831100, China
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3
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Wan M, Pan S, Shan B, Diao H, Jin H, Wang Z, Wang W, Han S, Liu W, He J, Zheng Z, Pan Y, Han X, Zhang J. Lipid metabolic reprograming: the unsung hero in breast cancer progression and tumor microenvironment. Mol Cancer 2025; 24:61. [PMID: 40025508 PMCID: PMC11874147 DOI: 10.1186/s12943-025-02258-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 02/02/2025] [Indexed: 03/04/2025] Open
Abstract
Aberrant lipid metabolism is a well-recognized hallmark of cancer. Notably, breast cancer (BC) arises from a lipid-rich microenvironment and depends significantly on lipid metabolic reprogramming to fulfill its developmental requirements. In this review, we revisit the pivotal role of lipid metabolism in BC, underscoring its impact on the progression and tumor microenvironment. Firstly, we delineate the overall landscape of lipid metabolism in BC, highlighting its roles in tumor progression and patient prognosis. Given that lipids can also act as signaling molecules, we next describe the lipid signaling exchanges between BC cells and other cellular components in the tumor microenvironment. Additionally, we summarize the therapeutic potential of targeting lipid metabolism from the aspects of lipid metabolism processes, lipid-related transcription factors and immunotherapy in BC. Finally, we discuss the possibilities and problems associated with clinical applications of lipid‑targeted therapy in BC, and propose new research directions with advances in spatiotemporal multi-omics.
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Affiliation(s)
- Mengting Wan
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Shuaikang Pan
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
- School of Medical Oncology, Wan Nan Medical College, Wuhu, Anhui, China
| | - Benjie Shan
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Haizhou Diao
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Hongwei Jin
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
- School of Medical Oncology, Anhui Medical University, Hefei, China
| | - Ziqi Wang
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Wei Wang
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
- School of Medical Oncology, Wan Nan Medical College, Wuhu, Anhui, China
| | - Shuya Han
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Wan Liu
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
| | - Jiaying He
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
- Graduate School of Bengbu Medical University, Bengbu, Anhui Province, China
| | - Zihan Zheng
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China
- School of Medical Oncology, Anhui Medical University, Hefei, China
| | - Yueyin Pan
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China.
| | - Xinghua Han
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China.
| | - Jinguo Zhang
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China.
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4
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Huang X, Liu B, Shen S. Lipid Metabolism in Breast Cancer: From Basic Research to Clinical Application. Cancers (Basel) 2025; 17:650. [PMID: 40002245 PMCID: PMC11852908 DOI: 10.3390/cancers17040650] [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: 01/23/2025] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
Breast cancer remains the most prevalent cancer among women globally, with significant links to obesity and lipid metabolism abnormalities. This review examines the role of lipid metabolism in breast cancer progression, highlighting its multifaceted contributions to tumor biology. We discuss key metabolic processes, including fatty acid metabolism, triglyceride metabolism, phospholipid metabolism, and cholesterol metabolism, detailing the reprogramming that occurs in these pathways within breast cancer cells. Alterations in lipid metabolism are emphasized for their roles in supporting energy production, membrane biogenesis, and tumor aggressiveness. Furthermore, we examine how lipid metabolism influences immune responses in the tumor microenvironment, affecting immune cell function and therapeutic efficacy. The potential of lipid metabolism as a target for novel therapeutic strategies is also addressed, with a focus on inhibitors of key metabolic enzymes. By integrating lipid metabolism with breast cancer research, this review underscores the importance of lipid metabolism in understanding breast cancer biology and developing treatment approaches aimed at improving patient outcomes.
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Affiliation(s)
- Xiangyu Huang
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100032, China; (X.H.); (B.L.)
- School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Bowen Liu
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100032, China; (X.H.); (B.L.)
| | - Songjie Shen
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100032, China; (X.H.); (B.L.)
- Ambulatory Medical Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100032, China
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5
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Zhu J, Wang Y, Zhu K, Zhang C. Advances in understanding the role of squalene epoxidase in cancer prognosis and resistance. Mol Biol Rep 2025; 52:162. [PMID: 39869140 DOI: 10.1007/s11033-025-10276-x] [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: 10/23/2024] [Accepted: 01/20/2025] [Indexed: 01/28/2025]
Abstract
Recently, there has been burgeoning interest in the involvement of cholesterol metabolism in cancer. Squalene epoxidase (SQLE), as a critical rate-limiting enzyme in the cholesterol synthesis pathway, has garnered attention due to its overexpression in various cancer types, thereby significantly impacting tumor prognosis and resistance mechanisms. Firstly, SQLE contributes to unfavorable prognosis through diverse mechanisms, encompassing modulation of the PI3K/AKT signaling pathway, manipulation of the cancer microenvironment, and participation in ferroptosis. Secondly, directing efforts towards targeting SQLE, via mechanisms such as the PI3K/AKT pathway, presents promising avenues for overcoming resistance to conventional therapies such as endocrine cancer therapy, chemotherapy, immunotherapy, or radiotherapy. Moreover, the effectiveness of SQLE protein inhibitors in impeding cancer progression may either depend directly on SQLE inhibition or function through alternative pathways separate from SQLE. This mini-review offers insights into the intricate mechanisms through which SQLE affects the prognosis and resistance profiles across diverse cancer types, while succinctly elucidating the mechanisms underpinning the anticancer effects of SQLE protein inhibitors. Furthermore, this mini-review underscores the necessity for further investigations into the interplay between SQLE and cancer, proposing potential avenues for future research, with the aim of serving as a reference for exploring the mechanisms governing the role of SQLE in cancer regulation.
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Affiliation(s)
- Jiazhuang Zhu
- Department of Orthopedic Surgery, Institute of Bone Tumor, Shanghai Tenth People's Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai, 200092, China
| | - Yongjie Wang
- Department of Orthopedic Surgery, Institute of Bone Tumor, Shanghai Tenth People's Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai, 200092, China
| | - Kunpeng Zhu
- Department of Orthopedic Surgery, Institute of Bone Tumor, Shanghai Tenth People's Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai, 200092, China.
| | - Chunlin Zhang
- Department of Orthopedic Surgery, Institute of Bone Tumor, Shanghai Tenth People's Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai, 200092, China.
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6
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Mo JS, Lamichhane S, Sharma G, Chae SC. MicroRNA 133A Regulates Squalene Epoxidase Expression in Colorectal Cancer Cells to Control Cell Proliferation and Cholesterol Production. GASTROENTEROLOGY INSIGHTS 2025; 16:5. [DOI: 10.3390/gastroent16010005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/01/2025] Open
Abstract
Background/Objectives: Colorectal cancer (CRC) is one of the most common cancers worldwide, with high incidence and mortality rates. MicroRNAs are endogenous and non-coding RNAs that play a pivotal role in the development and progression of various cancers by targeting specific genes. Previously, we identified MIR133A to be significantly decreased in human CRC tissues. This study aims to identify the relationship with SQLE, one of the candidate target genes of MIR133A, and study their interaction in CRC cells. Methods: Through the luciferase reporter assay, quantitative RT-PCR (qRT-PCR), and Western blot analysis. Results: We identified SQLE as a direct target gene of MIR133A. Using the MIR133A KI cell lines, which knocked-in MIR133A1 or MIR133A2 in CRC cell lines, and CRC cells transfected with siSQLE, we found that MIR133A regulated the proliferation and migration of CRC cells by modulating SQLE-mediated PIK3CA-AKT1 and CYP24A1 signaling. We also found that cholesterol production was regulated by MIR133A in CRC cells. Conclusions: Our results suggest that MIR133A is an important therapeutic target for colorectal cancer.
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Affiliation(s)
- Ji-Su Mo
- Department of Pathology, School of Medicine, Wonkwang University, Iksan, Chonbuk 54538, Republic of Korea
- Digestive Disease Research Institute, Wonkwang University, Iksan, Chonbuk 54538, Republic of Korea
| | - Santosh Lamichhane
- Department of Pathology, School of Medicine, Wonkwang University, Iksan, Chonbuk 54538, Republic of Korea
- Department of Interdisciplinary Oncology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Grinsun Sharma
- Department of Pathology, School of Medicine, Wonkwang University, Iksan, Chonbuk 54538, Republic of Korea
- School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA
| | - Soo-Cheon Chae
- Department of Pathology, School of Medicine, Wonkwang University, Iksan, Chonbuk 54538, Republic of Korea
- Digestive Disease Research Institute, Wonkwang University, Iksan, Chonbuk 54538, Republic of Korea
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7
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Ebrahimi A, Barati T, Mirzaei Z, Fattahi F, Mansoori Derakhshan S, Shekari Khaniani M. An overview on the interaction between non-coding RNAs and CTLA-4 gene in human diseases. Med Oncol 2024; 42:13. [PMID: 39585522 DOI: 10.1007/s12032-024-02552-w] [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: 07/07/2024] [Accepted: 10/29/2024] [Indexed: 11/26/2024]
Abstract
Cytotoxic T lymphocyte antigen 4 (CTLA-4), in conjunction with PD-1 and CD28, plays a pivotal role in the modulation of T-cell activation. Specifically, CTLA-4 exerts its influence by impeding the generation of IL-2 and the proliferation of T cells. CTLA-4, being a receptor with a high affinity, engages in competitive binding with CD28 for the interaction with primary T-cell activator molecules, specifically CD80 and CD86. The appropriate functioning of T-cell activation is contingent upon maintaining a precise equilibrium between CTLA-4 and CD28. Consequently, any disruption in the expression of CTLA-4 significantly enhances the risk for a range of severe ailments, such as cancer, infectious diseases, allergies, and notably autoimmune diseases. The significance of epigenetic regulation of CTLA-4, particularly through non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), has considerable weight within this particular framework. To date, there have been associations shown between various abnormalities in the expression of ncRNAs that regulate CTLA-4 and clinicopathological characteristics. Nevertheless, it is evident that there is a lack of a comprehensive investigation. Hence, the present work was undertaken to summarize the existing research on the epigenetic control of CTLA-4, with a primary emphasis on elucidating the regulatory procedures, biological processes, and clinical applications in human diseases. The objective of this review is to acquire a thorough comprehension of the relationship between RNA/lncRNA/miRNA/mRNA (CTLA-4) and its role in the progression of diverse human disorders.
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Affiliation(s)
- Amir Ebrahimi
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Genetics, Tabriz, Iran
| | - Tahereh Barati
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Genetics, Tabriz, Iran
| | - Zohreh Mirzaei
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Genetics, Tabriz, Iran
| | - Fatemeh Fattahi
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Genetics, Tabriz, Iran
| | - Sima Mansoori Derakhshan
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Genetics, Tabriz, Iran
| | - Mahmoud Shekari Khaniani
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Genetics, Tabriz, Iran.
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8
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Chen M, Yang Y, Chen S, He Z, Du L. Targeting squalene epoxidase in the treatment of metabolic-related diseases: current research and future directions. PeerJ 2024; 12:e18522. [PMID: 39588004 PMCID: PMC11587872 DOI: 10.7717/peerj.18522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 10/23/2024] [Indexed: 11/27/2024] Open
Abstract
Metabolic-related diseases are chronic diseases caused by multiple factors, such as genetics and the environment. These diseases are difficult to cure and seriously affect human health. Squalene epoxidase (SQLE), the second rate-limiting enzyme in cholesterol synthesis, plays an important role in cholesterol synthesis and alters the gut microbiota and tumor immunity. Research has shown that SQLE is expressed in many tissues and organs and is involved in the occurrence and development of various metabolic-related diseases, such as cancer, nonalcoholic fatty liver disease, diabetes mellitus, and obesity. SQLE inhibitors, such as terbinafine, NB598, natural compounds, and their derivatives, can effectively ameliorate fungal infections, nonalcoholic fatty liver disease, and cancer. In this review, we provide an overview of recent research progress on the role of SQLE in metabolic-related diseases. Further research on the regulation of SQLE expression is highly important for developing drugs for the treatment of metabolic-related diseases with good pharmacological activity.
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Affiliation(s)
- Mingzhu Chen
- School of Basic Medical Sciences, Chengdu University of Chinese Medicine, Chengdu, Sichuan Province, China
| | - Yongqi Yang
- Harbin Medical University, Department of Pharmacology, College of Pharmacy, Harbin, Heilongjiang Province, China
| | - Shiting Chen
- School of Basic Medical Sciences, Chengdu University of Chinese Medicine, Chengdu, Sichuan Province, China
| | - Zhigang He
- School of Basic Medical Sciences, Chengdu University of Chinese Medicine, Chengdu, Sichuan Province, China
| | - Lian Du
- School of Basic Medical Sciences, Chengdu University of Chinese Medicine, Chengdu, Sichuan Province, China
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9
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Jia W, Yu L, Xu B, Feng Y, Wang J, Zhu D, Xu C, Liang L, Zhou Y, Kong L, Ding W. HNF4A-AS1 inhibits the progression of hepatocellular carcinoma by promoting the ubiquitin-modulated degradation of PCBP2 and suppressing the stability of ARG2 mRNA. Int J Biol Sci 2024; 20:5087-5108. [PMID: 39430249 PMCID: PMC11488582 DOI: 10.7150/ijbs.95276] [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: 02/13/2024] [Accepted: 09/06/2024] [Indexed: 10/22/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor with a poor prognosis. Extensive research has revealed the significant role of long noncoding RNAs (lncRNAs) in the regulation of tumor development. In this study, high-throughput sequencing analysis was used to assess the expression levels of lncRNAs in three pairs of HCC tissues and their corresponding noncancerous tissues. Through quantitative real-time polymerase chain reaction (qRT-PCR) analysis and clinicopathological analysis, it was discovered that HNF4A-AS1 was downregulated in HCC tissues. Furthermore, its expression levels were found to be positively correlated with the prognosis of HCC patients. Subsequent in vitro and in vivo functional studies demonstrated that HNF4A-AS1 inhibits the proliferation, invasion, and stemness of HCC cells. Mechanistically, it was observed that HNF4A-AS1 physically interacts with the KH3 domain of PCBP2 through a specific segment (491-672 nt). This interaction facilitates the recruitment of PCBP2 by AIP4, leading to the ubiquitination and subsequent degradation of PCBP2. Furthermore, HNF4A-AS1 was found to regulate the stability of AGR2 mRNA by modulating PCBP2, thereby influencing the malignant phenotype of HCC. Overall, our study demonstrated a positive association between the decrease in HNF4A-AS1 expression and the prognosis of patients with HCC in a clinical setting. HNF4A-AS1 can suppress the stability of ARG2 mRNA by promoting the ubiquitin-modulated degradation of PCBP2, which suppresses HCC progression. HNF4A-AS1 may serve as a potential therapeutic target for HCC.
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MESH Headings
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Humans
- Liver Neoplasms/metabolism
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- RNA-Binding Proteins/metabolism
- RNA-Binding Proteins/genetics
- Hepatocyte Nuclear Factor 4/metabolism
- Hepatocyte Nuclear Factor 4/genetics
- RNA, Long Noncoding/metabolism
- RNA, Long Noncoding/genetics
- Male
- RNA, Messenger/metabolism
- RNA, Messenger/genetics
- Cell Line, Tumor
- Female
- Ubiquitin/metabolism
- Gene Expression Regulation, Neoplastic
- Animals
- Middle Aged
- Mice
- Disease Progression
- Cell Proliferation/genetics
- RNA Stability
- Mice, Nude
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Affiliation(s)
- Wenbo Jia
- Hepatobiliary Centre, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission (NHC) Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Liang Yu
- Department of General Surgery, the Second Affiliated Hospital of Anhui Medical University, China
| | - Bin Xu
- Hepatobiliary Centre, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission (NHC) Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Yanzhi Feng
- Hepatobiliary Centre, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission (NHC) Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Jinyi Wang
- Hepatobiliary Centre, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission (NHC) Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Deming Zhu
- Hepatobiliary Centre, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission (NHC) Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Chao Xu
- Hepatobiliary Centre, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission (NHC) Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Litao Liang
- Hepatobiliary Centre, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission (NHC) Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Yongping Zhou
- Department of Hepatobiliary, Jiangnan University Medical Center, JUMC, China
| | - Lianbao Kong
- Hepatobiliary Centre, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission (NHC) Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Wenzhou Ding
- Hepatobiliary Centre, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission (NHC) Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China
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10
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Mao X, Wang L, Chen Z, Huang H, Chen J, Su J, Li Z, Shen G, Ren Y, Li Z, Wang W, Ou J, Guo W, Hu Y. SCD1 promotes the stemness of gastric cancer stem cells by inhibiting ferroptosis through the SQLE/cholesterol/mTOR signalling pathway. Int J Biol Macromol 2024; 275:133698. [PMID: 38972654 DOI: 10.1016/j.ijbiomac.2024.133698] [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: 10/06/2023] [Revised: 07/03/2024] [Accepted: 07/04/2024] [Indexed: 07/09/2024]
Abstract
Cancer stem cells (CSCs) play a substantial role in cancer onset and recurrence. Anomalous iron and lipid metabolism have been documented in CSCs, suggesting that ferroptosis, a recently discovered form of regulated cell death characterised by lipid peroxidation, could potentially exert a significant influence on CSCs. However, the precise role of ferroptosis in gastric cancer stem cells (GCSCs) remains unknown. To address this gap, we screened ferroptosis-related genes in GCSCs using The Cancer Genome Atlas and corroborated our findings through quantitative polymerase chain reaction and western blotting. These results indicate that stearoyl-CoA desaturase (SCD1) is a key player in the regulation of ferroptosis in GCSCs. This study provides evidence that SCD1 positively regulates the transcription of squalene epoxidase (SQLE) by eliminating transcriptional inhibition of P53. This mechanism increases the cholesterol content and the elevated cholesterol regulated by SCD1 inhibits ferroptosis via the mTOR signalling pathway. Furthermore, our in vivo studies showed that SCD1 knockdown or regulation of cholesterol intake affects the stemness of GCSCs and their sensitivity to ferroptosis inducers. Thus, targeting the SCD1/squalene epoxidase/cholesterol signalling axis in conjunction with ferroptosis inducers may represent a promising therapeutic approach for the treatment of gastric cancer based on GCSCs.
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Affiliation(s)
- Xinyuan Mao
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China
| | - Lingzhi Wang
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China
| | - Zhian Chen
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China
| | - Huilin Huang
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China
| | - Jialin Chen
- Hepatobiliary and Pancreatic Center, The First Affiliated Hospital, Sun Yat-sen University, 510515, PR China
| | - Jin Su
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China; Department of General Surgery, Zhuzhou Hospital affiliated to Xiangya School of Medicine, Central South University, Zhuzhou 412000, PR China
| | - Zhenhao Li
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China
| | - Guodong Shen
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China
| | - Yingxin Ren
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China
| | - Zhenyuan Li
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China
| | - Weisheng Wang
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China
| | - Jinzhou Ou
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China
| | - Weihong Guo
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China.
| | - Yanfeng Hu
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China.
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11
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Obaid Saleh R, Shbeer AM, Jetti R, Ahmed Robadi I, Hjazi A, Hussein Kareem A, Noori Shakir M, Qasim Alasheqi M, Alawadi A, Haslany A. Association between lncRNAs with stem cells in cancer; a particular focus on lncRNA-CSCs axis in cancer immunopathogenesis. Int Immunopharmacol 2024; 136:112306. [PMID: 38833843 DOI: 10.1016/j.intimp.2024.112306] [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: 04/02/2024] [Revised: 05/10/2024] [Accepted: 05/16/2024] [Indexed: 06/06/2024]
Abstract
A unique population of cells known as cancer stem cells (CSCs) is essential to developing and spreading cancer. Cancer initiation, maintenance, and progression are all believed to be significantly impacted by the distinct characteristics these cells exhibit regarding self-renewal, proliferation, and differentiation. Transcriptional, post-transcriptional, and translational processes are the only steps of gene expression that lncRNAs can affect. As a result, these proteins participate in numerous biological processes, including the repair of DNA damage, inflammatory reactions, metabolic control, the survival of cells, intercellular communication, and the development and specialization of cells. Studies have indicated that lncRNAs are important for controlling the increase in the subset of CSCs contributing to cancer development. The knowledge that is currently available about lncRNAs and their critical role in maintaining the biological properties of CSCs is highlighted in this study.
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Affiliation(s)
- Raed Obaid Saleh
- Department of Medical Laboratory Techniques, Al-Maarif University College, Al-Anbar, Iraq
| | - Abdullah M Shbeer
- Department of Surgery, Faculty of Medicine, Jazan University, Jazan, Saudi Arabia.
| | - Raghu Jetti
- Department of Basic Medical Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Ibrahim Ahmed Robadi
- Department of Pathology, Faculty of Medicine, Jazan University, Jazan, Saudi Arabia
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | | | - Maha Noori Shakir
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
| | | | - Ahmed Alawadi
- College of Technical Engineering, the Islamic University, Najaf, Iraq; College of Technical Engineering, the Islamic University of Al Diwaniyah, Iraq; College of Technical Engineering, the Islamic University of Babylon, Iraq
| | - Ali Haslany
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq
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12
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Duan Y, Yan Y, Fu H, Dong Y, Li K, Ye Z, Dou Y, Huang B, Kang W, Wei GH, Cai Q, Xu D, Zhou D. SNHG15-mediated feedback loop interplays with HNRNPA1/SLC7A11/GPX4 pathway to promote gastric cancer progression. Cancer Sci 2024; 115:2269-2285. [PMID: 38720175 PMCID: PMC11247605 DOI: 10.1111/cas.16181] [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: 01/13/2024] [Revised: 03/26/2024] [Accepted: 04/01/2024] [Indexed: 07/13/2024] Open
Abstract
Dysregulation of long noncoding RNA (lncRNA) expression plays a pivotal role in the initiation and progression of gastric cancer (GC). However, the regulation of lncRNA SNHG15 in GC has not been well studied. Mechanisms for ferroptosis by SNHG15 have not been revealed. Here, we aimed to explore SNHG15-mediated biological functions and underlying molecular mechanisms in GC. The novel SNHG15 was identified by analyzing RNA-sequencing (RNA-seq) data of GC tissues from our cohort and TCGA dataset, and further validated by qRT-PCR in GC cells and tissues. Gain- and loss-of-function assays were performed to examine the role of SNHG15 on GC both in vitro and in vivo. SNHG15 was highly expressed in GC. The enhanced SNHG15 was positively correlated with malignant stage and poor prognosis in GC patients. Gain- and loss-of-function studies showed that SNHG15 was required to affect GC cell growth, migration and invasion both in vitro and in vivo. Mechanistically, the oncogenic transcription factors E2F1 and MYC could bind to the SNHG15 promoter and enhance its expression. Meanwhile, SNHG15 increased E2F1 and MYC mRNA expression by sponging miR-24-3p. Notably, SNHG15 could also enhance the stability of SLC7A11 in the cytoplasm by competitively binding HNRNPA1. In addition, SNHG15 inhibited ferroptosis through an HNRNPA1-dependent regulation of SLC7A11/GPX4 axis. Our results support a novel model in which E2F1- and MYC-activated SNHG15 regulates ferroptosis via an HNRNPA1-dependent modulation of the SLC7A11/GPX4 axis, which serves as the critical effectors in GC progression, and provides a new therapeutic direction in the treatment of GC.
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Affiliation(s)
- Yantao Duan
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yonghao Yan
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hongbing Fu
- Department of Gastrointestinal Surgery, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Yang Dong
- Department of Breast Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Kun Li
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zaisheng Ye
- Department of Gastrointestinal Surgical Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China
| | - Yi Dou
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Binhao Huang
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China
| | - Gong-Hong Wei
- Fudan University Shanghai Cancer Center; MOE Key Laboratory of Metabolism and Molecular Medicine & Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Qiliang Cai
- MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infections Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Dazhi Xu
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Donglei Zhou
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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13
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Zhang W, Hou Y, Yin S, Miao Q, Lee K, Zhou X, Wang Y. Advanced gene nanocarriers/scaffolds in nonviral-mediated delivery system for tissue regeneration and repair. J Nanobiotechnology 2024; 22:376. [PMID: 38926780 PMCID: PMC11200991 DOI: 10.1186/s12951-024-02580-8] [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: 03/09/2024] [Accepted: 05/24/2024] [Indexed: 06/28/2024] Open
Abstract
Tissue regeneration technology has been rapidly developed and widely applied in tissue engineering and repair. Compared with traditional approaches like surgical treatment, the rising gene therapy is able to have a durable effect on tissue regeneration, such as impaired bone regeneration, articular cartilage repair and cancer-resected tissue repair. Gene therapy can also facilitate the production of in situ therapeutic factors, thus minimizing the diffusion or loss of gene complexes and enabling spatiotemporally controlled release of gene products for tissue regeneration. Among different gene delivery vectors and supportive gene-activated matrices, advanced gene/drug nanocarriers attract exceptional attraction due to their tunable physiochemical properties, as well as excellent adaptive performance in gene therapy for tissue regeneration, such as bone, cartilage, blood vessel, nerve and cancer-resected tissue repair. This paper reviews the recent advances on nonviral-mediated gene delivery systems with an emphasis on the important role of advanced nanocarriers in gene therapy and tissue regeneration.
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Affiliation(s)
- Wanheng Zhang
- Institute of Geriatrics, School of Medicine, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), Shanghai University, Shanghai, 200444, China
- Department of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Yan Hou
- Institute of Geriatrics, School of Medicine, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), Shanghai University, Shanghai, 200444, China
- Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education), Shanghai University, Shanghai, 200444, China
| | - Shiyi Yin
- Department of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Qi Miao
- Department of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Kyubae Lee
- Department of Biomedical Materials, Konyang University, Daejeon, 35365, Republic of Korea
| | - Xiaojian Zhou
- Department of Pediatrics, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200080, China.
| | - Yongtao Wang
- Institute of Geriatrics, School of Medicine, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), Shanghai University, Shanghai, 200444, China.
- Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education), Shanghai University, Shanghai, 200444, China.
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14
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Wang X, Zhong F, Chen T, Wang H, Wang W, Jin H, Li C, Guo X, Liu Y, Zhang Y, Li B. Cholesterol neutralized vemurafenib treatment by promoting melanoma stem-like cells via its metabolite 27-hydroxycholesterol. Cell Mol Life Sci 2024; 81:226. [PMID: 38775844 PMCID: PMC11111659 DOI: 10.1007/s00018-024-05267-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 04/14/2024] [Accepted: 05/05/2024] [Indexed: 05/25/2024]
Abstract
Vemurafenib has been used as first-line therapy for unresectable or metastatic melanoma with BRAFV600E mutation. However, overall survival is still limited due to treatment resistance after about one year. Therefore, identifying new therapeutic targets for melanoma is crucial for improving clinical outcomes. In the present study, we found that lowering intracellular cholesterol by knocking down DHCR24, the limiting synthetase, impaired tumor cell proliferation and migration and abrogated the ability to xenotransplant tumors. More importantly, administration of DHCR24 or cholesterol mediated resistance to vemurafenib and promoted the growth of melanoma spheroids. Mechanistically, we identified that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol synthesized by the enzyme cytochrome P450 27A1 (CYP27A1), reproduces the phenotypes induced by DHCR24 or cholesterol administration and activates Rap1-PI3K/AKT signaling. Accordingly, CYP27A1 is highly expressed in melanoma patients and upregulated by DHCR24 induction. Dafadine-A, a CYP27A1 inhibitor, attenuates cholesterol-induced growth of melanoma spheroids and abrogates the resistance property of vemurafenib-resistant melanoma cells. Finally, we confirmed that the effects of cholesterol on melanoma resistance require its metabolite 27HC through CYP27A1 catalysis, and that 27HC further upregulates Rap1A/Rap1B expression and increases AKT phosphorylation. Thus, our results suggest that targeting 27HC may be a useful strategy to overcome treatment resistance in metastatic melanoma.
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Affiliation(s)
- Xiaohong Wang
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-Related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
- College of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Feiliang Zhong
- Key Laboratory of Industrial Fermentation Microbiology of the Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, People's Republic of China
| | - Tingting Chen
- School of Basic Medicine, Guangdong Medical University, Dongguan, 523808, Guangdong, China
| | - Hongbo Wang
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-Related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
- College of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Weifang Wang
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-Related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
- College of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Hongkai Jin
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-Related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Chouyang Li
- College of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Xuan Guo
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-Related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
- College of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Ying Liu
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-Related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
- College of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Yu Zhang
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-Related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, Liaoning, China.
- College of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China.
| | - Bo Li
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-Related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, Liaoning, China.
- College of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China.
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15
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Li M, Kang S, Deng X, Li H, Zhao Y, Tang W, Sheng M. Erianin inhibits the progression of triple-negative breast cancer by suppressing SRC-mediated cholesterol metabolism. Cancer Cell Int 2024; 24:166. [PMID: 38734640 PMCID: PMC11088164 DOI: 10.1186/s12935-024-03332-2] [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: 12/12/2023] [Accepted: 04/18/2024] [Indexed: 05/13/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is highly malignant and lacks effective biotherapeutic targets. The development of efficient anticancer drugs with low toxicity and few side effects is a hotspot in TNBC treatment research. Although erianin is known to have potent antitumor activity, its regulatory mechanism and target in TNBC have not been fully elucidated, hampering further drug development. This study showed that erianin can significantly inhibit TNBC cell proliferation and migration, promote cell apoptosis, and inhibit the growth of transplanted tumors in mice. Mechanistically, through network pharmacology analysis, molecular docking and cellular thermal shift assays, we preliminarily identified SRC as the cellular target of erianin. Erianin potently inhibited the expression of SRC, which mediated the anticancer effect of erianin in TNBC. Moreover, erianin can downregulate the expression of genes related to cholesterol synthesis and uptake by targeting SRC, interfering with cholesterol levels in TNBC, thereby inhibiting the progression of TNBC in vivo and in vitro. Taken together, our results suggest that erianin may inhibit the progression of TNBC by suppressing SRC-mediated cholesterol metabolism, and erianin has the great potential to be an effective treatment for TNBC patients.
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Affiliation(s)
- Ming Li
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China
| | - Shiyao Kang
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China
| | - Xuming Deng
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China
| | - Huimin Li
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China
| | - Yuan Zhao
- Kunming University of Science and Technology Affiliated Puer City People's Hospital, Puer, Yunnan, 665000, China
| | - Wenru Tang
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China
| | - Miaomiao Sheng
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China.
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16
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Kong L, He Q, Ma D, Shi W, Xin Q, Jiang C, Wu J. Ezetimibe inhibits the migration and invasion of triple-negative breast cancer cells by targeting TGFβ2 and EMT. FEBS Open Bio 2024; 14:831-842. [PMID: 38531630 PMCID: PMC11073500 DOI: 10.1002/2211-5463.13797] [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: 09/16/2023] [Revised: 01/31/2024] [Accepted: 03/15/2024] [Indexed: 03/28/2024] Open
Abstract
The important role of cholesterol in tumor metastasis has been widely studied in recent years. Ezetimibe is currently the only selective cholesterol uptake inhibitor on the market. Here, we explored the effect of ezetimibe on breast cancer metastasis by studying its impact on breast cancer cell migration, invasion, and epithelial-mesenchymal transition (EMT). Differential gene expression analysis and validation were also carried out to compare ezetimibe-treated and untreated breast cancer cells. Finally, breast cancer cells overexpressing TGFβ2 were constructed, and the effect of TGFβ2 on the migration and invasion of ezetimibe-treated breast cancer cells was examined. Our results show that ezetimibe treatment of breast cancer cells inhibited cell migration, invasion, and EMT, and it significantly suppressed the expression of TGFβ2. Overexpression of TGFβ2 reversed the inhibitory effect of ezetimibe on the migration and invasion of breast cancer cells. Taken together, our results suggest that ezetimibe might be a potential candidate for the treatment of breast cancer metastasis.
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Affiliation(s)
- Lingkai Kong
- Jinan Microecological Biomedicine Shandong LaboratoryChina
- State Key Laboratory of Pharmaceutical Biotechnology, National Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical SchoolNanjing UniversityChina
| | - Qinyu He
- State Key Laboratory of Pharmaceutical Biotechnology, National Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical SchoolNanjing UniversityChina
| | - Ding Ma
- State Key Laboratory of Pharmaceutical Biotechnology, National Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical SchoolNanjing UniversityChina
| | - Weiwei Shi
- State Key Laboratory of Pharmaceutical Biotechnology, National Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical SchoolNanjing UniversityChina
| | - Qilei Xin
- Jinan Microecological Biomedicine Shandong LaboratoryChina
| | - Chunping Jiang
- Jinan Microecological Biomedicine Shandong LaboratoryChina
- State Key Laboratory of Pharmaceutical Biotechnology, National Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical SchoolNanjing UniversityChina
| | - Junhua Wu
- Jinan Microecological Biomedicine Shandong LaboratoryChina
- State Key Laboratory of Pharmaceutical Biotechnology, National Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical SchoolNanjing UniversityChina
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17
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Coates HW, Nguyen TB, Du X, Olzomer EM, Farrell R, Byrne FL, Yang H, Brown AJ. The constitutively active form of a key cholesterol synthesis enzyme is lipid droplet-localized and upregulated in endometrial cancer tissues. J Biol Chem 2024; 300:107232. [PMID: 38537696 PMCID: PMC11061744 DOI: 10.1016/j.jbc.2024.107232] [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: 02/29/2024] [Accepted: 03/18/2024] [Indexed: 04/26/2024] Open
Abstract
Cholesterol is essential for both normal cell viability and cancer cell proliferation. Aberrant activity of squalene monooxygenase (SM, also known as squalene epoxidase), the rate-limiting enzyme of the committed cholesterol synthesis pathway, is accordingly implicated in a growing list of cancers. We previously reported that hypoxia triggers the truncation of SM to a constitutively active form, thus preserving sterol synthesis during oxygen shortfalls. Here, we show SM truncation is upregulated and correlates with the magnitude of hypoxia in endometrial cancer tissues, supporting the in vivo relevance of our earlier work. To further investigate the pathophysiological consequences of SM truncation, we examined its lipid droplet-localized pool using complementary immunofluorescence and cell fractionation approaches and found that it exclusively comprises the truncated enzyme. This partitioning is facilitated by the loss of an endoplasmic reticulum-embedded region at the SM N terminus, whereas the catalytic domain containing membrane-associated C-terminal helices is spared. Moreover, we determined multiple amphipathic helices contribute to the lipid droplet localization of truncated SM. Taken together, our results expand on the striking differences between the two forms of SM and suggest upregulated truncation may contribute to SM-related oncogenesis.
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Affiliation(s)
- Hudson W Coates
- School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, New South Wales, Australia
| | - Tina B Nguyen
- School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, New South Wales, Australia
| | - Ximing Du
- School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, New South Wales, Australia
| | - Ellen M Olzomer
- School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, New South Wales, Australia
| | - Rhonda Farrell
- Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia; Prince of Wales Private Hospital, Randwick, New South Wales, Australia
| | - Frances L Byrne
- School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, New South Wales, Australia
| | - Hongyuan Yang
- School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, New South Wales, Australia
| | - Andrew J Brown
- School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, New South Wales, Australia.
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18
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Liu Y, Wang Z, Jin H, Cui L, Huo B, Xie C, Li J, Ding H, Zhang H, Xiong W, Li M, Zhang H, Guo H, Li C, Wang T, Wang X, He W, Wang Z, Bei JX, Huang P, Liu J, Xia X. Squalene-epoxidase-catalyzed 24(S),25-epoxycholesterol synthesis promotes trained-immunity-mediated antitumor activity. Cell Rep 2024; 43:114094. [PMID: 38613784 DOI: 10.1016/j.celrep.2024.114094] [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: 10/30/2023] [Revised: 02/18/2024] [Accepted: 03/27/2024] [Indexed: 04/15/2024] Open
Abstract
The importance of trained immunity in antitumor immunity has been increasingly recognized, but the underlying metabolic regulation mechanisms remain incompletely understood. In this study, we find that squalene epoxidase (SQLE), a key enzyme in cholesterol synthesis, is required for β-glucan-induced trained immunity in macrophages and ensuing antitumor activity. Unexpectedly, the shunt pathway, but not the classical cholesterol synthesis pathway, catalyzed by SQLE, is required for trained immunity induction. Specifically, 24(S),25-epoxycholesterol (24(S),25-EC), the shunt pathway metabolite, activates liver X receptor and increases chromatin accessibility to evoke innate immune memory. Meanwhile, SQLE-induced reactive oxygen species accumulation stabilizes hypoxia-inducible factor 1α protein for metabolic switching into glycolysis. Hence, our findings identify 24(S),25-EC as a key metabolite for trained immunity and provide important insights into how SQLE regulates trained-immunity-mediated antitumor activity.
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Affiliation(s)
- Yongxiang Liu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Zifeng Wang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Huan Jin
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Lei Cui
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Bitao Huo
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Chunyuan Xie
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Jiahui Li
- School of Food Science and Technology, Dalian Polytechnic University, Dalian, P.R. China
| | - Honglu Ding
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China; Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Huanling Zhang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Wenjing Xiong
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Mengyun Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China; College of Life Science, Sun Yat-sen University, Guangzhou, P.R. China
| | - Hongxia Zhang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Hui Guo
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Chunwei Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Tiantian Wang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Xiaojuan Wang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Wenzhuo He
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China; VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Zining Wang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Jin-Xin Bei
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Peng Huang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China; Metabolic Center, Sun Yat-sen University, Guangzhou, P.R. China
| | - Jinyun Liu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China; Metabolic Center, Sun Yat-sen University, Guangzhou, P.R. China
| | - Xiaojun Xia
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China.
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Zhang L, Cao Z, Hong Y, He H, Chen L, Yu Z, Gao Y. Squalene Epoxidase: Its Regulations and Links with Cancers. Int J Mol Sci 2024; 25:3874. [PMID: 38612682 PMCID: PMC11011400 DOI: 10.3390/ijms25073874] [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: 01/09/2024] [Revised: 03/09/2024] [Accepted: 03/19/2024] [Indexed: 04/14/2024] Open
Abstract
Squalene epoxidase (SQLE) is a key enzyme in the mevalonate-cholesterol pathway that plays a critical role in cellular physiological processes. It converts squalene to 2,3-epoxysqualene and catalyzes the first oxygenation step in the pathway. Recently, intensive efforts have been made to extend the current knowledge of SQLE in cancers through functional and mechanistic studies. However, the underlying mechanisms and the role of SQLE in cancers have not been fully elucidated yet. In this review, we retrospected current knowledge of SQLE as a rate-limiting enzyme in the mevalonate-cholesterol pathway, while shedding light on its potential as a diagnostic and prognostic marker, and revealed its therapeutic values in cancers. We showed that SQLE is regulated at different levels and is involved in the crosstalk with iron-dependent cell death. Particularly, we systemically reviewed the research findings on the role of SQLE in different cancers. Finally, we discussed the therapeutic implications of SQLE inhibitors and summarized their potential clinical values. Overall, this review discussed the multifaceted mechanisms that involve SQLE to present a vivid panorama of SQLE in cancers.
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Affiliation(s)
- Lin Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
| | - Zheng Cao
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yuheng Hong
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Haihua He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Leifeng Chen
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Zhentao Yu
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
| | - Yibo Gao
- Central Laboratory & Shenzhen Key Laboratory of Epigenetics and Precision Medicine for Cancers, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Laboratory of Translational Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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20
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Zhou X, Chang L, Liang Q, Zhao R, Xiao Y, Xu Z, Yu L. The m6A methyltransferase METTL3 drives thyroid cancer progression and lymph node metastasis by targeting LINC00894. Cancer Cell Int 2024; 24:47. [PMID: 38291427 PMCID: PMC10826051 DOI: 10.1186/s12935-024-03240-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 01/24/2024] [Indexed: 02/01/2024] Open
Abstract
BACKGROUND Long noncoding RNAs (lncRNAs) are significant contributors to various human malignancies. The aberrant expression of lncRNA LINC00894 has been reported in various human malignancies. We aimed to illustrate the role of LINC00894 and its underlying mechanism in the development of papillary thyroid carcinoma (PTC). METHODS We performed bioinformatics analysis of differentially expressed RNAs from TCGA and GEO datasets and selected the target lncRNA LINC00894. SRAMP analysis revealed abundant M6A modification sites in LINC00894. Further analysis of StarBase, GEPIA, and TCGA datasets was performed to identify the related differentially expressed genes METTL3. Colony formation and CCK-8 assays confirmed the relationship between LINC00894, METTL3, and the proliferative capacity of PTC cells. The analysis of AnnoLnc2, Starbase datasets, and meRIP-PCR and qRT‒PCR experiments confirmed the influence of METTL3-mediated m6A modification on LINC00894. The study employed KEGG enrichment analysis as well as Western blotting to investigate the impact of LINC00894 on the expression of proteins related to the Hippo signalling pathway. RESULTS LINC00894 downregulation was detected in PTC tissues and cells and was even further downregulated in PTC with lymphatic metastasis. LINC00894 inhibits the lymphangiogenesis of vascular endothelial cells and the proliferation of cancer cells. METTL3 enhances PTC progression by upregulating LINC00894 by enhancing LINC00894 mRNA stability through the m6A-YTHDC2-dependent pathway. LINC00894 may inhibit PTC malignant phenotypes through the Hippo signalling pathway. CONCLUSION The METTL3-YTHDC2 axis stabilizes LINC00894 mRNA in an m6A-dependent manner and subsequently inhibits tumour malignancy through the Hippo signalling pathway.
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Affiliation(s)
- Xiang Zhou
- Head and neck surgery, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People's Republic of China
| | - Lisha Chang
- Oncology department, The Second Affiliated Hospital of Nanjing Medical University, Nanjing City, People's Republic of China
| | - Qiaoqiao Liang
- Head and neck surgery, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People's Republic of China
| | - Rongjie Zhao
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, People's Republic of China
| | - Yong Xiao
- Head and neck surgery, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People's Republic of China
| | - Zheng Xu
- Head and neck surgery, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People's Republic of China
| | - Leitao Yu
- Head and neck surgery, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People's Republic of China.
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21
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Li S, Peng M, Tan S, Oyang L, Lin J, Xia L, Wang J, Wu N, Jiang X, Peng Q, Zhou Y, Liao Q. The roles and molecular mechanisms of non-coding RNA in cancer metabolic reprogramming. Cancer Cell Int 2024; 24:37. [PMID: 38238756 PMCID: PMC10795359 DOI: 10.1186/s12935-023-03186-0] [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: 11/09/2023] [Accepted: 12/20/2023] [Indexed: 01/22/2024] Open
Abstract
One of the key features of cancer is energy metabolic reprogramming which is tightly related to cancer proliferation, invasion, metastasis, and chemotherapy resistance. NcRNAs are a class of RNAs having no protein-coding potential and mainly include microRNAs, lncRNAs and circRNAs. Accumulated evidence has suggested that ncRNAs play an essential role in regulating cancer metabolic reprogramming, and the altered metabolic networks mediated by ncRNAs primarily drive carcinogenesis by regulating the expression of metabolic enzymes and transporter proteins. Importantly, accumulated research has revealed that dysregulated ncRNAs mediate metabolic reprogramming contributing to the generation of therapeutic tolerance. Elucidating the molecular mechanism of ncRNAs in cancer metabolic reprogramming can provide promising metabolism-related therapeutic targets for treatment as well as overcome therapeutic tolerance. In conclusion, this review updates the latest molecular mechanisms of ncRNAs related to cancer metabolic reprogramming.
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Affiliation(s)
- Shizhen Li
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China
- Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Mingjing Peng
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Shiming Tan
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Linda Oyang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Jinguan Lin
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Longzheng Xia
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Jiewen Wang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Nayiyuan Wu
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Xianjie Jiang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Qiu Peng
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China
| | - Yujuan Zhou
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China.
- Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
| | - Qianjin Liao
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China.
- Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
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22
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Yang F, Yang Y, Qiu Y, Tang L, Xie L, Guan X. Long Non-Coding RNAs as Regulators for Targeting Breast Cancer Stem Cells and Tumor Immune Microenvironment: Biological Properties and Therapeutic Potential. Cancers (Basel) 2024; 16:290. [PMID: 38254782 PMCID: PMC10814583 DOI: 10.3390/cancers16020290] [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: 11/22/2023] [Revised: 01/01/2024] [Accepted: 01/08/2024] [Indexed: 01/24/2024] Open
Abstract
Breast cancer stem cells (BCSCs) is a subpopulation of cancer cells with self-renewal and differentiation capacity, have been suggested to give rise to tumor heterogeneity and biologically aggressive behavior. Accumulating evidence has shown that BCSCs play a fundamental role in tumorigenesis, progression, and recurrence. The development of immunotherapy, primarily represented by programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors, has greatly changed the treatment landscape of multiple malignancies. Recent studies have identified pervasive negative associations between cancer stemness and anticancer immunity. Stemness seems to play a causative role in the formation of cold tumor immune microenvironment (TIME). The multiple functions of long non-coding RNAs (lncRNAs) in regulating stemness and immune responses has been recently highlighted in breast cancer. The review focus on lncRNAs and keys pathways involved in the regulation of BCSCs and TIME. Potential clinical applications using lncRNAs as biomarkers or therapies will be discussed.
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Affiliation(s)
- Fang Yang
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; (F.Y.); (Y.Y.); (Y.Q.)
- Clinical Cancer Institute, Nanjing University, Nanjing 210008, China
| | - Yiqi Yang
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; (F.Y.); (Y.Y.); (Y.Q.)
- Clinical Cancer Institute, Nanjing University, Nanjing 210008, China
| | - Yuling Qiu
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; (F.Y.); (Y.Y.); (Y.Q.)
- Clinical Cancer Institute, Nanjing University, Nanjing 210008, China
| | - Lin Tang
- Department of Rheumatology and Immunology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, China;
| | - Li Xie
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; (F.Y.); (Y.Y.); (Y.Q.)
- Clinical Cancer Institute, Nanjing University, Nanjing 210008, China
| | - Xiaoxiang Guan
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
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Liu S, Jiao B, Zhao H, Liang X, Jin F, Liu X, Hu J. LncRNAs-circRNAs as Rising Epigenetic Binary Superstars in Regulating Lipid Metabolic Reprogramming of Cancers. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2303570. [PMID: 37939296 PMCID: PMC10767464 DOI: 10.1002/advs.202303570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 08/28/2023] [Indexed: 11/10/2023]
Abstract
As one of novel hallmarks of cancer, lipid metabolic reprogramming has recently been becoming fascinating and widely studied. Lipid metabolic reprogramming in cancer is shown to support carcinogenesis, progression, distal metastasis, and chemotherapy resistance by generating ATP, biosynthesizing macromolecules, and maintaining appropriate redox status. Notably, increasing evidence confirms that lipid metabolic reprogramming is under the control of dysregulated non-coding RNAs in cancer, especially lncRNAs and circRNAs. This review highlights the present research findings on the aberrantly expressed lncRNAs and circRNAs involved in the lipid metabolic reprogramming of cancer. Emphasis is placed on their regulatory targets in lipid metabolic reprogramming and associated mechanisms, including the clinical relevance in cancer through lipid metabolism modulation. Such insights will be pivotal in identifying new theranostic targets and treatment strategies for cancer patients afflicted with lipid metabolic reprogramming.
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Affiliation(s)
- Shanshan Liu
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of EducationCancer Center, First HospitalJilin UniversityChangchun130021China
- Hematology DepartmentFirst HospitalJilin UniversityChangchun130021China
| | - Benzheng Jiao
- NHC Key Laboratory of Radiobiology (Jilin University)School of Public HealthJilin UniversityChangchun130021China
- Nuclear Medicine DepartmentFirst HospitalJilin UniversityChangchun130021China
| | - Hongguang Zhao
- Nuclear Medicine DepartmentFirst HospitalJilin UniversityChangchun130021China
| | - Xinyue Liang
- Hematology DepartmentFirst HospitalJilin UniversityChangchun130021China
| | - Fengyan Jin
- Hematology DepartmentFirst HospitalJilin UniversityChangchun130021China
| | - Xiaodong Liu
- NHC Key Laboratory of Radiobiology (Jilin University)School of Public HealthJilin UniversityChangchun130021China
- Radiation Medicine Department, School of Public Health and ManagementWenzhou Medical UniversityWenzhou325035China
| | - Ji‐Fan Hu
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of EducationCancer Center, First HospitalJilin UniversityChangchun130021China
- Palo Alto Veterans Institute for ResearchStanford University Medical SchoolPalo AltoCA94304USA
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24
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Zeng Z, Fu M, Hu Y, Wei Y, Wei X, Luo M. Regulation and signaling pathways in cancer stem cells: implications for targeted therapy for cancer. Mol Cancer 2023; 22:172. [PMID: 37853437 PMCID: PMC10583419 DOI: 10.1186/s12943-023-01877-w] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 10/05/2023] [Indexed: 10/20/2023] Open
Abstract
Cancer stem cells (CSCs), initially identified in leukemia in 1994, constitute a distinct subset of tumor cells characterized by surface markers such as CD133, CD44, and ALDH. Their behavior is regulated through a complex interplay of networks, including transcriptional, post-transcriptional, epigenetic, tumor microenvironment (TME), and epithelial-mesenchymal transition (EMT) factors. Numerous signaling pathways were found to be involved in the regulatory network of CSCs. The maintenance of CSC characteristics plays a pivotal role in driving CSC-associated tumor metastasis and conferring resistance to therapy. Consequently, CSCs have emerged as promising targets in cancer treatment. To date, researchers have developed several anticancer agents tailored to specifically target CSCs, with some of these treatment strategies currently undergoing preclinical or clinical trials. In this review, we outline the origin and biological characteristics of CSCs, explore the regulatory networks governing CSCs, discuss the signaling pathways implicated in these networks, and investigate the influential factors contributing to therapy resistance in CSCs. Finally, we offer insights into preclinical and clinical agents designed to eliminate CSCs.
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Affiliation(s)
- Zhen Zeng
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Minyang Fu
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yuan Hu
- Department of Pediatric Nephrology Nursing, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yuquan Wei
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Min Luo
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China.
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25
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Liu G, Bu C, Guo G, Zhang Z, Sheng Z, Deng K, Wu S, Xu S, Bu Y, Gao Y, Wang M, Liu G, Kong L, Li T, Li M, Bu X. Genomic alterations of oligodendrogliomas at distant recurrence. Cancer Med 2023; 12:17171-17183. [PMID: 37533228 PMCID: PMC10501240 DOI: 10.1002/cam4.6327] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 06/19/2023] [Accepted: 06/28/2023] [Indexed: 08/04/2023] Open
Abstract
BACKGROUND Oligodendroglioma is known for its relatively better prognosis and responsiveness to radiotherapy and chemotherapy. However, little is known about the evolution of genetic changes as oligodendroglioma progresses. METHODS In this study, we evaluated gene evolution invivo during tumor progression based on deep whole-genome sequencing data (ctDNA). We analyzed longitudinal genomic data from six patients during tumor evolution, of which five patients developed distant recurrence. RESULTS Whole-exome sequencing demonstrated that the rate of shared mutations between the primary and recurrent samples was relatively low. In two cases, even well-known major driver mutations in CIC and FUBP1 that were detected in primary tumors were not detected in the relapse samples. Among these cases, two patients had a conversion from the IDH mutation in the originating state to the IDH1 wild state during the process of gene evolution under chemotherapy treatment, indicating that the cell phenotype and genetic characteristics of oligodendroglioma may change during tumor evolution. Two patients received long-term temozolomide (TMZ) treatment before the operation, and we found that recurrence tumors harbored mutations in the PI3K/AKT and Sonic hedgehog (SHh) signaling pathways. Hypermutation occurred with mutations in MMR genes in one patient, contributing to the rapid progression of the tumor. CONCLUSION Oligodendroglioma displayed great spatial and temporal heterogeneity during tumor evolution. The PI3K/AKT and SHh signaling pathways may play an important role in promoting treatment resistance and distant relapse during oligodendroglioma evolution. In addition, there was a tendency to increase the degree of tumor malignancy during evolution. Distant recurrence may be a later event duringoligodendroglioma progression. CLINICALTRIALS gov, Identifier: NCT05512325.
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Affiliation(s)
- Guanzheng Liu
- Department of NeurosurgeryZhengzhou University People's Hospital, Henan Provincial People's HospitalZhengzhouChina
- Juha International Central Laboratory of NeurosurgeryHenan Provincial People's HospitalZhengzhouChina
| | - Chaojie Bu
- Department of NeurosurgeryZhengzhou University People's Hospital, Henan Provincial People's HospitalZhengzhouChina
- Juha International Central Laboratory of NeurosurgeryHenan Provincial People's HospitalZhengzhouChina
| | - Guangzhong Guo
- Department of NeurosurgeryZhengzhou University People's Hospital, Henan Provincial People's HospitalZhengzhouChina
- Juha International Central Laboratory of NeurosurgeryHenan Provincial People's HospitalZhengzhouChina
| | - Zhiyue Zhang
- Department of NeurosurgeryZhengzhou University People's Hospital, Henan Provincial People's HospitalZhengzhouChina
- Juha International Central Laboratory of NeurosurgeryHenan Provincial People's HospitalZhengzhouChina
| | - Zhiyuan Sheng
- Department of NeurosurgeryZhengzhou University People's Hospital, Henan Provincial People's HospitalZhengzhouChina
- Juha International Central Laboratory of NeurosurgeryHenan Provincial People's HospitalZhengzhouChina
| | - Kaiyuan Deng
- Department of NeurosurgeryZhengzhou University People's Hospital, Henan Provincial People's HospitalZhengzhouChina
- Juha International Central Laboratory of NeurosurgeryHenan Provincial People's HospitalZhengzhouChina
| | - Shuang Wu
- Department of NeurosurgeryZhengzhou University People's Hospital, Henan Provincial People's HospitalZhengzhouChina
- Juha International Central Laboratory of NeurosurgeryHenan Provincial People's HospitalZhengzhouChina
| | - Sensen Xu
- Department of NeurosurgeryZhengzhou University People's Hospital, Henan Provincial People's HospitalZhengzhouChina
- Juha International Central Laboratory of NeurosurgeryHenan Provincial People's HospitalZhengzhouChina
| | - Yage Bu
- Department of NeurosurgeryZhengzhou University People's Hospital, Henan Provincial People's HospitalZhengzhouChina
- Juha International Central Laboratory of NeurosurgeryHenan Provincial People's HospitalZhengzhouChina
| | - Yushuai Gao
- Department of NeurosurgeryZhengzhou University People's Hospital, Henan Provincial People's HospitalZhengzhouChina
- Juha International Central Laboratory of NeurosurgeryHenan Provincial People's HospitalZhengzhouChina
| | - Meiyun Wang
- Department of RadiologyHenan Provincial People's HospitalZhengzhouChina
| | - Gang Liu
- Department of Center for Clinical Single Cell Biomedicine, Department of Oncology, Clinical Research Center, Henan Provincial People's HospitalZhengzhou University People's HospitalZhengzhouChina
| | - Lingfei Kong
- Department of PathologyHenan Provincial People's HospitalZhengzhouChina
| | - Tianxiao Li
- Department of NeurosurgeryZhengzhou University People's Hospital, Henan Provincial People's HospitalZhengzhouChina
- Juha International Central Laboratory of NeurosurgeryHenan Provincial People's HospitalZhengzhouChina
| | - Ming Li
- Department of NeurosurgeryZhengzhou University People's Hospital, Henan Provincial People's HospitalZhengzhouChina
- Juha International Central Laboratory of NeurosurgeryHenan Provincial People's HospitalZhengzhouChina
| | - Xingyao Bu
- Department of NeurosurgeryZhengzhou University People's Hospital, Henan Provincial People's HospitalZhengzhouChina
- Juha International Central Laboratory of NeurosurgeryHenan Provincial People's HospitalZhengzhouChina
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Xing Y, Zhang F, Ji P, Wei M, Yin C, Yang A, Yang G, Zhao J. Efficient Delivery of GSDMD-N mRNA by Engineered Extracellular Vesicles Induces Pyroptosis for Enhanced Immunotherapy. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2204031. [PMID: 36635060 DOI: 10.1002/smll.202204031] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 12/12/2022] [Indexed: 05/18/2023]
Abstract
Pyroptosis is a newly discovered inflammatory form of programmed cell death, which promotes systemic immune response in cancer immunotherapy. GSDMD is one of the key molecules executing pyroptosis, while therapeutical delivery of GSDMD to tumor cells is of great challenge. In this study, an extracellular vesicles-based GSDMD-N mRNA delivery system (namely EVTx ) is developed for enhanced cancer immunotherapy, with GSDMD-N mRNA encapsulated inside, Ce6 (Chlorin e6 (Ce6), a hydrophilic sensitizer) incorporated into extracellular vesicular membrane, and HER2 antibody displayed onto the surface. Briefly, GSDMD-N mRNA is translationally repressed in donor cells by optimized puromycin, ensuring the cell viability and facilitating the mRNA encapsulation into extracellular vesicles. When targeted and delivered into HER2+ breast cancer cells by the engineered extracellular vesicles, the translational repression is unleashed in the recipient cells as the puromycin is diluted and additionally inactivated by sonodynamic treatment as the extracellular vesicles are armed with Ce6, allowing GSDMD-N translation and pyroptosis induction. In addition, sonodynamic treatment also induces cell death in the recipient cells. In the SKBR3- and HER2 transfected 4T1- inoculated breast tumor mouse models, the engineered EVTx efficiently induces a powerful tumor immune response and suppressed tumor growth, providing a nanoplatform for cancer immunotherapy.
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Affiliation(s)
- Yuqi Xing
- The State Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Feiyu Zhang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Panpan Ji
- The State Laboratory of Cancer Biology, Department of Gastrointestinal Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Mengying Wei
- The State Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Chunhui Yin
- The State Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Angang Yang
- The State Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, No. 169 Changlexi Road, Xi'an, Shaanxi, 710032, China
| | - Guodong Yang
- The State Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Jing Zhao
- The State Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
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Dong C, Luan F, Tian W, Duan K, Chen T, Ren J, Li W, Li D, Zhi Q, Zhou J. Identification and validation of crucial lnc-TRIM28-14 and hub genes promoting gastric cancer peritoneal metastasis. BMC Cancer 2023; 23:76. [PMID: 36690975 PMCID: PMC9872371 DOI: 10.1186/s12885-023-10544-8] [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: 09/05/2022] [Accepted: 01/12/2023] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Gastric cancer peritoneal metastasis (GCPM) is an important cause of cancer-related deaths worldwide. Long non-coding RNAs (lncRNAs) play a key role in the regulation of GCPM, but the underlying mechanisms have not been elucidated. METHODS High-throughput RNA sequencing (RNA-seq) was performed on four groups of clinical specimens (non-metastatic gastric cancer primary tumor, adjacent normal gastric mucosal tissue, gastric cancer primary tumor with peritoneal metastasis and adjacent normal gastric mucosal tissue). After sequencing, many lncRNAs and mRNAs were screened for further Weighted Gene Co-expression Network Analysis (WGCNA). GCPM-related hub lncRNAs and genes were identified by cytoHubba and validated by Quantitative real-time PCR (qRT-PCR), Receiver operating characteristic curve (ROC) analysis and Kaplan-Meier survival analysis. GO, KEGG and GSEA showed GCPM-related pathways. Correlation analysis revealed the potential relationship between hub lncRNAs and genes. RESULTS By analyzing lncRNA expression data by WGCNA, we found that blue module was highly correlated with GCPM (r = 0.44, p = 0.04) and six lncRNAs involved in this module (DNM3OS, lnc-MFAP2-53, lnc-PPIAL4C-4, lnc-RFNG-1, lnc-TRIM28-14 and lnc-YARS2-4) were identified. We then performed qRT-PCR validation of gastric cancer specimens and found that the expression of lnc-RFNG-1 and lnc-TRIM28-14 was significantly increased in gastric cancer tissues with peritoneal metastasis. Kaplan-Meier survival analysis showed shorter overall survival time (OS) for gastric cancer patients with high expression of lnc-TRIM28-14. Receiver operating characteristic curve (ROC) analysis showed that lnc-TRIM28-14 could improve the sensitivity and specificity of GCPM diagnosis. In addition, we identified three key mRNAs (CD93, COL3A1 and COL4A1) associated with gastric cancer peritoneal metastasis through WGCNA analysis and clinical specimen validation. Moreover, there was a positive correlation between lnc-TRIM28-14 and the expression of CD93 and COL4A1 in gastric cancer peritoneal metastasis, suggesting a regulatory relationship between them. Subsequent GO, KEGG and GSEA analysis suggested that ECM-receptor interaction and focal adhesion were the hub pathways of GCPM. CONCLUSION In summary, lnc-RFNG-1, lnc-TRIM28-14, CD93, COL3A1 and COL4A1 could be novel tumor biomarkers and potential therapeutic targets for GCPM.
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Affiliation(s)
- Chao Dong
- grid.429222.d0000 0004 1798 0228Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China
| | - Fujuan Luan
- grid.429222.d0000 0004 1798 0228Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China
| | - Wenyan Tian
- grid.429222.d0000 0004 1798 0228Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China
| | - Kaipeng Duan
- grid.429222.d0000 0004 1798 0228Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China
| | - Tao Chen
- grid.429222.d0000 0004 1798 0228Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China
| | - Jiayu Ren
- grid.429222.d0000 0004 1798 0228Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China
| | - Weikang Li
- grid.429222.d0000 0004 1798 0228Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China
| | - Dongbao Li
- grid.429222.d0000 0004 1798 0228Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China
| | - Qiaoming Zhi
- grid.429222.d0000 0004 1798 0228Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China
| | - Jin Zhou
- grid.429222.d0000 0004 1798 0228Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006 China
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28
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Kashyap D, Sharma R, Goel N, Buttar HS, Garg VK, Pal D, Rajab K, Shaikh A. Coding roles of long non-coding RNAs in breast cancer: Emerging molecular diagnostic biomarkers and potential therapeutic targets with special reference to chemotherapy resistance. Front Genet 2023; 13:993687. [PMID: 36685962 PMCID: PMC9852779 DOI: 10.3389/fgene.2022.993687] [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: 07/14/2022] [Accepted: 11/07/2022] [Indexed: 01/08/2023] Open
Abstract
Dysregulation of epigenetic mechanisms have been depicted in several pathological consequence such as cancer. Different modes of epigenetic regulation (DNA methylation (hypomethylation or hypermethylation of promotor), histone modifications, abnormal expression of microRNAs (miRNAs), long non-coding RNAs, and small nucleolar RNAs), are discovered. Particularly, lncRNAs are known to exert pivot roles in different types of cancer including breast cancer. LncRNAs with oncogenic and tumour suppressive potential are reported. Differentially expressed lncRNAs contribute a remarkable role in the development of primary and acquired resistance for radiotherapy, endocrine therapy, immunotherapy, and targeted therapy. A wide range of molecular subtype specific lncRNAs have been assessed in breast cancer research. A number of studies have also shown that lncRNAs may be clinically used as non-invasive diagnostic biomarkers for early detection of breast cancer. Such molecular biomarkers have also been found in cancer stem cells of breast tumours. The objectives of the present review are to summarize the important roles of oncogenic and tumour suppressive lncRNAs for the early diagnosis of breast cancer, metastatic potential, and chemotherapy resistance across the molecular subtypes.
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Affiliation(s)
- Dharambir Kashyap
- Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Riya Sharma
- Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Neelam Goel
- Department of Information Technology, University Institute of Engineering & Technology, Panjab University, Chandigarh, India
| | - Harpal S. Buttar
- Department of Pathology and Laboratory Medicine, University of Ottawa, Faculty of Medicine, Ottawa, ON, Canada
| | - Vivek Kumar Garg
- Department of Medical Lab Technology, University Institute of Applied Health Sciences, Chandigarh University, Gharuan, Mohali, India
| | - Deeksha Pal
- Department of Translational and Regenerative Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Khairan Rajab
- College of Computer Science and Information Systems, Najran University, Najran, Saudi Arabia
| | - Asadullah Shaikh
- College of Computer Science and Information Systems, Najran University, Najran, Saudi Arabia
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29
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Zhang C, Bai X, Peng X, Shi W, Li Y, Chen G, Yu H, Feng Z, Deng Y. Starvation-induced long non-coding RNAs are significant for prognosis evaluation of bladder cancer. Aging (Albany NY) 2022; 14:10067-10080. [PMID: 36541918 PMCID: PMC9831724 DOI: 10.18632/aging.204444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 12/10/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Starving intratumoral microenvironment prominently alters genic profiles including long non-coding RNAs (lncRNAs), which further regulate bladder cancer (BCa) malignant biological properties, such as invasion and migration. METHODS Transcriptome RNA-sequencing data of 414 BCa tumor tissues and 19 normal tissues were obtained from TCGA database and paired samples of 132 BCa patients. A chain of in vitro validations such as qPCR, migration and invasion assays were performed to reveal the clinical relevance of AC011472.4 and AL157895.1. RESULTS A total of 11 lncRNAs were identified as starvation-related lncRNAs, of which AC011472.4 and AL157895.1 were relevant to overall survival of BCa patients. Besides, a starvation-related risk score model was established based on the levels of AC011472.4 and AL157895.1. BCa patients with higher levels of AL157895.1 were divided into the high-risk group and usually obtained higher mortality rate, but AC011472.4 was contrary. AL157895.1 expressed highly in BCa cell lines and tumour tissues, especially in patients with the advanced grade, stage and T-stage, while AC011472.4 showed the reversed result. Moreover, increased level of AL157895.1 was remarkably correlated to T-stage, muscle invasion status and distant metastasis. SiRNAs-mediated silence of AC011472.4 and AL157895.1 respectively increased and diminished invasion and migration properties of BCa cells. CONCLUSIONS In this study, we highlight the significant roles of AC011472.4 and AL157895.1 on evaluating prognoses of BCa patients and validate their correlation with various clinical parameters. These findings provide an appropriate risk score model for BCa clinical decision making.
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Affiliation(s)
- Chunlin Zhang
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China,Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing 400016, China
| | - Xuesong Bai
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Xiang Peng
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China,Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing 400016, China
| | - Wei Shi
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China,Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing 400016, China
| | - Yang Li
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China,Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing 400016, China
| | - Guo Chen
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China,Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing 400016, China
| | - Haitao Yu
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China,Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing 400016, China
| | - Zhenwei Feng
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China,Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing 400016, China
| | - Yuanzhong Deng
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
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30
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Nadhan R, Dhanasekaran DN. Regulation of Tumor Metabolome by Long Non-Coding RNAs. J Mol Signal 2022. [DOI: 10.55233/1750-2187-16-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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31
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Abedi-Gaballu F, Kamal Kazemi E, Salehzadeh SA, Mansoori B, Eslami F, Emami A, Dehghan G, Baradaran B, Mansoori B, Cho WC. Metabolic Pathways in Breast Cancer Reprograming: An Insight to Non-Coding RNAs. Cells 2022; 11:2973. [PMID: 36230935 PMCID: PMC9563138 DOI: 10.3390/cells11192973] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/10/2022] [Accepted: 09/19/2022] [Indexed: 11/16/2022] Open
Abstract
Cancer cells reprogram their metabolisms to achieve high energetic requirements and produce precursors that facilitate uncontrolled cell proliferation. Metabolic reprograming involves not only the dysregulation in glucose-metabolizing regulatory enzymes, but also the enzymes engaging in the lipid and amino acid metabolisms. Nevertheless, the underlying regulatory mechanisms of reprograming are not fully understood. Non-coding RNAs (ncRNAs) as functional RNA molecules cannot translate into proteins, but they do play a regulatory role in gene expression. Moreover, ncRNAs have been demonstrated to be implicated in the metabolic modulations in breast cancer (BC) by regulating the metabolic-related enzymes. Here, we will focus on the regulatory involvement of ncRNAs (microRNA, circular RNA and long ncRNA) in BC metabolism, including glucose, lipid and glutamine metabolism. Investigation of this aspect may not only alter the approaches of BC diagnosis and prognosis, but may also open a new avenue in using ncRNA-based therapeutics for BC treatment by targeting different metabolic pathways.
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Affiliation(s)
- Fereydoon Abedi-Gaballu
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51666-14731, Iran
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 51666-16471, Iran
| | - Elham Kamal Kazemi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51666-14731, Iran
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 51666-16471, Iran
| | - Seyed Ahmad Salehzadeh
- Department of Medicinal Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 175-14115, Iran
| | - Behnaz Mansoori
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran 175-14115, Iran
| | - Farhad Eslami
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 51666-16471, Iran
| | - Ali Emami
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 51666-16471, Iran
| | - Gholamreza Dehghan
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 51666-16471, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51666-14731, Iran
| | - Behzad Mansoori
- Cellular and Molecular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China
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32
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Advances in Biomarkers and Endogenous Regulation of Breast Cancer Stem Cells. Cells 2022; 11:cells11192941. [PMID: 36230903 PMCID: PMC9562239 DOI: 10.3390/cells11192941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 11/16/2022] Open
Abstract
Breast cancer is one of the most common cancers. Even if breast cancer patients initially respond to treatment, developed resistance can lead to a poor prognosis. Cancer stem cells (CSCs) are a group of undifferentiated cells with self-renewal and multipotent differentiation characteristics. Existing evidence has shown that CSCs are one of the determinants that contribute to the heterogeneity of primary tumors. The emergence of CSCs causes tumor recurrence, metastasis, and therapeutic resistance. Previous studies indicated that different stemness-associated surface markers can identify other breast cancer stem cell (BCSC) subpopulations. Deciphering the critical signaling networks that are involved in the induction and maintenance of stemness is essential to develop novel BCSC-targeting strategies. In this review, we reviewed the biomarkers of BCSCs, critical regulators of BCSCs, and the signaling networks that regulate the stemness of BCSCs.
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33
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Zou Y, Zhang H, Bi F, Tang Q, Xu H. Targeting the key cholesterol biosynthesis enzyme squalene monooxygenasefor cancer therapy. Front Oncol 2022; 12:938502. [PMID: 36091156 PMCID: PMC9449579 DOI: 10.3389/fonc.2022.938502] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 07/26/2022] [Indexed: 11/22/2022] Open
Abstract
Cholesterol metabolism is often dysregulated in cancer. Squalene monooxygenase (SQLE) is the second rate-limiting enzyme involved in cholesterol synthesis. Since the discovery of SQLE dysregulation in cancer, compelling evidence has indicated that SQLE plays a vital role in cancer initiation and progression and is a promising therapeutic target for cancer treatment. In this review, we provide an overview of the role and regulation of SQLE in cancer and summarize the updates of antitumor therapy targeting SQLE.
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Affiliation(s)
- Yuheng Zou
- Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Hongying Zhang
- Laboratory of Oncogene, West China Hospital, Sichuan University, Chengdu, China
| | - Feng Bi
- Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Qiulin Tang
- Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Qiulin Tang, ; Huanji Xu,
| | - Huanji Xu
- Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Qiulin Tang, ; Huanji Xu,
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34
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Chen Y, Qin H, Zheng L. Research progress on RNA-binding proteins in breast cancer. Front Oncol 2022; 12:974523. [PMID: 36059653 PMCID: PMC9433872 DOI: 10.3389/fonc.2022.974523] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 07/27/2022] [Indexed: 11/16/2022] Open
Abstract
Breast cancer is the most common malignancy in women and has a high incidence rate and mortality. Abnormal regulation of gene expression plays an important role in breast cancer occurrence and development. RNA-binding proteins (RBPs) are one kind of the key regulators for gene expression. By interacting with RNA, RBPs are widely involved in RNA cutting, transport, editing, intracellular localization, and translation regulation. RBPs are important during breast cancer occurrence and progression by engaging in many aspects, like proliferation, migration, invasion, and stemness. Therefore, comprehensively understanding the role of RBPs in breast cancer progression can facilitate early diagnosis, timely treatment, and long-term survival and quality of life of breast cancer patients.
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Affiliation(s)
- Ying Chen
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Hai Qin
- Department of Clinical Laboratory, Guizhou Provincial Orthopedic Hospital, Guiyang, China
| | - Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
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35
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Hu H, Xiang Y, Zhang XY, Deng Y, Wan FJ, Huang Y, Liao XH, Zhang TC. CDCA5 promotes the progression of breast cancer and serves as a potential prognostic biomarker. Oncol Rep 2022; 48:172. [PMID: 36004470 PMCID: PMC9478967 DOI: 10.3892/or.2022.8387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/13/2022] [Indexed: 11/06/2022] Open
Affiliation(s)
- Hao Hu
- College of Life and Health Sciences, Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan, Hubei 430000, P.R. China
| | - Yuan Xiang
- Department of Medical Laboratory, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, P.R. China
| | - Xiao-Yu Zhang
- College of Life and Health Sciences, Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan, Hubei 430000, P.R. China
| | - Yang Deng
- College of Life and Health Sciences, Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan, Hubei 430000, P.R. China
| | - Fu-Jian Wan
- College of Life and Health Sciences, Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan, Hubei 430000, P.R. China
| | - You Huang
- College of Life and Health Sciences, Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan, Hubei 430000, P.R. China
| | - Xing-Hua Liao
- College of Life and Health Sciences, Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan, Hubei 430000, P.R. China
| | - Tong-Cun Zhang
- College of Life and Health Sciences, Institute of Biology and Medicine, Wuhan University of Science and Technology, Wuhan, Hubei 430000, P.R. China
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36
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Xu H, Zhang F, Gao X, Zhou Q, Zhu L. Fate decisions of breast cancer stem cells in cancer progression. Front Oncol 2022; 12:968306. [PMID: 36046046 PMCID: PMC9420991 DOI: 10.3389/fonc.2022.968306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 07/26/2022] [Indexed: 11/13/2022] Open
Abstract
Breast cancer has a marked recurrence and metastatic trait and is one of the most prevalent malignancies affecting women’s health worldwide. Tumor initiation and progression begin after the cell goes from a quiescent to an activated state and requires different mechanisms to act in concert to regulate t a specific set of spectral genes for expression. Cancer stem cells (CSCs) have been proven to initiate and drive tumorigenesis due to their capability of self-renew and differentiate. In addition, CSCs are believed to be capable of causing resistance to anti-tumor drugs, recurrence and metastasis. Therefore, exploring the origin, regulatory mechanisms and ultimate fate decision of CSCs in breast cancer outcomes has far-reaching clinical implications for the development of breast cancer stem cell (BCSC)-targeted therapeutic strategies. In this review, we will highlight the contribution of BCSCs to breast cancer and explore the internal and external factors that regulate the fate of BCSCs.
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37
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Yao L, Li J, Zhang X, Zhou L, Hu K. Downregulated ferroptosis-related gene SQLE facilitates temozolomide chemoresistance, and invasion and affects immune regulation in glioblastoma. CNS Neurosci Ther 2022; 28:2104-2115. [PMID: 35962621 PMCID: PMC9627366 DOI: 10.1111/cns.13945] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 07/29/2022] [Accepted: 08/05/2022] [Indexed: 02/06/2023] Open
Abstract
Chemoresistance in patients with glioblastoma multiforme (GBM) is a common reason hindering the success of treatment. Recently, ferroptosis has been reported to be associated with chemoresistance in different types of cancer, while the role of ferroptosis-related genes in GBM have not been fully elucidated. This study aimed to demonstrate the roles and mechanism of ferroptosis-related genes in chemoresistance and metastasis of GBM. First, two candidate genes, squalene epoxidase (SQLE) and FANCD2, were identified to be associated with ferroptosis-related chemoresistance in GBM from three temozolomide (TMZ) therapeutic datasets and one ferroptosis-related gene dataset. Then, comprehensive bio-informatics data from different databases testified that SQLE was significantly downregulated both in GBM tissue and cells and displayed a better prognosis in GBM. Clinical data identified lower expression of SQLE was significantly associated with WHO grade and 1p/19q codeletion. Moreover, through in vitro experiments, SQLE was confirmed to suppress ERK-mediated TMZ chemoresistance and metastasis of GBM cells. The KEGG analysis of SQLE-associated co-expressed genes indicated SQLE was potentially involved in the cell cycle. Furthermore, SQLE was found to have the most significant correlations with tumor-infiltrating lymphocytes and immunomodulators. These findings highlighted that SQLE could be a potential target and a biomarker for therapy and prognosis of patients with GBM.
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Affiliation(s)
- Lei Yao
- Department of Hepatobiliary SurgeryXiangya Hospital, Central South UniversityChangshaChina
| | - Juanni Li
- Department of PathologyXiangya Hospital, Central South UniversityChangshaChina,National Clinical Research Center for Geriatric DisordersXiangya Hospital, Central South UniversityChangshaChina
| | - Xiaofang Zhang
- Departments of Burn and PlasticNingxiang People's Hospital, Hunan University of Chinese MedicineChangshaChina
| | - Lei Zhou
- Department of AnesthesiologyThird Xiangya Hospital of Central South UniversityChangshaChina
| | - Kuan Hu
- Department of Hepatobiliary SurgeryXiangya Hospital, Central South UniversityChangshaChina
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Li X, Xu W, Lin X, Wu J, Wu B. Effect of LncRNA-MALAT1 on mineralization of dental pulp cells in a high-glucose microenvironment. Front Cell Dev Biol 2022; 10:921364. [PMID: 36035997 PMCID: PMC9402893 DOI: 10.3389/fcell.2022.921364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 07/18/2022] [Indexed: 11/21/2022] Open
Abstract
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) belongs to the long non-coding RNA (LncRNA) family. LncRNA-MALAT1 is expressed in a variety of tissues and is involved in a variety of diseases and biological processes. Although LncRNA-MALAT1 is upregulated in a high-glucose microenvironment and may participate in odontogenic differentiation, the underlying mechanism is not yet well elucidated. Here, we show that MALAT1 was mainly expressed in the cytoplasm of dental pulp cells (DPCs) in situ hybridization. In addition, high levels of mineralization-related factors, namely, tumor growth factors β 1 and 2 (TGFβ-1 and TGFβ-2), bone morphogenetic proteins 2 and 4 (BMP2 and BMP4), bone morphogenetic protein receptor 1 (BMPR1), SMAD family member 2 (SMAD2), runt-related transcription factor 2 (RUNX2), Msh homeobox 2 (MSX2), transcription factor SP7 (SP7), alkaline phosphatase (ALP), dentin matrix acidic phosphoprotein 1 (DMP1), and dentin sialophosphoprotein (DSPP), were expressed, and MALAT1 was significantly overexpressed in DPCs 7 and 14 days after mineralization induction in a high-glucose microenvironment, but only TGFβ-1, BMP2, MSX2, SP7, ALP, and DSPP were significantly downregulated in DPCs after MALAT1 inhibition. MALAT1 may participate in the mineralization process of DPCs by regulating multiple factors (TGFβ-1, BMP2, MSX2, SP7, ALP, and DSPP).
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Affiliation(s)
- Xinzhu Li
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wenan Xu
- Department of Pediatric Dentistry, Shenzhen Stomatology Hospital (Pingshan), Southern Medical University, Shenzhen, China
| | - Xiaoyu Lin
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jingyi Wu
- Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Buling Wu
- Department of Pediatric Dentistry, Shenzhen Stomatology Hospital (Pingshan), Southern Medical University, Shenzhen, China
- *Correspondence: Buling Wu,
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Cholesterol Synthesis Is Important for Breast Cancer Cell Tumor Sphere Formation and Invasion. Biomedicines 2022; 10:biomedicines10081908. [PMID: 36009455 PMCID: PMC9405659 DOI: 10.3390/biomedicines10081908] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/25/2022] [Accepted: 08/01/2022] [Indexed: 11/17/2022] Open
Abstract
Breast cancer has a high risk of recurrence and distant metastasis after remission. Controlling distant metastasis is important for reducing breast cancer mortality, but accomplishing this goal remains elusive. In this study, we investigated the molecular pathways underlying metastasis using cells that mimic the breast cancer distant metastasis process. HCC1143 breast cancer cells were cultured under two-dimensional (2D)-adherent, tumor sphere (TS), and reattached (ReA) culture conditions to mimic primary tumors, circulating tumor cells, and metastasized tumors, respectively. ReA cells demonstrated increased TS formation and enhanced invasion capacity compared to the original 2D-cultured parental cells. In addition, ReA cells had a higher frequency of ESA+CD44+CD24− population, which represents a stem-cell-like cell population. RNA sequencing identified the cholesterol synthesis pathway as one of the most significantly increased pathways in TS and ReA cells compared to parental cells, which was verified by measuring intracellular cholesterol levels. Furthermore, the pharmacological inhibition of the cholesterol synthesis pathway decreased the ability of cancer cells to form TSs and invade. Our results suggest that the cholesterol synthesis pathway plays an important role in the distant metastasis of breast cancer cells by augmenting TS formation and invasion capacity.
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Wang S, Dong L, Ma L, Yang S, Zheng Y, Zhang J, Wu C, Zhao Y, Hou Y, Li H, Wang T. SQLE facilitates the pancreatic cancer progression via the lncRNA-TTN-AS1/miR-133b/SQLE axis. J Cell Mol Med 2022; 26:3636-3647. [PMID: 35638462 PMCID: PMC9258714 DOI: 10.1111/jcmm.17347] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 03/24/2022] [Accepted: 04/05/2022] [Indexed: 02/04/2023] Open
Abstract
Studies have shown that SQLE is highly expressed in a variety of tumours and promotes tumour progression. However, the role of SQLE in pancreatic cancer (PC) has not been reported. Here, we aim to study the role and molecular mechanism of SQLE in PC. Immunohistochemistry and functional experiments showed that SQLE was highly expressed in PC tissues and promoted the proliferation and invasion of PC cells. Terbinafine, an inhibitor of SQLE, inhibited this effect. In order to further study the upstream mechanism that regulates SQLE, we used bioinformatics technology to lock miR-133b and lncRNA-TTN-AS. In situ hybridization was used to detect the expression of miR-133b and lncRNA-TTN-AS1 in PC tissues. The luciferase reporter gene experiment was used to confirm the binding of miR-133b and lncRNA-TTN-AS1. The results showed that miR-133b was down-regulated in PC tissues and negatively correlated with the expression of SQLE. LncRNA-TTN-AS1 was upregulated in pancreatic cancer tissues and positively correlated with the expression of SQLE. Luciferase gene reporter gene analysis confirmed lncRNA-TTN-AS1 directly binded to miR-133b. Therefore, we propose that targeting the lncRNA-TTN-AS1/miR-133b/SQLE axis is expected to provide new ideas for the clinical treatment of PC patients.
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Affiliation(s)
- Shuhui Wang
- Department of Digestive Disease and Gastrointestinal Motility Research RoomThe Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
- Department of Infectious DiseasesShenzhen Nanshan District Shekou People’s HospitalShenzhenChina
| | - Lei Dong
- Department of Digestive Disease and Gastrointestinal Motility Research RoomThe Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
| | - Lin Ma
- Department of GastroenterologyShaanxi Provincial People’s HospitalXi’anChina
| | - Suzhen Yang
- Department of Digestive Disease and Gastrointestinal Motility Research RoomThe Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
| | - Ying Zheng
- Department of Digestive Disease and Gastrointestinal Motility Research RoomThe Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
| | - Jing Zhang
- Department of Kidney TransplantationNephropathy HospitalThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi’anChina
| | - Chuanghong Wu
- Department of Infectious DiseasesShenzhen Nanshan District Shekou People’s HospitalShenzhenChina
| | - Yidi Zhao
- Emergency DepartmentThe Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
| | - Yangfan Hou
- Department of Respiratory and Critical Care MedicineThe Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
| | - Hong Li
- Department of Digestive Disease and Gastrointestinal Motility Research RoomThe Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
| | - Ting Wang
- Department of Digestive Disease and Gastrointestinal Motility Research RoomThe Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
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Xiao S, Zuo Y, Li Y, Huang Y, Fu S, Yuan D, Qiao X, Wang H, Wang J. Long Noncoding RNA HAGLROS Promotes the Malignant Progression of Bladder Cancer by Regulating the miR-330-5p/SPRR1B Axis. Front Oncol 2022; 12:876090. [PMID: 35664787 PMCID: PMC9159766 DOI: 10.3389/fonc.2022.876090] [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: 02/15/2022] [Accepted: 04/01/2022] [Indexed: 11/13/2022] Open
Abstract
Bladder cancer (BC) is the most common genitourinary malignancy worldwide, and its aetiology and pathogenesis remain unclear. Accumulating evidence has shown that HAGLROS is closely related to the occurrence and progression of various cancers. However, the biological functions and underlying mechanisms of HAGLROS in BC remain unknown. In the present study, the expression of HAGLROS in BC was determined by public dataset analysis, transcriptome sequencing analysis, qRT–PCR and ISH assays. Gain- or loss-of-function assays were performed to study the biological roles of HAGLROS in BC cells and nude mouse xenograft model. Bioinformatic analysis, qRT–PCR, western blot, immunohistochemistry, FISH assays, subcellular fractionation assays and luciferase reporter assays were performed to explore the underlying molecular mechanisms of HAGLROS in BC. Here, we found that HAGLROS expression is significantly upregulated in BC tissues and cells, and elevated HAGLROS expression was related to higher pathologic grade and advanced clinical stage, which is significant for BC diagnosis. HAGLROS can enhance the growth and metastasis of BC in vitro and in vivo. Furthermore, miR-330-5p downregulation reversed the BC cells proliferation, migration and invasion inhibited by silencing HAGLROS. SPRR1B silencing restored the malignant phenotypes of BC cells promoted by miR-330--5p inhibitor. Mechanistically, we found that HAGLROS functions as a microRNA sponge to positively regulate SPRR1B expression by sponging miR-330-5p. Together, these results demonstrate that HAGLROS plays an oncogenic role and may serve as a potential biomarker for the diagnosis and treatment of BC.
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Affiliation(s)
- Shiwei Xiao
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, China.,Department of Urology, Guizhou Provincial People's Hospital, Guiyang, China
| | - Yigang Zuo
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, China
| | - Yanan Li
- Department of Basic Chemistry, College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Yinglong Huang
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, China
| | - Shi Fu
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, China
| | - Dongbo Yuan
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, China
| | - Xuhua Qiao
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, China
| | - Haifeng Wang
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, China
| | - Jiansong Wang
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, China
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Li Y, Zhang J, Sun H, Yu X, Chen Y, Ma C, Zheng X, Zhang L, Zhao X, Jiang Y, Xin W, Wang S, Hu J, Wang M, Zhu D. RPS4XL encoded by lnc-Rps4l inhibits hypoxia-induced pyroptosis by binding HSC70 glycosylation site. MOLECULAR THERAPY - NUCLEIC ACIDS 2022; 28:920-934. [PMID: 35757299 PMCID: PMC9185019 DOI: 10.1016/j.omtn.2022.05.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 05/18/2022] [Indexed: 10/25/2022]
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You W, Ke J, Chen Y, Cai Z, Huang ZP, Hu P, Wu X. SQLE, A Key Enzyme in Cholesterol Metabolism, Correlates With Tumor Immune Infiltration and Immunotherapy Outcome of Pancreatic Adenocarcinoma. Front Immunol 2022; 13:864244. [PMID: 35720314 PMCID: PMC9204319 DOI: 10.3389/fimmu.2022.864244] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 04/26/2022] [Indexed: 12/26/2022] Open
Abstract
Background Pancreatic adenocarcinoma (PAAD) is a treatment-refractory cancer with poor prognosis. Accumulating evidence suggests that squalene epoxidase (SQLE) plays a pivotal role in the development and progression of several cancer types in humans. However, the function and underlying mechanism of SQLE in PAAD remain unclear. Methods SQLE expression data were downloaded from The Cancer Genome Atlas and the Genotype-Tissue Expression database. SQLE alterations were demonstrated based on the cBioPortal database. The upstream miRNAs regulating SQLE expression were predicted using starBase. The function of miRNA was validated by Western blotting and cell proliferation assay. The relationship between SQLE expression and biomarkers of the tumor immune microenvironment (TME) was analyzed using the TIMER and TISIDB databases. The correlation between SQLE and immunotherapy outcomes was assessed using Tumor Immune Dysfunction and Exclusion. The log-rank test was performed to compare prognosis between the high and low SQLE groups. Results We demonstrated a potential oncogenic role of SQLE. SQLE expression was upregulated in PAAD, and it predicted poor disease-free survival (DFS) and overall survival (OS) in patients with PAAD. "Amplification" was the dominant type of SQLE alteration. In addition, this alteration was closely associated with the OS, disease-specific survival, DFS, and progression-free survival of patients with PAAD. Subsequently, hsa-miR-363-3p was recognized as a critical microRNA regulating SQLE expression and thereby influencing PAAD patient outcome. In vitro experiments suggested that miR-363-3p could knock down the expression of SQLE and inhibit the proliferation of PANC-1. SQLE was significantly associated with tumor immune cell infiltration, immune checkpoints (including PD-1 and CTLA-4), and biomarkers of the TME. KEGG and GO analyses indicated that cholesterol metabolism-associated RNA functions are implicated in the mechanisms of SQLE. SQLE was inversely associated with cytotoxic lymphocytes and predicted immunotherapy outcomes. Conclusions Collectively, our results indicate that cholesterol metabolism-related overexpression of SQLE is strongly correlated with tumor immune infiltration and immunotherapy outcomes in patients with PAAD.
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Affiliation(s)
| | | | | | | | | | | | - Xiaojian Wu
- Department of Colorectal Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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The Role of Long Noncoding RNA BST2-2 in the Innate Immune Response to Viral Infection. J Virol 2022; 96:e0020722. [PMID: 35297670 DOI: 10.1128/jvi.00207-22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) widely exist in the cells and play important roles in various biological processes. The role of lncRNAs in immunity remains largely unknown. lncRNA BST2-2 (lncBST2-2) was upregulated upon viral infection and dependent on the interferon (IFN)/JAK/STAT signaling pathway. There was no coding potential found in the lncBST2-2 transcript. Overexpression of lncBST2-2 inhibited the replication of hepatitis C virus (HCV), Newcastle disease virus (NDV), vesicular stomatitis virus (VSV), and herpes simplex virus (HSV), while knockdown of lncBST2-2 facilitated viral replication. Further studies showed that lncBST2-2 promoted the phosphorylation, dimerization, and nuclear transport of IRF3, promoting the production of IFNs. Importantly, lncBST2-2 interacted with the DNA-binding domain of IRF3, which augmented TBK1 and IRF3 interaction, thereby inducing robust production of IFNs. Moreover, lncBST2-2 impaired the interaction between IRF3 and PP2A-RACK1 complex, an essential step for the dephosphorylation of IRF3. These data shown that lncBST2-2 promotes the innate immune response to viral infection through targeting IRF3. Our study reveals the lncRNA involved in the activation of IRF3 and provides a new insight into the role of lncRNA in antiviral innate immunity. IMPORTANCE Innate immunity is an important part of the human immune system to resist the invasion of foreign pathogens. IRF3 plays a critical role in the innate immune response to viral infection. In this study, we demonstrated that lncBST2-2 plays an important role in innate immunity. Virus-induced lncBST2-2 positively regulates innate immunity by interacting with IRF3 and blocking the dephosphorylation effect of RACK1-PP2A complex on IRF3, thus inhibiting viral infection. Our study provides a new insight into the role of lncBST2-2 in the regulation of IRF3 signaling activation.
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Yang X, Weng X, Yang Y, Jiang Z. Pyroptosis-Related lncRNAs Predict the Prognosis and Immune Response in Patients With Breast Cancer. Front Genet 2022; 12:792106. [PMID: 35360412 PMCID: PMC8963933 DOI: 10.3389/fgene.2021.792106] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Accepted: 12/21/2021] [Indexed: 12/24/2022] Open
Abstract
Background: Breast cancer (BC) is the most common malignant tumor and the leading cause of cancer-related death in women worldwide. Pyroptosis and long noncoding RNAs (lncRNAs) have been demonstrated to play vital roles in the tumorigenesis and development of BC. However, the clinical significance of pyroptosis-related lncRNAs in BC remains unclear. Methods: Using the mRNA and lncRNA profiles of BC obtained from TCGA dataset, a risk model based on the pyroptosis-related lncRNAs for prognosis was constructed using univariate and multivariate Cox regression model, and least absolute shrinkage and selection operator. Patients were divided into high- and low-risk groups based on the risk model, and the prognosis value and immune response in different risk groups were analyzed. Furthermore, functional enrichment annotation, therapeutic signature, and tumor mutation burden were performed to evaluate the risk model we established. Moreover, the expression level and clinical significance of the selected pyroptosis-related lncRNAs were further validated in BC samples. Results: 3,364 pyroptosis-related lncRNAs were identified using Pearson’s correlation analysis. The risk model we constructed comprised 10 pyroptosis-related lncRNAs, which was identified as an independent predictor of overall survival (OS) in BC. The nomogram we constructed based on the clinicopathologic features and risk model yielded favorable performance for prognosis prediction in BC. In terms of immune response and mutation status, patients in the low-risk group had a higher expression of immune checkpoint markers and exhibited higher fractions of activated immune cells, while the high-risk group had a highly percentage of TMB. Further analyses in our cohort BC samples found that RP11-459E5.1 was significantly upregulated, while RP11-1070N10.3 and RP11-817J15.3 were downregulated and significantly associated with worse OS. Conclusion: The risk model based on the pyroptosis-related lncRNAs we established may be a promising tool for predicting the prognosis and personalized therapeutic response in BC patients.
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Affiliation(s)
- Xia Yang
- Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xin Weng
- Department of Pathology, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Yajie Yang
- Department of Pathology, Shenzhen Second People’s Hospital, Shenzhen, China
| | - ZhiNong Jiang
- Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: ZhiNong Jiang,
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Zhang Y, Yang X, Cui Y, Zhang X. Suppression of RNA editing by miR-17 inhibits the stemness of melanoma stem cells. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 27:439-455. [PMID: 35036056 PMCID: PMC8728536 DOI: 10.1016/j.omtn.2021.12.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 12/15/2021] [Indexed: 12/13/2022]
Abstract
More and more evidence suggests that microRNA (miRNA) and RNA editing play key roles in the development and progression of tumor. However, the influence of miRNA-mediated RNA editing on tumor stem cells remains unclear. In this study, the results demonstrated that miR-17, which was downregulated in melanoma stem cells, acted as a tumor inhibitor by suppressing the stemness of melanoma stem cells and promoting cell differentiation. MiR-17 targeted ADAR2 (adenosine deaminase acting on RNA 2), a gene encoding an editing enzyme required for the maintenance of melanoma stem cell stemness. In melanoma stem cells, ADAR2 was responsible for DOCK2 mRNA editing, which was able to increase the stability of DOCK2 mRNA. The in vitro and in vivo data demonstrated that DOCK2 mRNA editing upregulated the expressions of stemness and anti-apoptotic genes by activating Rac1 and then phosphorylating Akt and NF-κB, thus leading to oncogenesis of melanoma stem cells. Our findings contribute new perspectives to miRNA-regulated RNA editing in tumor progression.
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Affiliation(s)
- Yu Zhang
- College of Life Sciences, Laboratory for Marine Biology and Biotechnology of Pilot National Laboratory for Marine Science and Technology (Qingdao) and Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhejiang University, Hangzhou 310058, People’s Republic of China
| | - Xiaoyuan Yang
- College of Life Sciences, Laboratory for Marine Biology and Biotechnology of Pilot National Laboratory for Marine Science and Technology (Qingdao) and Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhejiang University, Hangzhou 310058, People’s Republic of China
| | - Yalei Cui
- College of Life Sciences, Laboratory for Marine Biology and Biotechnology of Pilot National Laboratory for Marine Science and Technology (Qingdao) and Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhejiang University, Hangzhou 310058, People’s Republic of China
| | - Xiaobo Zhang
- College of Life Sciences, Laboratory for Marine Biology and Biotechnology of Pilot National Laboratory for Marine Science and Technology (Qingdao) and Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhejiang University, Hangzhou 310058, People’s Republic of China
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Wang SY, Hu QC, Wu T, Xia J, Tao XA, Cheng B. Abnormal lipid synthesis as a therapeutic target for cancer stem cells. World J Stem Cells 2022; 14:146-162. [PMID: 35432735 PMCID: PMC8963380 DOI: 10.4252/wjsc.v14.i2.146] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/19/2021] [Accepted: 02/20/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) comprise a subpopulation of cancer cells with stem cell properties, which exhibit the characteristics of high tumorigenicity, self-renewal, and tumor initiation and are associated with the occurrence, metastasis, therapy resistance, and relapse of cancer. Compared with differentiated cells, CSCs have unique metabolic characteristics, and metabolic reprogramming contributes to the self-renewal and maintenance of stem cells. It has been reported that CSCs are highly dependent on lipid metabolism to maintain stemness and satisfy the requirements of biosynthesis and energy metabolism. In this review, we demonstrate that lipid anabolism alterations promote the survival of CSCs, including de novo lipogenesis, lipid desaturation, and cholesterol synthesis. In addition, we also emphasize the molecular mechanism underlying the relationship between lipid synthesis and stem cell survival, the signal trans-duction pathways involved, and the application prospect of lipid synthesis reprogramming in CSC therapy. It is demonstrated that the dependence on lipid synthesis makes targeting of lipid synthesis metabolism a promising therapeutic strategy for eliminating CSCs. Targeting key molecules in lipid synthesis will play an important role in anti-CSC therapy.
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Affiliation(s)
- Si-Yu Wang
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Qin-Chao Hu
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Tong Wu
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Juan Xia
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Xiao-An Tao
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Bin Cheng
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
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Zhou H, Sun C, Li C, Hua S, Li F, Li R, Cai D, Zou Y, Cai Y, Jiang X. The MicroRNA-106a/20b Strongly Enhances the Antitumour Immune Responses of Dendritic Cells Pulsed with Glioma Stem Cells by Targeting STAT3. J Immunol Res 2022; 2022:9721028. [PMID: 36157880 PMCID: PMC9499788 DOI: 10.1155/2022/9721028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 08/28/2022] [Accepted: 09/01/2022] [Indexed: 12/08/2022] Open
Abstract
BACKGROUND Evaluate the effect of the miRNA-106a/20b on the efficacy of DCs pulsed with GSCs in activating GSC-specific T cell responses. METHODS We cultured GSCs and prepared GSC antigen lysates by apoptosis. Then, immature DCs were pulsed with GSC antigen lysates in vitro. STAT3 levels in DCs were assessed by Western blotting, and the expression of CD80, CD86, and MHC-II was tested by fluorescence-activated cell sorting. The production and secretion of the cytokines IL-6, IL-12, TNF-α, and IL-10 in DCs induced by GSCs were determined by enzyme-linked immunosorbent assay. Finally, the cytotoxic functions of T cells stimulated by GSC-DC fusion cells transfected with a miR-106a/20b mimic in vitro and the antitumour activity in vivo were detected. RESULTS We found that the levels of miR-106a/20b were downregulated, but the expression of STAT3 was significantly upregulated. Simultaneously, the inhibition of STAT3 in the fusion cells by STAT3-specific siRNA caused significant upregulation of the expression of CD80, CD86, and MHC-II, and the secretion of the cytokines IL-6 and IL-12 was substantially increased, IL-10 was markedly decreased. These findings revealed that STAT3 is an important regulator of DC maturation. Furthermore, the interactional binding sites between the 3'-untranslated region (3'-UTR) of STAT3 mRNA and miR-106a/20b were predicted by bioinformatics and verified by a dual-luciferase assay. Moreover, the reduction in STAT3 levels in GSC-DCs enhanced the generation of CD8+ T cells and reduced the generation of Foxp3+ regulatory T cells. Meanwhile, the secretion of the T cell cytokine IFN-γ was significantly increased. Further research showed that DCs after miR-106a/20b-mimics transfection could promote the inhibition of GSC proliferation by T cells in vitro and suppress tumour growth in vivo. CONCLUSIONS This study indicted that the miR-106a/20b activation could be one of the important molecular mechanisms leading to enhance antitumour immune responses of GSC-mediated DCs, which downregulated the expression of STAT3 to alleviate its the inhibitory effect.
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Affiliation(s)
- Hui Zhou
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou 510515, China
- Department of Neurosurgery, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - Chengmei Sun
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou 510515, China
| | - Cong Li
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou 510515, China
| | - Shiting Hua
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou 510515, China
| | - Feng Li
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou 510515, China
| | - Ruichun Li
- Department of Neurosurgery, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - Dongpeng Cai
- Department of Neurosurgery, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - Yuxi Zou
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou 510515, China
| | - Yingqian Cai
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou 510515, China
| | - Xiaodan Jiang
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou 510515, China
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Li P, Yang B, Xiu B, Chi Y, Xue J, Wu J. Development and Validation of a Robust Ferroptosis-Related Gene Panel for Breast Cancer Disease-Specific Survival. Front Cell Dev Biol 2021; 9:709180. [PMID: 34900981 PMCID: PMC8655913 DOI: 10.3389/fcell.2021.709180] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 11/02/2021] [Indexed: 12/17/2022] Open
Abstract
Background: New biomarker combinations have been increasingly developed to improve the precision of current diagnostic and therapeutic modalities. Recently, researchers have found that tumor cells are more vulnerable to ferroptosis. Furthermore, ferroptosis-related genes (FRG) are promising therapeutic targets in breast cancer patients. Therefore, this study aimed to identify FRG that could predict disease-specific survival (DSS) in breast cancer patients. Methods: Gene expression matrix and clinical data were downloaded from public databases. We included 960, 1,900, and 234 patients from the TCGA, METABRIC, and GSE3494 cohorts, respectively. Data for FRG were downloaded from the FerrDb website. Differential expression of FRG was analyzed by comparing the tumors with adjacent normal tissues. Univariate Cox analysis of DSS was performed to identify prognostic FRG. The TCGA-BRCA cohort was used to generate a nine-gene panel with the LASSO cox regression. The METABRIC and GSE3494 cohorts were used to validate the panel. The panel's median cut-off value was used to divide the patients into high- or low-risk subgroups. Analyses of immune microenvironment, functional pathways, and clinical correlation were conducted via GO and KEGG analyses to determine the differences between the two subgroups. Results: The DSS of the low-risk subgroup was longer than that of the high-risk subgroup. The panel's predictive ability was confirmed by ROC curves (TCGA cohort AUC values were 0.806, 0.695, and 0.669 for 2, 3, and 5 years respectively, and the METABRIC cohort AUC values were 0.706, 0.734, and 0.7, respectively for the same periods). The panel was an independent DSS prognostic indicator in the Cox regression analyses. (TCGA cohort: HR = 3.51, 95% CI = 1.792-6.875, p < 0.001; METABRIC cohort: HR = 1.76, 95% CI = 1.283-2.413, p < 0.001). Immune-related pathways were enriched in the high-risk subgroup. The two subgroups that were stratified by the nine-gene panel were also associated with histology type, tumor grade, TNM stage, and Her2-positive and TNBC subtypes. The patients in the high-risk subgroup, whose CTLA4 and PD-1 statuses were both positive or negative, demonstrated a substantial clinical benefit from combination therapy with anti-CTLA4 and anti-PD-1. Conclusion: The new gene panel consisting of nine FRG may be used to assess the prognosis and immune status of patients with breast cancer. A precise therapeutic approach can also be possible with risk stratification.
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Affiliation(s)
- Pei Li
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Benlong Yang
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Bingqiu Xiu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yayun Chi
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jingyan Xue
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jiong Wu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China.,Collaborative Innovation Center for Cancer Medicine, Shanghai, China
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50
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Zhu Y, Li B, Xu G, Han C, Xing G. lncRNA MIR4435‑2HG promotes the progression of liver cancer by upregulating B3GNT5 expression. Mol Med Rep 2021; 25:38. [PMID: 34859256 PMCID: PMC8669657 DOI: 10.3892/mmr.2021.12554] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 10/04/2021] [Indexed: 02/07/2023] Open
Abstract
Several studies have indicated that dysregulation of long non-coding RNAs (lncRNAs) participates in the initiation and progression of cancer. The lncRNA MIR4435-2HG was previously reported to act as an oncogene in human cancer, including liver cancer. However, its role in the pathogenesis in liver cancer is largely unclear. The present study aimed to reveal the molecular mechanism by which MIR4435-2HG regulates liver cancer. The expression levels of MIR4435-2HG in liver cancer and adjacent normal tissues were analyzed using The Cancer Genome Atlas database. MIR4435-2HG expression was validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in cancer cells in vitro. The target genes of MIR4435-2HG were predicted using bioinformatics analysis. Interactions between miR-136-5p, MIR4435-2HG and B3GNT5 were detected using luciferase reporter assays, and their effects on cell viability, migration and invasion were assessed using Cell Counting Kit-8, wound healing and Transwell assays. The effects of miR-136-5p and MIR4435-2HG on B3GNT5 expression were confirmed by western blot analysis. The results revealed that MIR4435-2HG expression was upregulated in primary liver cancer and liver cancer cell lines, and was positively associated with advanced tumor stage, metastasis and poor prognosis in patients with liver cancer. Knockdown of MIR4435-2HG significantly inhibited the proliferation, migration and invasion of liver cancer cells. Furthermore, miR-136-5p was determined to be a direct target of MIR4435-2HG and suppressed MIR4435-2HG expression by binding with the seed region of the 3′-UTR of MIR4435-2HG in liver cancer cells. Functional studies showed that the inhibitory effects of MIR4435-2HG knockdown on cell proliferation, migration and invasion were significantly rescued by inhibiting miR-136-5p. Furthermore, the target gene, B3GNT5, of miR-136-5p was confirmed by bioinformatics analysis and RT-qPCR. In addition, B3GNT5 expression was regulated by the MIR4435-2HG/miR-136-5p axis. In conclusion, the present study indicated that MIR4435-2HG facilitated the progression of liver cancer via the MIR4435-2HG/miR-136-5p/B3GNT5 axis, which demonstrated that MIR4435-2HG may be a potential biomarker for the prognosis and treatment of liver cancer.
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Affiliation(s)
- Yungang Zhu
- Radiology Department, Tianjin Teda Hospital, Tianjin 300457, P.R. China
| | - Baoguo Li
- Department of Interventional Treatment, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China
| | - Guoping Xu
- Medical Imaging Department, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Changrui Han
- Radiology Department, Tianjin Teda Hospital, Tianjin 300457, P.R. China
| | - Gang Xing
- Radiology Department, Tianjin Teda Hospital, Tianjin 300457, P.R. China
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