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Nor WMFSBWM, Kwong SC, Fuzi AAM, Said NABM, Jamil AHA, Lee YY, Lee SC, Lim YAL, Chung I. Linking microRNA to metabolic reprogramming and gut microbiota in the pathogenesis of colorectal cancer (Review). Int J Mol Med 2025; 55:46. [PMID: 39820715 PMCID: PMC11759585 DOI: 10.3892/ijmm.2025.5487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 12/03/2024] [Indexed: 01/19/2025] Open
Abstract
Colorectal cancer (CRC), an emerging public health concern, is one of the leading causes of cancer morbidity and mortality worldwide. An increasing body of evidence shows that dysfunction in metabolic reprogramming is a crucial characteristic of CRC progression. Specifically, metabolic reprogramming abnormalities in glucose, glutamine and lipid metabolism provide the tumour with energy and nutrients to support its rapid cell proliferation and survival. More recently, microRNAs (miRNAs) appear to be involved in the pathogenesis of CRC, including regulatory roles in energy metabolism. In addition, it has been revealed that dysbiosis in CRC might play a key role in impairing the host metabolic reprogramming processes, and while the exact interactions remain unclear, the link may lie with miRNAs. Hence, the aims of the current review include first, to delineate the metabolic reprogramming abnormalities in CRC; second, to explain how miRNAs mediate the aberrant regulations of CRC metabolic pathways; third, linking miRNAs with metabolic abnormalities and dysbiosis in CRC and finally, to discuss the roles of miRNAs as potential biomarkers.
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Affiliation(s)
| | - Soke Chee Kwong
- Centre for Population Health (CePH), Department of Social and Preventive Medicine, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Afiqah Alyaa Md Fuzi
- Office of Deputy Vice Chancellor (Research and Innovation), Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Nur Akmarina Binti Mohd Said
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Amira Hajirah Abd Jamil
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Yeong Yeh Lee
- School of Medical Sciences, Universiti Sains Malaysia, 16150 Kota Bharu, Malaysia
| | - Soo Ching Lee
- Department of Parasitology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Yvonne Ai-Lian Lim
- Department of Parasitology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Ivy Chung
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
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Liu H, Wang S, Wang J, Guo X, Song Y, Fu K, Gao Z, Liu D, He W, Yang LL. Energy metabolism in health and diseases. Signal Transduct Target Ther 2025; 10:69. [PMID: 39966374 PMCID: PMC11836267 DOI: 10.1038/s41392-025-02141-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 11/08/2024] [Accepted: 12/25/2024] [Indexed: 02/20/2025] Open
Abstract
Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.
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Affiliation(s)
- Hui Liu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuo Wang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianhua Wang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xin Guo
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yujing Song
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kun Fu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenjie Gao
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Danfeng Liu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Wei He
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Lei-Lei Yang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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Liu D, Liu S, Ji Y, Jin Z, He Z, Hou M, Li D, Ma X. Lactylation modulation identifies key biomarkers and therapeutic targets in KMT2A-rearranged AML. Sci Rep 2025; 15:1511. [PMID: 39789150 PMCID: PMC11718094 DOI: 10.1038/s41598-025-86136-2] [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: 10/07/2024] [Accepted: 01/08/2025] [Indexed: 01/12/2025] Open
Abstract
Acute Myeloid Leukemia (AML) with KMT2A rearrangements (KMT2Ar), found on chromosome 11q23, is often called KMT2A-rearranged AML (KMT2Ar-AML). This variant is highly aggressive, characterized by rapid disease progression and poor outcomes. Growing knowledge of epigenetic changes, especially lactylation, has opened new avenues for investigation and management of this subtype. Lactylation plays a significant role in cancer, inflammation, and tissue regeneration, but the underlying mechanisms are not yet fully understood. This research examined the influence of lactylation on gene expression within KMT2Ar-AML, initially identifying twelve notable lactylation-dependent differentially expressed genes (DEGs). Using advanced machine learning techniques, six key lactylation-associated genes (PFN1, S100A6, CBR1, LDHB, LGALS1, PRDX1) were identified as essential for prognostic evaluation and linked to relevant disease pathways. The study also suggested PI3K inhibitors and Pevonedistat as possible therapeutic options to modulate immune cell infiltration. Our findings confirm the critical role of lactylation in KMT2Ar-AML and identify six key genes that may serve as biomarkers for diagnosis and treatment. In addition to highlighting the need for further validation in clinical settings, these findings contribute to our understanding of KMT2Ar-AML's molecular mechanisms.
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Grants
- No. wzyw2021012 Science and Technology Bureau of Wuzhong District, Suzhou, Jiangsu Province, China
- No. wzyw2021012 Science and Technology Bureau of Wuzhong District, Suzhou, Jiangsu Province, China
- No. wzyw2021012 Science and Technology Bureau of Wuzhong District, Suzhou, Jiangsu Province, China
- No. wzyw2021012 Science and Technology Bureau of Wuzhong District, Suzhou, Jiangsu Province, China
- No. 2020WSB03 Translational Research Grant of NCRCH
- No. 2020WSB03 Translational Research Grant of NCRCH
- No. 2020WSB03 Translational Research Grant of NCRCH
- No. 18KJA320005 Natural Science Foundation of the Jiangsu Higher Education Institution of China
- No. 18KJA320005 Natural Science Foundation of the Jiangsu Higher Education Institution of China
- No. 81900130 National Natural Science Foundation of China
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Affiliation(s)
- Dan Liu
- Soochow Hopes Hematonosis Hospital, Wudong Road 1339, Wuzhong District, Suzhou, 215100, China.
| | - Silu Liu
- Soochow Hopes Hematonosis Hospital, Wudong Road 1339, Wuzhong District, Suzhou, 215100, China
| | - Yujie Ji
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Ziyan Jin
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Zhewei He
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Mengjia Hou
- Soochow Hopes Hematonosis Hospital, Wudong Road 1339, Wuzhong District, Suzhou, 215100, China
| | - Dongyang Li
- Soochow Hopes Hematonosis Hospital, Wudong Road 1339, Wuzhong District, Suzhou, 215100, China
| | - Xiao Ma
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
- The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, 215006, China.
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Gholami M, Asouri M, Ahmadi AA. Genetic Variants and Haplotype Structures in the CASC Gene Family to Predict Cancer Risk: A Bioinformatics Study. Health Sci Rep 2024; 7:e70228. [PMID: 39640032 PMCID: PMC11618408 DOI: 10.1002/hsr2.70228] [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: 04/10/2024] [Revised: 10/01/2024] [Accepted: 11/05/2024] [Indexed: 12/07/2024] Open
Abstract
Background and Aims The cancer susceptibility (CASC) gene family of long noncoding RNAs (lncRNAs) plays an important role in cancer. The aim of this study was to identify genetic variants and haplotype structures of CASC genes associated with cancer risk. Methods Genome-wide association studies (GWAS) significant variants (p ≤ 5 × 10-8) on CASC family genes were identified from the GWAS Catalog-EMBL-EBI, and then cancer-associated variants on CASC genes were extracted. These variants were functionally analyzed, including lncRNA:miRNA binding sites, Regulomedb scores, and eQTL. The 1000 Genome Project genotyping data Phase III were used to identify haplotypic blocks. Finally, the genes associated with them were examined for expression and gene-gene correlation analyses using OncoDB. Results There were six haplotypic blocks in four genes. The GC, TA, and AGAC haplotypes are located in the CASC8 gene and increase the risk of prostate cancer, breast cancer, and colorectal cancer, respectively. The CA haplotype in the CASC15 gene increases the risk of neuroblastoma, AA haplotype in the CASC16 gene increases the risk of breast cancer, and ACGATG haplotype in the CASC17 gene increases the risk of prostate cancer (p ≤ 5 × 10-8). Their genes are interrelated and their expression is increased in these cancers. The rs2294214 is associated with skin cancer and has positive effects on five CASC15:miRNA binding sites. The rs3803662 is located in CASC16:miRNA binding sites, which has positive effects on hsa-miR-4475 and hsa-miR-7845-5p and negative effects on hsa-miR-4524a-3p and hsa-miR-4524b-3p. Conclusion These haplotypic structures and lncRNA:miRNA:SNP interactions on CASC family lncRNAs reveal novel genetic associations between CASC genes and various cancers.
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Affiliation(s)
- Morteza Gholami
- Department of ParamedicineAmol School of Paramedicine, Mazandaran University of Medical SciencesSariIran
- Metabolic Disorders Research CenterEndocrinology and Metabolism Molecular‐Cellular Sciences Institute, Tehran University of Medical SciencesTehranIran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences InstituteTehran University of Medical SciencesTehranIran
| | - Mohsen Asouri
- Department of ParamedicineAmol School of Paramedicine, Mazandaran University of Medical SciencesSariIran
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Qin R, Fan X, Huang Y, Chen S, Ding R, Yao Y, Wu R, Duan Y, Li X, Khan HU, Hu J, Wang H. Role of glucose metabolic reprogramming in colorectal cancer progression and drug resistance. Transl Oncol 2024; 50:102156. [PMID: 39405607 PMCID: PMC11736406 DOI: 10.1016/j.tranon.2024.102156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 09/19/2024] [Accepted: 10/08/2024] [Indexed: 10/21/2024] Open
Abstract
Colorectal cancer (CRC), with the incidence and mortality rising on a yearly basis, greatly threatens people's health. It is considered an important hallmark of tumorigenesis that aberrant glucose metabolism in cancer cells, particularly the Warburg effect. In CRC, the Warburg effect predominantly influences cancer development and progression via its involvement in the glycolytic pathway regarding cell metabolism. The critical mechanisms underlying this process include key glycolytic enzymes, transport proteins, regulatory molecules, and signaling pathways. Furthermore, targeting the reprogrammed glucose metabolism in cancer cells can be potentially used for CRC treatment. However, the mechanisms driving CRC onset and progression, especially in relation to glucose metabolism reprogramming, are not fully understood and represent an emerging field of research. The review aims at providing new insights into the role that glucose metabolism reprogramming plays in the progression of CRC progression together with its resistance to treatment. Ultimately, these insights strive to diminish the risks of CRC metastasis and recurrence.
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Affiliation(s)
- Rong Qin
- Department of Gastroenterology, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650051, China; Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, China
| | - Xirui Fan
- Department of Gastroenterology, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650051, China; Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, China
| | - Yun Huang
- Department of Gastroenterology, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650051, China; Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, China
| | - Sijing Chen
- Department of Gastroenterology, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650051, China; Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, China
| | - Rui Ding
- Department of Gastroenterology, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650051, China; Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, China
| | - Ying Yao
- Department of Gastroenterology, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650051, China; Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, China
| | - Rui Wu
- Department of Gastroenterology, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650051, China; Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, China
| | - Yiyao Duan
- Department of Gastroenterology, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650051, China; Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, China
| | - Xiang Li
- Kunming Medical University, Kunming, Yunnan 650500, China
| | - Hameed Ullah Khan
- Department of Gastroenterology, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650051, China; Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, China
| | - Jun Hu
- The First People's Hospital of Kunming, Yunnan 650034, China.
| | - Hui Wang
- Department of Gastroenterology, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650051, China; Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, China.
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Zheng G, Shi J, Li Q, Jin X, Fang Y, Zhang Z, Cao Q, Zhu L, Shen J. BAP1 inactivation promotes lactate production by leveraging the subcellular localization of LDHA in melanoma. Cell Death Discov 2024; 10:483. [PMID: 39587076 PMCID: PMC11589756 DOI: 10.1038/s41420-024-02250-6] [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: 03/27/2024] [Revised: 11/13/2024] [Accepted: 11/20/2024] [Indexed: 11/27/2024] Open
Abstract
BRCA1-associated protein 1 (BAP1) acts as a tumor suppressor and can affect the cell cycle, tumor immunity, and cellular metabolism through multiple pathways. In melanoma, BAP1 mutations promote tumor cell glycolysis, leading to increased lactate production. The tumor microenvironment with high lactate levels is often associated with immunosuppression and tumor progression. The inhibitory effect of BAP1 on glycolysis has been found in a variety of tumors, but the specific mechanism by which BAP1 inhibits lactate production still needs to be elucidated. In this study, we show that BAP1 can interact directly with lactate dehydrogenase (LDHA), causing LDHA to accumulate in the nucleus. Conversely, BAP1 deletion leads to the accumulation of LDHA in the cytoplasm, catalyzing the production of lactate from pyruvate that results in increased lactate levels inside and outside the cell. By elucidating the interaction between BAP1 and LDHA and the subsequent effects on lactate production in melanoma cells, this work provides insights into the mechanism of BAP1-mediated metabolic regulation. Furthermore, it may provide novel directions for the clinical treatment of BAP1-mutant melanoma.
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Affiliation(s)
- Guopei Zheng
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
- Institute of Translational Medicine, National Facility for Translational Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jiahao Shi
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
| | - Qian Li
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
- Institute of Translational Medicine, National Facility for Translational Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoliang Jin
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
| | - Yan Fang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
- Institute of Translational Medicine, National Facility for Translational Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhe Zhang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
- Institute of Translational Medicine, National Facility for Translational Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qin Cao
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Lili Zhu
- Songjiang Research Institute and Songjiang Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Jianfeng Shen
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
- Institute of Translational Medicine, National Facility for Translational Medicine, Shanghai Jiao Tong University, Shanghai, China.
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Wu S, Li D, Han P, Li L, Zhao J, Zhang H, Zhou X, Li P, Mo Y. MicroRNA‑374a‑5p/ANLN axis promotes malignant progression of Oral squamous cell carcinoma. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2024:1-16. [PMID: 39449219 DOI: 10.1080/15257770.2024.2419555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 10/15/2024] [Indexed: 10/26/2024]
Abstract
BACKGROUND Recent research has revealed a significant association between Anillin (ANLN) and miR-374a‑5p with the progression of tumors. Additionally, bioinformatics analysis indicated an inverse relationship in transcript expression levels between ANLN and miR-374a-5p. However, the specific mechanisms driving the miR-374a-5p/ANLN signaling axis in oral squamous cell carcinoma (OSCC) have not been thoroughly explored. METHODS ANLN and miR-374a‑5p expression were evaluated within OSCC cell lines and tissues by RT-qPCR. Using bioinformatics databases, it has been demonstrated that the ANLN gene could be a target of miR-374a-5p. MiR-374a‑5p and ANLN correlation could be assessed via the dual-luciferase reporter assay and western blotting techniques. Functional studies were employed to investigate the behavioral patterns of miR-374a‑5p within OSCC cells. RESULTS miR-374a‑5p expression could be remarkably downregulated within both OSCC tissues and cells, coinciding with high ANLN expression. ANLN was a specific target gene for miR-374a‑5p by luciferase function assay. The expression of miR-374a‑5p could serve as a diagnostic biomarker and independently predict a poor prognosis in patients with OSCC, and the counteractive effect of upregulating miR-374a‑5p was observed on the proliferative, migratory, and invasive capabilities of OSCC cells. CONCLUSIONS The findings suggest that the miR-374a‑5p/ANLN signaling axis potentially modulates the advancement of OSCC, and miR-374a‑5p may serve as potential therapeutic targets of oral cancer.
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Affiliation(s)
- Shu Wu
- Guangxi Clinical Research Center for Craniofacial Deformity, Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Health Commission Key laboratory of prevention and treatment for oral infectious diseases, Nanning, P.R. China
- Department of Pathology, College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Danping Li
- Guangxi Clinical Research Center for Craniofacial Deformity, Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Health Commission Key laboratory of prevention and treatment for oral infectious diseases, Nanning, P.R. China
- Department of Pathology, College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Peipei Han
- Department of Pathology, College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Limei Li
- Guangxi Clinical Research Center for Craniofacial Deformity, Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Health Commission Key laboratory of prevention and treatment for oral infectious diseases, Nanning, P.R. China
- Department of Pathology, College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Jun Zhao
- Guangxi Clinical Research Center for Craniofacial Deformity, Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Health Commission Key laboratory of prevention and treatment for oral infectious diseases, Nanning, P.R. China
- Department of Pathology, College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Haishan Zhang
- Guangxi Clinical Research Center for Craniofacial Deformity, Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Health Commission Key laboratory of prevention and treatment for oral infectious diseases, Nanning, P.R. China
- Department of Pathology, College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Xiaohui Zhou
- Guangxi Clinical Research Center for Craniofacial Deformity, Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Health Commission Key laboratory of prevention and treatment for oral infectious diseases, Nanning, P.R. China
- Department of Pathology, College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Ping Li
- Guangxi Clinical Research Center for Craniofacial Deformity, Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Health Commission Key laboratory of prevention and treatment for oral infectious diseases, Nanning, P.R. China
- Department of Pathology, College & Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, P.R. China
| | - Yingxi Mo
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, P.R. China
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Thirunavukkarasu S, Banerjee S, Tantray I, Ojha R. Non-coding RNA and reprogrammed mitochondrial metabolism in genitourinary cancer. Front Genet 2024; 15:1364389. [PMID: 38544804 PMCID: PMC10965626 DOI: 10.3389/fgene.2024.1364389] [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: 01/02/2024] [Accepted: 03/04/2024] [Indexed: 11/11/2024] Open
Abstract
Non-coding ribonucleic acids (ncRNAs) have been recently shown to contribute to tumorigenesis by mediating changes in metabolism. ncRNAs act as key molecules in metabolic pathways regulation. The dysregulation of ncRNAs during cancer progression contributes to altered metabolic phenotypes leading to reprogrammed metabolism. Since ncRNAs affect different tumor processes by regulating mitochondrial dynamics and metabolism, in the future ncRNAs can be exploited in disease detection, diagnosis, treatment, and resistance. The purpose of this review is to highlight the role of ncRNAs in mitochondrial metabolic reprogramming and to relate their therapeutic potential in the management of genitourinary cancer.
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Affiliation(s)
- Sandiya Thirunavukkarasu
- Department of Urology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Shouryarudra Banerjee
- Department of Urology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Ishaq Tantray
- InventX Scientia, Kashmir, India
- Department of Pathology, School of Medicine, Stanford University, Stanford, CA, United States
| | - Rani Ojha
- Department of Urology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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9
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Han JH, Lee EJ, Park W, Ha KT, Chung HS. Natural compounds as lactate dehydrogenase inhibitors: potential therapeutics for lactate dehydrogenase inhibitors-related diseases. Front Pharmacol 2023; 14:1275000. [PMID: 37915411 PMCID: PMC10616500 DOI: 10.3389/fphar.2023.1275000] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 09/27/2023] [Indexed: 11/03/2023] Open
Abstract
Lactate dehydrogenase (LDH) is a crucial enzyme involved in energy metabolism and present in various cells throughout the body. Its diverse physiological functions encompass glycolysis, and its abnormal activity is associated with numerous diseases. Targeting LDH has emerged as a vital approach in drug discovery, leading to the identification of LDH inhibitors among natural compounds, such as polyphenols, alkaloids, and terpenoids. These compounds demonstrate therapeutic potential against LDH-related diseases, including anti-cancer effects. However, challenges concerning limited bioavailability, poor solubility, and potential toxicity must be addressed. Combining natural compounds with LDH inhibitors has led to promising outcomes in preclinical studies. This review highlights the promise of natural compounds as LDH inhibitors for treating cancer, cardiovascular, and neurodegenerative diseases.
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Affiliation(s)
- Jung Ho Han
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), Daegu, Republic of Korea
| | - Eun-Ji Lee
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), Daegu, Republic of Korea
| | - Wonyoung Park
- Korean Convergence Medical Science Major, KIOM Campus, University of Science and Technology (UST), Daegu, Republic of Korea
| | - Ki-Tae Ha
- Korean Convergence Medical Science Major, KIOM Campus, University of Science and Technology (UST), Daegu, Republic of Korea
| | - Hwan-Suck Chung
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), Daegu, Republic of Korea
- Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Republic of Korea
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10
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Ali M, Bamezai RNK, Singh RP. Invasive Breast Cancer: miR-24-2 Targets Genes Associated with Survival and Sensitizes MDA-MB-231 Cells to Berberine. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2023; 27:409-420. [PMID: 37669117 DOI: 10.1089/omi.2023.0092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/07/2023]
Abstract
MicroRNA aberrations including that of miR-24-2 have been reported in various cancers. However, the target genes for miR-24-2 are yet to be identified and validated in invasive breast cancer and the triple-negative breast cancer (TNBC). Using in silico approaches and gene expression analyses, we identified and validated the target genes of miR-24-2 in invasive breast cancer, majority of which were TNBC. We studied the translational potential of these target genes using berberine in a TNBC cell line. Differentially expressed genes targeted by miR-24-2 were identified and analyzed for their survival effects using the The Cancer Genome Atlas-Breast Invasive Carcinoma (-BRCA) samples. Furthermore, we carried out protein-protein interaction, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, gene expression, and Kaplan-Meier survival analyses using common targets of miR-24-2 in invasive breast cancer/TNBC. We identified 11 biomarker candidate genes as crucial targets of miR-24-2. The survival of breast cancer patients was significantly associated with the low expressions of nine genes, including RACGAP1, KIAA1199, TIMM17A, LYRM7, IL1R1, SLC1A3, DTX4, L1CAM, and SAP30-like (SAP30L), and high expressions of two genes, SOD2 and HLA-DQB2. These in silico findings were validated by overexpressing miR-24-2 and assessing the expression pattern of these target genes in the TNBC MDA-MB-231 cells. miR-24-2 overexpression inhibited (by 20%; p < 0.001) cell proliferation and sensitized the anticancer effect of berberine. In all, this study reports on the novel target genes of miR-24-2 in invasive breast cancer/TNBC, and that miR-24-2 sensitizes MDA-MB-231 cells to berberine. These data lend evidence for the translational potentials of miR-24-2 for invasive breast cancer diagnostic and therapeutic innovation.
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Affiliation(s)
- Mansoor Ali
- Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Rameshwar N K Bamezai
- Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Rana P Singh
- Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
- Special Centre for Systems Medicine, Jawaharlal Nehru University, New Delhi, India
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado, USA
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11
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Hoskin AJ, Holt AK, Legge DN, Collard TJ, Williams AC, Vincent EE. Aspirin and the metabolic hallmark of cancer: novel therapeutic opportunities for colorectal cancer. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2023; 4:600-615. [PMID: 37720350 PMCID: PMC10501897 DOI: 10.37349/etat.2023.00155] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 06/08/2023] [Indexed: 09/19/2023] Open
Abstract
Aspirin is a well-known nonsteroidal anti-inflammatory drug (NSAID) that has a recognized role in cancer prevention as well as evidence to support its use as an adjuvant for cancer treatment. Importantly there has been an increasing number of studies contributing to the mechanistic understanding of aspirins' anti-tumour effects and these studies continue to inform the potential clinical use of aspirin for both the prevention and treatment of cancer. This review focuses on the emerging role of aspirin as a regulator of metabolic reprogramming, an essential "hallmark of cancer" required to support the increased demand for biosynthetic intermediates needed for sustained proliferation. Cancer cells frequently undergo metabolic rewiring driven by oncogenic pathways such as hypoxia-inducible factor (HIF), wingless-related integration site (Wnt), mammalian target of rapamycin (mTOR), and nuclear factor kappa light chain enhancer of activated B cells (NF-κB), which supports the increased proliferative rate as tumours develop and progress. Reviewed here, cellular metabolic reprogramming has been identified as a key mechanism of action of aspirin and include the regulation of key metabolic drivers, the regulation of enzymes involved in glycolysis and glutaminolysis, and altered nutrient utilisation upon aspirin exposure. Importantly, as aspirin treatment exposes metabolic vulnerabilities in tumour cells, there is an opportunity for the use of aspirin in combination with specific metabolic inhibitors in particular, glutaminase (GLS) inhibitors currently in clinical trials such as telaglenastat (CB-839) and IACS-6274 for the treatment of colorectal and potentially other cancers. The increasing evidence that aspirin impacts metabolism in cancer cells suggests that aspirin could provide a simple, relatively safe, and cost-effective way to target this important hallmark of cancer. Excitingly, this review highlights a potential new role for aspirin in improving the efficacy of a new generation of metabolic inhibitors currently undergoing clinical investigation.
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Affiliation(s)
- Ashley J. Hoskin
- Department of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, BS8 1TW Bristol, UK
| | - Amy K. Holt
- Department of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, BS8 1TW Bristol, UK
| | - Danny N. Legge
- Department of Translational Health Sciences, Dorothy Hodgkin Building, University of Bristol, BS1 3NY Bristol, UK
| | - Tracey J. Collard
- Department of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, BS8 1TW Bristol, UK
| | - Ann C. Williams
- Department of Cellular and Molecular Medicine, Biomedical Sciences Building, University of Bristol, BS8 1TW Bristol, UK
| | - Emma E. Vincent
- Department of Translational Health Sciences, Dorothy Hodgkin Building, University of Bristol, BS1 3NY Bristol, UK
- MRC Integrative Epidemiology Unit, Oakfield House, University of Bristol, BS8 2BN Bristol, UK
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12
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Zhan L, Su F, Li Q, Wen Y, Wei F, He Z, Chen X, Yin X, Wang J, Cai Y, Gong Y, Chen Y, Ma X, Zeng J. Phytochemicals targeting glycolysis in colorectal cancer therapy: effects and mechanisms of action. Front Pharmacol 2023; 14:1257450. [PMID: 37693915 PMCID: PMC10484417 DOI: 10.3389/fphar.2023.1257450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 08/10/2023] [Indexed: 09/12/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common malignant tumor in the world, and it is prone to recurrence and metastasis during treatment. Aerobic glycolysis is one of the main characteristics of tumor cell metabolism in CRC. Tumor cells rely on glycolysis to rapidly consume glucose and to obtain more lactate and intermediate macromolecular products so as to maintain growth and proliferation. The regulation of the CRC glycolysis pathway is closely associated with several signal transduction pathways and transcription factors including phosphatidylinositol 3-kinases/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), hypoxia-inducible factor-1 (HIF-1), myc, and p53. Targeting the glycolytic pathway has become one of the key research aspects in CRC therapy. Many phytochemicals were shown to exert anti-CRC activity by targeting the glycolytic pathway. Here, we review the effects and mechanisms of phytochemicals on CRC glycolytic pathways, providing a new method of drug development.
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Affiliation(s)
- Lu Zhan
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Fangting Su
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiang Li
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yueqiang Wen
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Feng Wei
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhelin He
- Guang’an Hospital of Traditional Chinese Medicine, Guang’an, China
| | - Xiaoyan Chen
- Guang’an Hospital of Traditional Chinese Medicine, Guang’an, China
| | - Xiang Yin
- Guang’an Hospital of Traditional Chinese Medicine, Guang’an, China
| | - Jian Wang
- Guang’an Hospital of Traditional Chinese Medicine, Guang’an, China
| | - Yilin Cai
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuxia Gong
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yu Chen
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jinhao Zeng
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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13
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Chen M, Zhang Q, Xu F, Li Z, Li J, Wang W, Wang S, Wang M, Qiu T, Li J, Zhang H, Wang W. Ti 3C 2 and Ti 2C MXene materials for high-performance isolation of extracellular vesicles via coprecipitation. Anal Chim Acta 2023; 1269:341426. [PMID: 37290854 DOI: 10.1016/j.aca.2023.341426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 04/28/2023] [Accepted: 05/24/2023] [Indexed: 06/10/2023]
Abstract
Two-dimensional (2D) materials such as MXenes, are usually well utilized in the field of catalysts and battery due to their good hydrophilicity and diversified surface terminals. However, their potential applications in the treatment of biological samples have not been widely concerned. Extracellular vesicles (EVs) contain unique molecular signatures and could be used as biomarkers for the detection of severe diseases such as cancer, as well as monitoring the therapeutic response. In this work, two kinds of MXene materials (Ti3C2 and Ti2C) were successfully synthesized and employed in the isolation of EVs from the biological samples by taking advantage of the affinity interaction between the titanium (Ti) in MXenes and the phospholipid membrane of EVs. Compared with Ti2C MXene materials, TiO2 beads and the other EVs isolation methods, Ti3C2 MXene materials exhibited excellent isolation performance via the coprecipitation with EVs due to the abundant unsaturated coordination of Ti2+/Ti3+, and the dosage of materials was the lowest. Meanwhile, the whole isolation process could be done within 30 min and integrated well with the following analysis of proteins and ribonucleic acids (RNAs), which was also convenient and economic. Furthermore, the Ti3C2 MXene materials were used to isolate the EVs from the blood plasma of colorectal cancer (CRC) patients and healthy donors. Proteomics analysis of EVs showed that 67 proteins were up-regulated, in which most of them were closely related to CRC progression. These findings indicate that the MXene material-based EVs isolation method via coprecipitation provides an efficient tool for early diagnosis of diseases.
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Affiliation(s)
- Mengxi Chen
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Qi Zhang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Fang Xu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Zhi Li
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Jiaxi Li
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Wenjing Wang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Shuang Wang
- Zhengzhou Tobacco Research Institute of CNTC, Zhengzhou, 450001, China
| | - Mengmeng Wang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Tian Qiu
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Jiawei Li
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
| | - Haiyang Zhang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
| | - Weipeng Wang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
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14
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Hosseini-Abgir A, Naghizadeh MM, Igder S, Miladpour B. Insilco prediction of the role of the FriZZled5 gene in colorectal cancer. Cancer Treat Res Commun 2023; 36:100751. [PMID: 37595345 DOI: 10.1016/j.ctarc.2023.100751] [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: 03/19/2023] [Revised: 07/27/2023] [Accepted: 08/14/2023] [Indexed: 08/20/2023]
Abstract
INTRODUCTION In this study, we aimed to elucidate the crosstalk between the Wnt/β-catenin signaling pathway and colorectal cancer (CRC) associated with inflammatory bowel disease (IBD) using a bioinformatics analysis of putative common biomarkers and a systems biology approach. MATERIALS AND METHODS The following criteria were used to search the GEO and ArrayExpress databases for terms related to CRC and IBD: 1. The dataset containing the transcriptomic data, and 2. Untreated samples by medications or drugs. A total of 42 datasets were selected for additional analysis. The GEO2R identified the differentially expressed genes. The genes involved in the Wnt signaling pathway were extracted from the KEGG database. Enrichment analysis and miRNA target prediction were conducted through the ToppGene online tool. RESULTS In CRC datasets, there were 1168 up- and 998 down-regulated probes, whereas, in IBD datasets, there were 256 up- and 200 down-regulated probes. There were 65 upregulated and 57 downregulated genes shared by CRC and IBD. According to KEGG, there were 166 genes in the Wnt pathway. FriZZled5 (FZD5) was a down-regulated gene in both CRC and IBD, as determined by the intersection of CRC- and IBD-related DEGs with the Wnt pathway. It was also demonstrated that miR-191, miR-885-5p, miR-378a-3p, and miR-396-3p affect the FriZZled5 gene expression. CONCLUSION It is possible that increased expression of miR-191 and miR-885-5p, or decreased expression of miR-378a -3p and miR396-3, in IBD and CRC results in decreased expression of the FZD5 gene. Based on the function of this gene, FZD5 may be a potential therapeutic target in IBD that progresses to CRC.
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Affiliation(s)
| | | | - Somayeh Igder
- Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran
| | - Behnoosh Miladpour
- Department of Clinical Biochemistry, Fasa University of Medical Sciences, Fasa, Iran.
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15
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Xiong B, Huang Q, Zheng H, Lin S, Xu J. Recent advances microRNAs and metabolic reprogramming in colorectal cancer research. Front Oncol 2023; 13:1165862. [PMID: 37576895 PMCID: PMC10415904 DOI: 10.3389/fonc.2023.1165862] [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: 02/16/2023] [Accepted: 06/07/2023] [Indexed: 08/15/2023] Open
Abstract
Colorectal cancer (CRC) is a cancer with the highest incidence and mortality. Alteration of gene expression is the main pathophysiological mechanism of CRC, which results in disturbed signaling pathways and cellular metabolic processes. MicroRNAs are involved in almost all pathophysiological processes and are correlative with colorectal cancer metabolism, proliferation, and chemotherapy resistance. Metabolic reprogramming, an important feature of cancer, is strongly correlative with the development and prognosis of cancers, including colorectal cancer. MicroRNAs can target enzymes involved in metabolic processes, thus playing a regulatory role in tumor metabolism. The disorder of the signaling pathway is another characteristic of tumor, which induces the occurrence and proliferation of tumors, and is closely correlative with the prognosis and chemotherapy resistance of tumor patients. MicroRNAs can target the components of the signaling pathways to regulate their transduction. Understanding the function of microRNAs in the occurrence and proliferation of CRC provides novel insights into the optimal treatment strategies, prognosis, and development of diagnosis in CRC. This article reviews the relationship between CRC and microRNA expression and hopes to provide new options for the diagnosis and treatment of CRC.
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Affiliation(s)
- Bin Xiong
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Qiaoyi Huang
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Huida Zheng
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
- Group of Neuroendocrinology, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Jianhua Xu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
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16
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Macharia JM, Kaposztas Z, Varjas T, Budán F, Zand A, Bodnar I, Bence RL. Targeted lactate dehydrogenase genes silencing in probiotic lactic acid bacteria: A possible paradigm shift in colorectal cancer treatment? Biomed Pharmacother 2023; 160:114371. [PMID: 36758316 DOI: 10.1016/j.biopha.2023.114371] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 01/31/2023] [Accepted: 02/03/2023] [Indexed: 02/10/2023] Open
Abstract
Even though the pathophysiology of colorectal cancer (CRC) is complicated and poorly understood, interactions between risk factors appear to be key in the development and progression of the malignancy. The popularity of using lactic acid bacteria (LAB) prebiotics and probiotics to modulate the tumor microenvironment (TME) has grown widely over the past decade. The objective of this study was therefore to determine the detrimental effects of LAB-derived lactic acid in the colonic mucosa in colorectal cancer management. Six library databases and a web search engine were used to execute a structured systematic search of the existing literature, considering all publications published up until August 2022. A total of 7817 papers were screened, all of which were published between 1995 and August 2022. However, only 118 articles met the inclusion criterion. Lactic acid has been directly linked to the massive proliferation of cancerous cells since the glycolytic pathway provides cancerous cells with not only ATP, but also biosynthetic intermediates for rapid growth and proliferation. Our research suggests that targeting LAB metabolic pathways is capable of suppressing tumor growth and that the LDH gene is critical for tumorigenesis. Silencing of Lactate dehydrogenase, A (LDHA), B (LDHB), (LDHL), and hicD genes should be explored to inhibit fermentative glycolysis yielding lactic acid as the by-product. More studies are necessary for a solid understanding of this topic so that LAB and their corresponding lactic acid by-products do not have more adverse effects than their widely touted positive outcomes in CRC management.
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Affiliation(s)
- John M Macharia
- Doctoral School of Health Sciences, Faculty of Health Science, University of Pẻcs, City of Pẻcs, Hungary.
| | | | - Tímea Varjas
- University of Pẻcs, Medical School, Department of Public Health Medicine, City of Pẻcs, Hungary
| | - Ferenc Budán
- University of Pẻcs, Medical School, Institute of Transdisciplinary Discoveries, City of Pẻcs, Hungary; University of Pécs, Medical School, Institute of Physiology, City of Pécs, Hungary
| | - Afshin Zand
- University of Pẻcs, Medical School, Department of Public Health Medicine, City of Pẻcs, Hungary
| | - Imre Bodnar
- Doctoral School of Health Sciences, Faculty of Health Science, University of Pẻcs, City of Pẻcs, Hungary
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17
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Liu Y, Jiang C, Liu Q, Huang R, Wang M, Guo X. CircRNAs: emerging factors for regulating glucose metabolism in colorectal cancer. Clin Transl Oncol 2023:10.1007/s12094-023-03131-7. [PMID: 36944731 DOI: 10.1007/s12094-023-03131-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 02/19/2023] [Indexed: 03/23/2023]
Abstract
Colorectal cancer is a malignant disease with a high incidence and low survival rate, and the effectiveness of traditional treatments, such as surgery and radiotherapy, is very limited. CircRNAs, a kind of stable endogenous circular RNA, generally function by sponging miRNAs and binding or translating proteins. CircRNAs have been identified to play an important role in regulating the proliferation and metabolism of CRC. In recent years, many reports have indicated that by regulating the expression of glycolysis-related proteins, such as GLUT1 and HK2, or directly translating proteins, circRNAs can promote the Warburg effect in cancer cells, thereby driving CRC metabolism. Moreover, the Warburg effect increases lactate production in cancer cells and promotes acidification of the TME, which further drives cancer progression. In this review, we summarized the remarkable role of circRNAs in regulating glucose metabolism in CRC in recent years, which might be useful for finding new targets for the clinical treatment of CRC.
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Affiliation(s)
- Yulin Liu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, The People's Republic of China
| | - Chenjun Jiang
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, The People's Republic of China
| | - Qianqian Liu
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, The People's Republic of China
| | - Runchun Huang
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, The People's Republic of China
| | - Mancai Wang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, The People's Republic of China
- General Surgery Department, The Second Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Xiaohu Guo
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, The People's Republic of China.
- General Surgery Department, The Second Hospital of Lanzhou University, Lanzhou, 730000, China.
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18
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Missiaen R, Lesner NP, Simon MC. HIF: a master regulator of nutrient availability and metabolic cross-talk in the tumor microenvironment. EMBO J 2023; 42:e112067. [PMID: 36808622 PMCID: PMC10015374 DOI: 10.15252/embj.2022112067] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 12/13/2022] [Accepted: 12/16/2022] [Indexed: 02/22/2023] Open
Abstract
A role for hypoxia-inducible factors (HIFs) in hypoxia-dependent regulation of tumor cell metabolism has been thoroughly investigated and covered in reviews. However, there is limited information available regarding HIF-dependent regulation of nutrient fates in tumor and stromal cells. Tumor and stromal cells may generate nutrients necessary for function (metabolic symbiosis) or deplete nutrients resulting in possible competition between tumor cells and immune cells, a result of altered nutrient fates. HIF and nutrients in the tumor microenvironment (TME) affect stromal and immune cell metabolism in addition to intrinsic tumor cell metabolism. HIF-dependent metabolic regulation will inevitably result in the accumulation or depletion of essential metabolites in the TME. In response, various cell types in the TME will respond to these hypoxia-dependent alterations by activating HIF-dependent transcription to alter nutrient import, export, and utilization. In recent years, the concept of metabolic competition has been proposed for critical substrates, including glucose, lactate, glutamine, arginine, and tryptophan. In this review, we discuss how HIF-mediated mechanisms control nutrient sensing and availability in the TME, the competition for nutrients, and the metabolic cross-talk between tumor and stromal cells.
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Affiliation(s)
- Rindert Missiaen
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - Nicholas P Lesner
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - M Celeste Simon
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
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19
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Pal S, Sharma A, Mathew SP, Jaganathan BG. Targeting cancer-specific metabolic pathways for developing novel cancer therapeutics. Front Immunol 2022; 13:955476. [PMID: 36618350 PMCID: PMC9815821 DOI: 10.3389/fimmu.2022.955476] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 10/20/2022] [Indexed: 12/24/2022] Open
Abstract
Cancer is a heterogeneous disease characterized by various genetic and phenotypic aberrations. Cancer cells undergo genetic modifications that promote their proliferation, survival, and dissemination as the disease progresses. The unabated proliferation of cancer cells incurs an enormous energy demand that is supplied by metabolic reprogramming. Cancer cells undergo metabolic alterations to provide for increased energy and metabolite requirement; these alterations also help drive the tumor progression. Dysregulation in glucose uptake and increased lactate production via "aerobic glycolysis" were described more than 100 years ago, and since then, the metabolic signature of various cancers has been extensively studied. However, the extensive research in this field has failed to translate into significant therapeutic intervention, except for treating childhood-ALL with amino acid metabolism inhibitor L-asparaginase. Despite the growing understanding of novel metabolic alterations in tumors, the therapeutic targeting of these tumor-specific dysregulations has largely been ineffective in clinical trials. This chapter discusses the major pathways involved in the metabolism of glucose, amino acids, and lipids and highlights the inter-twined nature of metabolic aberrations that promote tumorigenesis in different types of cancer. Finally, we summarise the therapeutic interventions which can be used as a combinational therapy to target metabolic dysregulations that are unique or common in blood, breast, colorectal, lung, and prostate cancer.
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Affiliation(s)
- Soumik Pal
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Amit Sharma
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Sam Padalumavunkal Mathew
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Bithiah Grace Jaganathan
- Stem Cells and Cancer Biology Research Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India,Jyoti and Bhupat Mehta School of Health Sciences and Technology, Indian Institute of Technology Guwahati, Guwahati, Assam, India,*Correspondence: Bithiah Grace Jaganathan,
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20
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Kocianova E, Piatrikova V, Golias T. Revisiting the Warburg Effect with Focus on Lactate. Cancers (Basel) 2022; 14:cancers14246028. [PMID: 36551514 PMCID: PMC9776395 DOI: 10.3390/cancers14246028] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 12/01/2022] [Accepted: 12/05/2022] [Indexed: 12/13/2022] Open
Abstract
Rewired metabolism is acknowledged as one of the drivers of tumor growth. As a result, aerobic glycolysis, or the Warburg effect, is a feature of many cancers. Increased glucose uptake and glycolysis provide intermediates for anabolic reactions necessary for cancer cell proliferation while contributing sufficient energy. However, the accompanying increased lactate production, seemingly wasting glucose carbon, was originally explained only by the need to regenerate NAD+ for successive rounds of glycolysis by the lactate dehydrogenase (LDH) reaction in the cytosol. After the discovery of a mitochondrial LDH isoform, lactate oxidation entered the picture, and lactate was recognized as an important oxidative fuel. It has also been revealed that lactate serves a variety of signaling functions and helps cells adapt to the new environment. Here, we discuss recent findings on lactate metabolism and signaling in cancer while attempting to explain why the Warburg effect is adopted by cancer cells.
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Affiliation(s)
- Eva Kocianova
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia
| | - Viktoria Piatrikova
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, 84215 Bratislava, Slovakia
| | - Tereza Golias
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia
- Correspondence:
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Tang Y, Gu S, Zhu L, Wu Y, Zhang W, Zhao C. LDHA: The Obstacle to T cell responses against tumor. Front Oncol 2022; 12:1036477. [PMID: 36518315 PMCID: PMC9742379 DOI: 10.3389/fonc.2022.1036477] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 11/03/2022] [Indexed: 11/16/2023] Open
Abstract
Immunotherapy has become a successful therapeutic strategy in certain solid tumors and hematological malignancies. However, this efficacy of immunotherapy is impeded by limited success rates. Cellular metabolic reprogramming determines the functionality and viability in both cancer cells and immune cells. Extensive research has unraveled that the limited success of immunotherapy is related to immune evasive metabolic reprogramming in tumor cells and immune cells. As an enzyme that catalyzes the final step of glycolysis, lactate dehydrogenase A (LDHA) has become a major focus of research. Here, we have addressed the structure, localization, and biological features of LDHA. Furthermore, we have discussed the various aspects of epigenetic regulation of LDHA expression, such as histone modification, DNA methylation, N6-methyladenosine (m6A) RNA methylation, and transcriptional control by noncoding RNA. With a focus on the extrinsic (tumor cells) and intrinsic (T cells) functions of LDHA in T-cell responses against tumors, in this article, we have reviewed the current status of LDHA inhibitors and their combination with T cell-mediated immunotherapies and postulated different strategies for future therapeutic regimens.
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Affiliation(s)
- Yu Tang
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Shuangshuang Gu
- Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Liqun Zhu
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yujiao Wu
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Wei Zhang
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Chuanxiang Zhao
- Institute of Medical Genetics and Reproductive Immunity, School of Medical Science and Laboratory Medicine, Jiangsu College of Nursing, Huai’an, Jiangsu, China
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22
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Abstract
High serum lactate dehydrogenase (LDH) levels are typically associated with a poor prognosis in many cancer types. Even the most effective drugs, which have radically improved outcomes in patients with melanoma over the past decade, provide only marginal benefit to those with high serum LDH levels. When viewed separately from the oncological, biochemical, biological and immunological perspectives, serum LDH is often interpreted in very different ways. Oncologists usually see high serum LDH only as a robust biomarker of a poor prognosis, and biochemists are aware of the complexity of the various LDH isoforms and of their key roles in cancer metabolism, whereas LDH is typically considered to be oncogenic and/or immunosuppressive by cancer biologists and immunologists. Integrating these various viewpoints shows that the regulation of the five LDH isoforms, and their enzymatic and non-enzymatic functions is closely related to key oncological processes. In this Review, we highlight that serum LDH is far more than a simple indicator of tumour burden; it is a complex biomarker associated with the activation of several oncogenic signalling pathways as well as with the metabolic activity, invasiveness and immunogenicity of many tumours, and constitutes an extremely attractive target for cancer therapy.
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Fan X, Nie X, Huang J, Zhang L, Wang X, Lu M. A Composite Bioinformatic Analysis to Explore Endoplasmic Reticulum Stress-Related Prognostic Marker and Potential Pathogenic Mechanisms in Glioma by Integrating Multiomics Data. JOURNAL OF ONCOLOGY 2022; 2022:9886044. [PMID: 36245971 PMCID: PMC9553508 DOI: 10.1155/2022/9886044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 07/18/2022] [Accepted: 08/14/2022] [Indexed: 11/18/2022]
Abstract
In recent years, abnormal endoplasmic reticulum stress (ERS) response, as an important regulator of immunity, may play a vital role in the occurrence, development, and treatment of glioma. Weighted correlation network analysis (WGCNA) based on six glioma datasets was used to screen eight prognostic-related differentially expressed ERS-related genes (PR-DE-ERSGs) and to construct a prognostic model. BMP2 and HEY2 were identified as protective factors (HR < 1), and NUP107, DRAM1, F2R, PXDN, RNF19A, and SCG5 were identified as risk factors for glioma (HR > 1). QRT-PCR further supported significantly higher DRAM1 and lower SCG5 relative mRNA expression in gliomas. Our model has demonstrated excellent performance in predicting the prognosis of glioma patients from numerous datasets. In addition, the model shows good stability in multiple tests. Our model also shows broad clinical promise in predicting drug treatment effects. More immune cells/processes in the high-risk population with poor prognosis illustrate the importance of the tumor immunosuppressive environment in glioma. The potential role of the HEY2-based competitive endogenous RNA (ceRNA) regulatory network in glioma was validated and revealed the possible important role of glycolysis in glioma ERS. IDH1 and TP53 mutations with better prognosis were strongly associated with the risk score and PR-DE-ERSGs expression in the model. mDNAsi was also closely related to the risk score and clinical characteristics.
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Affiliation(s)
- Xin Fan
- Department of Emergency, Shangrao Hospital Affiliated to Nanchang University, Shangrao People's Hospital, Shangrao 334000, China
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330000, China
| | - Xiyi Nie
- Department of Neurosurgery, Yichun Hospital Affiliated to Nanchang University, Yichun People's Hospital, Yichun 334000, China
| | - Junwen Huang
- The First Clinical Medical College of Nanchang University, Nanchang 330000, China
| | - Lingling Zhang
- School of Stomatology, Nanchang University, Nanchang 330000, China
| | - Xifu Wang
- Department of Emergency, Shangrao Hospital Affiliated to Nanchang University, Shangrao People's Hospital, Shangrao 334000, China
| | - Min Lu
- Department of Emergency, Shangrao Hospital Affiliated to Nanchang University, Shangrao People's Hospital, Shangrao 334000, China
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Fan X, Nie X, Huang J, Zhang L, Wang X, Lu M. A Composite Bioinformatic Analysis to Explore Endoplasmic Reticulum Stress-Related Prognostic Marker and Potential Pathogenic Mechanisms in Glioma by Integrating Multiomics Data. JOURNAL OF ONCOLOGY 2022. [DOI: https:/doi.org/10.1155/2022/9886044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2023]
Abstract
In recent years, abnormal endoplasmic reticulum stress (ERS) response, as an important regulator of immunity, may play a vital role in the occurrence, development, and treatment of glioma. Weighted correlation network analysis (WGCNA) based on six glioma datasets was used to screen eight prognostic-related differentially expressed ERS-related genes (PR-DE-ERSGs) and to construct a prognostic model. BMP2 and HEY2 were identified as protective factors (HR < 1), and NUP107, DRAM1, F2R, PXDN, RNF19A, and SCG5 were identified as risk factors for glioma (HR > 1). QRT-PCR further supported significantly higher DRAM1 and lower SCG5 relative mRNA expression in gliomas. Our model has demonstrated excellent performance in predicting the prognosis of glioma patients from numerous datasets. In addition, the model shows good stability in multiple tests. Our model also shows broad clinical promise in predicting drug treatment effects. More immune cells/processes in the high-risk population with poor prognosis illustrate the importance of the tumor immunosuppressive environment in glioma. The potential role of the HEY2-based competitive endogenous RNA (ceRNA) regulatory network in glioma was validated and revealed the possible important role of glycolysis in glioma ERS. IDH1 and TP53 mutations with better prognosis were strongly associated with the risk score and PR-DE-ERSGs expression in the model. mDNAsi was also closely related to the risk score and clinical characteristics.
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Affiliation(s)
- Xin Fan
- Department of Emergency, Shangrao Hospital Affiliated to Nanchang University, Shangrao People’s Hospital, Shangrao 334000, China
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330000, China
| | - Xiyi Nie
- Department of Neurosurgery, Yichun Hospital Affiliated to Nanchang University, Yichun People’s Hospital, Yichun 334000, China
| | - Junwen Huang
- The First Clinical Medical College of Nanchang University, Nanchang 330000, China
| | - Lingling Zhang
- School of Stomatology, Nanchang University, Nanchang 330000, China
| | - Xifu Wang
- Department of Emergency, Shangrao Hospital Affiliated to Nanchang University, Shangrao People’s Hospital, Shangrao 334000, China
| | - Min Lu
- Department of Emergency, Shangrao Hospital Affiliated to Nanchang University, Shangrao People’s Hospital, Shangrao 334000, China
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25
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Fan X, Nie X, Huang J, Zhang L, Wang X, Lu M. A Composite Bioinformatic Analysis to Explore Endoplasmic Reticulum Stress-Related Prognostic Marker and Potential Pathogenic Mechanisms in Glioma by Integrating Multiomics Data. JOURNAL OF ONCOLOGY 2022. [DOI: doi.org/10.1155/2022/9886044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2023]
Abstract
In recent years, abnormal endoplasmic reticulum stress (ERS) response, as an important regulator of immunity, may play a vital role in the occurrence, development, and treatment of glioma. Weighted correlation network analysis (WGCNA) based on six glioma datasets was used to screen eight prognostic-related differentially expressed ERS-related genes (PR-DE-ERSGs) and to construct a prognostic model. BMP2 and HEY2 were identified as protective factors (HR < 1), and NUP107, DRAM1, F2R, PXDN, RNF19A, and SCG5 were identified as risk factors for glioma (HR > 1). QRT-PCR further supported significantly higher DRAM1 and lower SCG5 relative mRNA expression in gliomas. Our model has demonstrated excellent performance in predicting the prognosis of glioma patients from numerous datasets. In addition, the model shows good stability in multiple tests. Our model also shows broad clinical promise in predicting drug treatment effects. More immune cells/processes in the high-risk population with poor prognosis illustrate the importance of the tumor immunosuppressive environment in glioma. The potential role of the HEY2-based competitive endogenous RNA (ceRNA) regulatory network in glioma was validated and revealed the possible important role of glycolysis in glioma ERS. IDH1 and TP53 mutations with better prognosis were strongly associated with the risk score and PR-DE-ERSGs expression in the model. mDNAsi was also closely related to the risk score and clinical characteristics.
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Affiliation(s)
- Xin Fan
- Department of Emergency, Shangrao Hospital Affiliated to Nanchang University, Shangrao People’s Hospital, Shangrao 334000, China
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330000, China
| | - Xiyi Nie
- Department of Neurosurgery, Yichun Hospital Affiliated to Nanchang University, Yichun People’s Hospital, Yichun 334000, China
| | - Junwen Huang
- The First Clinical Medical College of Nanchang University, Nanchang 330000, China
| | - Lingling Zhang
- School of Stomatology, Nanchang University, Nanchang 330000, China
| | - Xifu Wang
- Department of Emergency, Shangrao Hospital Affiliated to Nanchang University, Shangrao People’s Hospital, Shangrao 334000, China
| | - Min Lu
- Department of Emergency, Shangrao Hospital Affiliated to Nanchang University, Shangrao People’s Hospital, Shangrao 334000, China
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26
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Yao H, Yang F, Li Y. Natural products targeting human lactate dehydrogenases for cancer therapy: A mini review. Front Chem 2022; 10:1013670. [PMID: 36247675 PMCID: PMC9556992 DOI: 10.3389/fchem.2022.1013670] [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: 08/07/2022] [Accepted: 08/31/2022] [Indexed: 12/04/2022] Open
Abstract
Reprogramming cancer metabolism has become the hallmark of cancer progression. As the key enzyme catalyzing the conversion of pyruvate to lactate in aerobic glycolysis of cancer cells, human lactate dehydrogenase (LDH) has been a promising target in the discovery of anticancer agents. Natural products are important sources of new drugs. Up to now, some natural compounds have been reported with the activity to target LDH. To give more information on the development of LDH inhibitors and application of natural products, herein, we reviewed the natural compounds with inhibition of LDH from diverse structures and discussed the future direction of the discovery of natural LDH inhibitors for cancer therapy.
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Affiliation(s)
- Huankai Yao
- Department of Microbial and Biochemical Pharmacy, School of Pharmacy, Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China
- *Correspondence: Huankai Yao,
| | - Feng Yang
- School of Stomatology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yan Li
- Department of Microbial and Biochemical Pharmacy, School of Pharmacy, Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China
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27
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Suriya Muthukumaran N, Velusamy P, Akino Mercy CS, Langford D, Natarajaseenivasan K, Shanmughapriya S. MicroRNAs as Regulators of Cancer Cell Energy Metabolism. J Pers Med 2022; 12:1329. [PMID: 36013278 PMCID: PMC9410355 DOI: 10.3390/jpm12081329] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/11/2022] [Accepted: 08/16/2022] [Indexed: 11/17/2022] Open
Abstract
To adapt to the tumor environment or to escape chemotherapy, cancer cells rapidly reprogram their metabolism. The hallmark biochemical phenotype of cancer cells is the shift in metabolic reprogramming towards aerobic glycolysis. It was thought that this metabolic shift to glycolysis alone was sufficient for cancer cells to meet their heightened energy and metabolic demands for proliferation and survival. Recent studies, however, show that cancer cells rely on glutamine, lipid, and mitochondrial metabolism for energy. Oncogenes and scavenging pathways control many of these metabolic changes, and several metabolic and tumorigenic pathways are post-transcriptionally regulated by microRNA (miRNAs). Genes that are directly or indirectly responsible for energy production in cells are either negatively or positively regulated by miRNAs. Therefore, some miRNAs play an oncogenic role by regulating the metabolic shift that occurs in cancer cells. Additionally, miRNAs can regulate mitochondrial calcium stores and energy metabolism, thus promoting cancer cell survival, cell growth, and metastasis. In the electron transport chain (ETC), miRNAs enhance the activity of apoptosis-inducing factor (AIF) and cytochrome c, and these apoptosome proteins are directed towards the ETC rather than to the apoptotic pathway. This review will highlight how miRNAs regulate the enzymes, signaling pathways, and transcription factors of cancer cell metabolism and mitochondrial calcium import/export pathways. The review will also focus on the metabolic reprogramming of cancer cells to promote survival, proliferation, growth, and metastasis with an emphasis on the therapeutic potential of miRNAs for cancer treatment.
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Affiliation(s)
| | - Prema Velusamy
- Heart and Vascular Institute, Department of Medicine, Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Dauphin, PA 17033, USA
| | - Charles Solomon Akino Mercy
- Medical Microbiology Laboratory, Department of Microbiology, Centre for Excellence in Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamil Nadu, India
| | - Dianne Langford
- Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Kalimuthusamy Natarajaseenivasan
- Medical Microbiology Laboratory, Department of Microbiology, Centre for Excellence in Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, Tamil Nadu, India
- Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Santhanam Shanmughapriya
- Heart and Vascular Institute, Department of Medicine, Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Dauphin, PA 17033, USA
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28
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Yan S, Wang S, Wang X, Dai W, Chu J, Cheng M, Guo Z, Xu D. Emerging role of non-coding RNAs in glucose metabolic reprogramming and chemoresistance in colorectal cancer. Front Oncol 2022; 12:954329. [PMID: 35978828 PMCID: PMC9376248 DOI: 10.3389/fonc.2022.954329] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 07/11/2022] [Indexed: 11/28/2022] Open
Abstract
Metabolic reprogramming plays a critical role in colorectal cancer (CRC). It contributes to CRC by shaping metabolic phenotypes and causing uncontrolled proliferation of CRC cells. Glucose metabolic reprogramming is common in carcinogenesis and cancer progression. Growing evidence has implicated the modifying effects of non-coding RNAs (ncRNAs) in glucose metabolic reprogramming and chemoresistance in CRC. In this review, we have summarized currently published studies investigating the role of ncRNAs in glucose metabolic alterations and chemoresistance in CRC. Elucidating the interplay between ncRNAs and glucose metabolic reprogramming provides insight into exploring novel biomarkers for the diagnosis and prognosis prediction of CRC.
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Affiliation(s)
- Shushan Yan
- Department of Gastrointestinal and Anal Diseases Surgery of the Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Shufeng Wang
- Medical Experimental Training Center, Weifang Medical University, Weifang, China
| | - Xinyi Wang
- Clinical Medicine of Basic Medical School, Shandong First Medical University, Jinan, China
| | - Wenqing Dai
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Jinjin Chu
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Min Cheng
- Department of Physiology, Weifang Medical University, Weifang, China
| | - Zhiliang Guo
- Department of Spine Surgery, The 80th Group Army Hospital of Chinese People’s Liberation Army (PLA), Weifang, China
- *Correspondence: Zhiliang Guo, ; Donghua Xu,
| | - Donghua Xu
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
- Department of Rheumatology of the First Affiliated Hospital, Weifang Medical University, Weifang, China
- *Correspondence: Zhiliang Guo, ; Donghua Xu,
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29
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Liu X, Zhao Y, Wu X, Liu Z, Liu X. A novel strategy to fuel cancer immunotherapy: targeting glucose metabolism to remodel the tumor microenvironment. Front Oncol 2022; 12:931104. [PMID: 35924168 PMCID: PMC9340371 DOI: 10.3389/fonc.2022.931104] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/27/2022] [Indexed: 12/20/2022] Open
Abstract
The promising results of immunotherapy in tumors have changed the current treatment modality for cancer. However, the remarkable responses are limited to a minority of patients, which is due to immune suppression in the tumor microenvironment (TME). These include the pre-exists of suppressive immune cells, physical barriers to immune infiltration, antigen and antigen presentation deficiency, and expression of inhibitory immune checkpoint molecules. Recently, increasing evidence reveal that tumor metabolism, especially abnormal glucose metabolism of tumors, plays an essential role in tumor immune escape and is a potential target to combine with immunotherapy. By glucose uptake, tumor cells alter their metabolism to facilitate unregulated cellular proliferation and survival and regulate the expression of inhibitory immune checkpoint molecules. Meanwhile, glucose metabolism also regulates the activation, differentiation, and functions of immunocytes. In addition, tumor mainly utilizes glycolysis for energy generation and cellular proliferation, which cause the TME to deplete nutrients for infiltrating immune cells such as T cells and produce immunosuppressive metabolites. Thus, therapeutics that target glucose metabolism, such as inhibiting glycolytic activity, alleviating hypoxia, and targeting lactate, have shown promise as combination therapies for different types of cancer. In this review, we summarized the functions of glucose metabolism in the tumor cells, immune cells, and tumor microenvironment, as well as strategies to target glucose metabolism in combination with immune checkpoint blockade for tumor therapy.
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Affiliation(s)
- Xu Liu
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- Department of Head, Neck and Mammary Gland Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yujie Zhao
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xi Wu
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Zhihui Liu
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaowei Liu
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Xiaowei Liu,
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Circular RNA circVAMP3 promotes aerobic glycolysis and proliferation by regulating LDHA in renal cell carcinoma. Cell Death Dis 2022; 13:443. [PMID: 35525866 PMCID: PMC9079058 DOI: 10.1038/s41419-022-04863-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 04/12/2022] [Accepted: 04/19/2022] [Indexed: 12/14/2022]
Abstract
Metabolic dysfunction is seen in cancer cells where increased glycolysis provides energy for growth. Circular RNAs (circRNAs) are thought to assist in glucose metabolism and the switch to glycolysis. Through screening, we found that circVAMP3 was necessary for both glycolytic and proliferative activities in renal cell carcinoma (RCC). Furthermore, circVAMP3 expression was elevated in RCC patients in correspondence with TNM stage. Mechanistically, circVAMP3 was observed to interact directly with lactate dehydrogenase A (LDHA) and modulate its activity. The circVAMP3-LDHA interaction facilitated LDHA phosphorylation at tyrosine 10 (Y10) catalyzed by the upstream kinase fibroblast growth factor receptor type 1 (FGFR1). Therefore, this study reveals a novel molecular mechanism by which circVAMP3 promotes glycolysis and proliferation through regulating the enzymatic activity of glycolytic enzyme, suggesting that circVAMP3 may represent an RCC biomarker and treatment target.
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LINC01128 facilitates the progression of pancreatic cancer through up-regulation of LDHA by targeting miR-561-5p. Cancer Cell Int 2022; 22:93. [PMID: 35193567 PMCID: PMC8862213 DOI: 10.1186/s12935-022-02490-5] [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: 09/18/2021] [Accepted: 01/24/2022] [Indexed: 12/24/2022] Open
Abstract
Background Long non-coding RNAs (lncRNAs) regulate tumor development and metastasis in several types of cancers through various molecular mechanisms. However, the biological role of most lncRNAs in pancreatic cancer (PC) remains unclear. Here, we explored the expression, biological functions, and molecular mechanism of LINC01128 in PC. Methods Quantitive reverse transcription PCR was used to detect the expression level of LINC01128 in PC tissues and different PC cell lines. A loss-of-function and gain-of-function experiment was used to explore the biological effects of LINC01128 on PC carcinogenesis in vitro and in vivo. Western blot analysis, subcellular fractionation experiment, luciferase reporter gene assay, and MS2-RNA immunoprecipitation experiment were used to study the potential molecular mechanism of LINC01128 during carcinogenesis. Results The expression of LINC01128 was upregulated in PC tissues and cell lines, and overexpression of LINC01128 was significantly related to the poor prognosis of patients with PC. Furthermore, silencing LINC01128 significantly inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of PC cells in vitro and tumor growth in vivo, while LINC01128 overexpression promoted these processes. Further research showed that LINC01128 acted as a sponge for microRNA miR-561-5p, and lactate dehydrogenase A (LDHA) was the downstream target gene of miR-561-5p. It was also revealed that the expression of miR-561-5p in PC was decreased, and a negative correlation between miR-561-5p and LINC01128 was revealed. Based on rescue experiments, LDHA overexpression partially restored the inhibitory effect of LINC01128 knockdown on proliferation, migration, and invasion of PC cells. Conclusions LINC01128 promotes the proliferation, migration, invasion, and EMT of PC by regulating the miR-561-5p/LDHA axis, suggesting LINC01128 may be a new prognostic marker and therapeutic target in PC. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02490-5.
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Gibson MS, Noronha-Estima C, Gama-Carvalho M. Therapeutic Metabolic Reprograming Using microRNAs: From Cancer to HIV Infection. Genes (Basel) 2022; 13:273. [PMID: 35205318 PMCID: PMC8872267 DOI: 10.3390/genes13020273] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/27/2022] [Accepted: 01/27/2022] [Indexed: 02/04/2023] Open
Abstract
MicroRNAs (miRNAs) are crucial regulators of cellular processes, including metabolism. Attempts to use miRNAs as therapeutic agents are being explored in several areas, including the control of cancer progression. Recent evidence suggests fine tuning miRNA activity to reprogram tumor cell metabolism has enormous potential as an alternative treatment option. Indeed, cancer growth is known to be linked to profound metabolic changes. Likewise, the emerging field of immunometabolism is leading to a refined understanding of how immune cell proliferation and function is governed by glucose homeostasis. Different immune cell types are now known to have unique metabolic signatures that switch in response to a changing environment. T-cell subsets exhibit distinct metabolic profiles which underlie their alternative differentiation and phenotypic functions. Recent evidence shows that the susceptibility of CD4+ T-cells to HIV infection is intimately linked to their metabolic activity, with many of the metabolic features of HIV-1-infected cells resembling those found in tumor cells. In this review, we discuss the use of miRNA modulation to achieve metabolic reprogramming for cancer therapy and explore the idea that the same approach may serve as an effective mechanism to restrict HIV replication and eliminate infected cells.
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Affiliation(s)
| | | | - Margarida Gama-Carvalho
- BioISI—Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, 1749-016 Lisboa, Portugal; (M.S.G.); (C.N.-E.)
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Valacchi G, Pambianchi E, Coco S, Pulliero A, Izzotti A. MicroRNA Alterations Induced in Human Skin by Diesel Fumes, Ozone, and UV Radiation. J Pers Med 2022; 12:176. [PMID: 35207665 PMCID: PMC8880698 DOI: 10.3390/jpm12020176] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 11/17/2022] Open
Abstract
Epigenetic alterations are a driving force of the carcinogenesis process. MicroRNAs play a role in silencing mutated oncogenes, thus defending the cell against the adverse consequences of genotoxic damages induced by environmental pollutants. These processes have been well investigated in lungs; however, although skin is directly exposed to a great variety of environmental pollutants, more research is needed to better understand the effect on cutaneous tissue. Therefore, we investigated microRNA alteration in human skin biopsies exposed to diesel fumes, ozone, and UV light for over 24 h of exposure. UV and ozone-induced microRNA alteration right after exposure, while the peak of their deregulations induced by diesel fumes was reached only at the end of the 24 h. Diesel fumes mainly altered microRNAs involved in the carcinogenesis process, ozone in apoptosis, and UV in DNA repair. Accordingly, each tested pollutant induced a specific pattern of microRNA alteration in skin related to the intrinsic mechanisms activated by the specific pollutant. These alterations, over a short time basis, reflect adaptive events aimed at defending the tissue against damages. Conversely, whenever environmental exposure lasts for a long time, the irreversible alteration of the microRNA machinery results in epigenetic damage contributing to the pathogenesis of inflammation, dysplasia, and cancer induced by environmental pollutants.
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Affiliation(s)
- Giuseppe Valacchi
- Animal Science Department, Plants for Human Health Institute, North Carolina State University, Research Campus Kannapolis, Kannapolis, NC 28081, USA; (G.V.); (E.P.)
- Department of Environmental Sciences and Prevention, University of Ferrara, 44121 Ferrara, Italy
- Department of Food and Nutrition, Kyung Hee University, Seoul 130-701, Korea
| | - Erika Pambianchi
- Animal Science Department, Plants for Human Health Institute, North Carolina State University, Research Campus Kannapolis, Kannapolis, NC 28081, USA; (G.V.); (E.P.)
| | - Simona Coco
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy;
| | | | - Alberto Izzotti
- Department of Experimental Medicine, University of Genova, 16132 Genova, Italy
- UOC Mutagenesis and Cancer Prevention, IRCCS San Martino Hospital, 16132 Genova, Italy
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Li W, Lu Y, Ye C, Ouyang M. The Regulatory Network of MicroRNA in the Metabolism of Colorectal Cancer. J Cancer 2022; 12:7454-7464. [PMID: 35003365 PMCID: PMC8734415 DOI: 10.7150/jca.61618] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 10/24/2021] [Indexed: 01/26/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common malignant tumor in the world. During the progression of CRC, the entire metabolic network undergoes reprogramming, including marked changes in the regulation of glucose, lipid and amino acid metabolism. Although microRNAs (miRNAs) account for only 1% of the entire human genome, they play an important role in almost all physiological and pathological processes in the body. MiRNAs can react directly with key enzymes in the metabolic processes. MiRNAs also interact with other ncRNAs, as a member of non-coding RNA (ncRNA), to form their own regulatory network in various oncogenic pathways of CRC metabolism. The progression of colorectal cancer is closely related to the intestinal flora, where miRNAs act as important mediators. Understanding how miRNAs act in the regulatory network of CRC metabolism is helpful to elucidate the characteristics of tumor occurrence, proliferation, metastasis and drug resistance. This review summarizes the role of miRNAs in the metabolism of CRC and how miRNAs interact with key enzymes, ncRNA and intestinal flora to further discuss how miRNAs affect CRC and realize some new strategies for the early diagnosis and treatment of CRC.
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Affiliation(s)
- Wangji Li
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Foshan, Guangdong Province, 528300, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, 510080, China
| | - Yan Lu
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Foshan, Guangdong Province, 528300, China
| | - Changda Ye
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Foshan, Guangdong Province, 528300, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, 510080, China
| | - Manzhao Ouyang
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde, Foshan, Guangdong Province, 528300, China
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Zhang D, He Z, Shen Y, Wang J, Liu T, Jiang J. MiR-489-3p Reduced Pancreatic Cancer Proliferation and Metastasis By Targeting PKM2 and LDHA Involving Glycolysis. Front Oncol 2021; 11:651535. [PMID: 34868902 PMCID: PMC8632778 DOI: 10.3389/fonc.2021.651535] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 10/14/2021] [Indexed: 01/03/2023] Open
Abstract
Introduction Malignant proliferation and metastasis are some of the causes of high mortality in pancreatic cancer. MicroRNAs have been a hot spot in cancer research and are involved in tumor formation and metabolic stress responses. However, the biology function and underlying mechanism of miRNA regulating pancreatic cancer progress is remained uncleared. Methods RNA-seq analysis the glycolysis associated miRNAs and verified miRNA-489-3p was involving in glycolysis. We used RNA in situ hybridization (ISH) and qRT-PCR to analyze the differential expression of miR-489-3p in pancreatic cancer tissues and adjacent tissues and cell lines. Then the function assay of in vivo and in vitro were used to evaluated the role of miR-489-3p in the proliferation, metastasis and glucose metabolism of pancreatic cancer. Furthermore, dual luciferase reporter and rescue experiments were performed to explore the mechanism underlying in the role of miRNA-489-3p. Results We determined that glycolysis associated miRNA miR-489-3p was downregulated in pancreatic cancer tissues and cell lines. The gain and loos of function experiments confirmed that miR-489-3p could inhibit the proliferation, metastasis and glucose metabolism of pancreatic cancer. Further, we found that miR-489-3p could target regulating LDHA and PKM through the luciferase report experiment. Finally, in vivo experiment confirmed that highly expressed miR-489-3p inhibited the growth of pancreatic cancer. Conclusion In short, this study identified miR-489-3p as a novel therapy target for pancreatic cancer which was involving in the proliferation, metastasis and glycolysis, but its diagnostic value deserves further study.
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Affiliation(s)
- Dan Zhang
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhiwei He
- Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Yiyi Shen
- Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Jie Wang
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Tao Liu
- Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Jianxin Jiang
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, China
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Hon KW, Zainal Abidin SA, Othman I, Naidu R. The Crosstalk Between Signaling Pathways and Cancer Metabolism in Colorectal Cancer. Front Pharmacol 2021; 12:768861. [PMID: 34887764 PMCID: PMC8650587 DOI: 10.3389/fphar.2021.768861] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/05/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. Metabolic reprogramming represents an important cancer hallmark in CRC. Reprogramming core metabolic pathways in cancer cells, such as glycolysis, glutaminolysis, oxidative phosphorylation, and lipid metabolism, is essential to increase energy production and biosynthesis of precursors required to support tumor initiation and progression. Accumulating evidence demonstrates that activation of oncogenes and loss of tumor suppressor genes regulate metabolic reprogramming through the downstream signaling pathways. Protein kinases, such as AKT and c-MYC, are the integral components that facilitate the crosstalk between signaling pathways and metabolic pathways in CRC. This review provides an insight into the crosstalk between signaling pathways and metabolic reprogramming in CRC. Targeting CRC metabolism could open a new avenue for developing CRC therapy by discovering metabolic inhibitors and repurposing protein kinase inhibitors/monoclonal antibodies.
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Affiliation(s)
| | | | | | - Rakesh Naidu
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Malaysia
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37
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Wang N, Zhou Y, Zuo Z, Wang R, Li J, Han T, Yang B. Construction of a competing endogenous RNA network related to the prognosis of cholangiocarcinoma and comprehensive analysis of the immunological correlation. J Gastrointest Oncol 2021; 12:2287-2309. [PMID: 34790393 DOI: 10.21037/jgo-21-619] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 10/19/2021] [Indexed: 12/21/2022] Open
Abstract
Background Cholangiocarcinoma (CCA) is a malignant tumor of the digestive system, with occult onset in the early stage, a high degree of malignancy in the late stage, and poor prognosis. At present, the pathogenesis of CCA is not clear, and there is a lack of effective immunotherapy. The purpose of this study was to identify the potential regulatory mechanism of CCA and analyze the possibility of its related immunotherapy. Methods The circular RNAs (circRNAs) expression profile data of CCA was downloaded from the Gene Expression Omnibus (GEO) database; the miRNA and mRNA expression profile data of CCA were downloaded from The Cancer Genome Atlas (TCGA) database. Prognostic factors were screened by univariate Cox regression analysis, and the competing endogenous RNA (ceRNA) network was constructed via survival analysis. Multivariate Cox analysis was used to screen the independent prognostic factors and construct a prognostic correlation subnetwork. Analyzing the tumor microenvironment of CCA and survival analysis were performed according to the score of the microenvironment, and the distribution of tumor infiltrating immune cells (TICs) in CCA was calculated using the CIBERSORT algorithm. We explored the expression pattern of the target genes in pan-cancer, and the correlation between the key genes in the ceRNA subnetwork, TICs and immune checkpoints was analyzed using an online database. Finally, the expression levels of target genes were validated based on the Human Protein Atlas (HPA) databases. Results We screened four circRNAs, 10 miRNAs, and 17 mRNAs with significant differences, and constructed the ceRNA network. Independent prognostic factors were screened by multivariate Cox regression analysis, and a subnetwork containing five nodes (hsa_circ_0002073→hsa-mir-4524a-3p→SLC16A3/SLC35E4/DDX4) was constructed. Further analysis showed that SLC16A3 was not only an independent posterior factor of CCA, but was also closely correlated with immune cells, immune checkpoints, and immunotherapy, and had a certain regulatory effect on the tumor microenvironment. Conclusions Our study identified a novel prognostic marker of CCA, SLC16A3, and revealed the regulatory role of SLC16A3 in the tumor microenvironment, which is expected to provide new insights for the early diagnosis, prognosis, and targeted therapy of CCA.
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Affiliation(s)
- Ning Wang
- Department of Oncology, the Second Affiliated Hospital of Liaoning Traditional Chinese Medicine University, Shenyang, China
| | - Yinghui Zhou
- Jinzhou Medical University, General Hospital of Northern Theater Command Training Base for Graduate, Shenyang, China.,Department of Hepatobiliary surgery, General Hospital of Northern Theater Command, Shenyang, China
| | - Zhifan Zuo
- Department of Oncology, the First Hospital of China Medical University, Shenyang, China
| | - Ruoyu Wang
- Department of Hepatic Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai, China
| | - Jing Li
- Liaoning Academy of Traditional Chinese Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Tao Han
- Department of Oncology, the First Hospital of China Medical University, Shenyang, China
| | - Bin Yang
- Department of General Surgery, 967 Hospital of PLA, Dalian, China
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Ethoxyquin Inhibits the Progression of Murine Ehrlich Ascites Carcinoma through the Inhibition of Autophagy and LDH. Biomedicines 2021; 9:biomedicines9111526. [PMID: 34829755 PMCID: PMC8615101 DOI: 10.3390/biomedicines9111526] [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: 08/16/2021] [Revised: 10/13/2021] [Accepted: 10/22/2021] [Indexed: 12/20/2022] Open
Abstract
Cancer cells exhibit an increased glycolysis rate for ATP generation (the Warburg effect) to sustain an increased proliferation rate. In tumor cells, the oxidation of pyruvate in the Krebs cycle is substituted by lactate production, catalyzed by LDH. In this study, we use ethoxyquin (EQ) as a novel inhibitor to target LDH in murine Ehrlich ascites carcinoma (EAC) and as a combination therapy to improve the therapeutic efficacy of the conventional chemotherapy drug, cisplatin (CIS). We investigated the anti-tumor effect of EQ on EAC-bearing mice and checked whether EQ can sustain the anti-tumor potential of CIS and whether it influences LDH activity. Treatment with EQ had evident anti-tumor effects on EAC as revealed by the remarkable decrease in the expression of the anti-apoptotic gene Bcl-2 and by a significant increase in the expression of apoptotic genes (BAX and caspase-3). EQ also caused a significant decrease in the autophagic activity of EAC cells, as shown by a reduction in the fluorescence intensity of the autophagosome marker. Additionally, EQ restored the altered hematological and biochemical parameters and improved the disrupted hepatic tissues of EAC-bearing mice. Co-administration of EQ and CIS showed the highest anti-tumor effect against EAC. Collectively, our findings propose EQ as a novel inhibitor of LDH in cancer cells and as a combinatory drug to increase the efficacy of cisplatin. Further studies are required to validate this therapeutic strategy in different cancer models and preclinical trials.
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MicroRNAs and Metabolism: Revisiting the Warburg Effect with Emphasis on Epigenetic Background and Clinical Applications. Biomolecules 2021; 11:biom11101531. [PMID: 34680164 PMCID: PMC8533942 DOI: 10.3390/biom11101531] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/10/2021] [Accepted: 10/13/2021] [Indexed: 12/31/2022] Open
Abstract
Since the well-known hallmarks of cancer were described by Hanahan and Weinberg, fundamental advances of molecular genomic technologies resulted in the discovery of novel puzzle pieces in the multistep pathogenesis of cancer. MicroRNAs are involved in the altered epigenetic pattern and metabolic phenotype of malignantly transformed cells. They contribute to the initiation, progression and metastasis-formation of cancers, also interacting with oncogenes, tumor-suppressor genes and epigenetic modifiers. Metabolic reprogramming of cancer cells results from the dysregulation of a complex network, in which microRNAs are located at central hubs. MicroRNAs regulate the expression of several metabolic enzymes, including tumor-specific isoforms. Therefore, they have a direct impact on the levels of metabolites, also influencing epigenetic pattern due to the metabolite cofactors of chromatin modifiers. Targets of microRNAs include numerous epigenetic enzymes, such as sirtuins, which are key regulators of cellular metabolic homeostasis. A better understanding of reversible epigenetic and metabolic alterations opened up new horizons in the personalized treatment of cancer. MicroRNA expression levels can be utilized in differential diagnosis, prognosis stratification and prediction of chemoresistance. The therapeutic modulation of microRNA levels is an area of particular interest that provides a promising tool for restoring altered metabolism of cancer cells.
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Interplay between Epigenetics and Cellular Metabolism in Colorectal Cancer. Biomolecules 2021; 11:biom11101406. [PMID: 34680038 PMCID: PMC8533383 DOI: 10.3390/biom11101406] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/17/2021] [Accepted: 09/18/2021] [Indexed: 01/30/2023] Open
Abstract
Cellular metabolism alterations have been recognized as one of the most predominant hallmarks of colorectal cancers (CRCs). It is precisely regulated by many oncogenic signaling pathways in all kinds of regulatory levels, including transcriptional, post-transcriptional, translational and post-translational levels. Among these regulatory factors, epigenetics play an essential role in the modulation of cellular metabolism. On the one hand, epigenetics can regulate cellular metabolism via directly controlling the transcription of genes encoding metabolic enzymes of transporters. On the other hand, epigenetics can regulate major transcriptional factors and signaling pathways that control the transcription of genes encoding metabolic enzymes or transporters, or affecting the translation, activation, stabilization, or translocation of metabolic enzymes or transporters. Interestingly, epigenetics can also be controlled by cellular metabolism. Metabolites not only directly influence epigenetic processes, but also affect the activity of epigenetic enzymes. Actually, both cellular metabolism pathways and epigenetic processes are controlled by enzymes. They are highly intertwined and are essential for oncogenesis and tumor development of CRCs. Therefore, they are potential therapeutic targets for the treatment of CRCs. In recent years, both epigenetic and metabolism inhibitors are studied for clinical use to treat CRCs. In this review, we depict the interplay between epigenetics and cellular metabolism in CRCs and summarize the underlying molecular mechanisms and their potential applications for clinical therapy.
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41
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Chen L, Zhong Y, Yang X, Zhang Q, Wu X. Downregulation of GTSE1 leads to the inhibition of proliferation, migration, and Warburg effect in cervical cancer by blocking LHDA expression. J Obstet Gynaecol Res 2021; 47:3913-3922. [PMID: 34482592 DOI: 10.1111/jog.15000] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 06/15/2021] [Accepted: 08/18/2021] [Indexed: 01/11/2023]
Abstract
AIM G2 and S phase-expressed-1 (GTSE1) has been identified to play a vital role in several kinds of cancers, but its role in cervical cancer development remains unknown. Herein, we aimed to reveal the role and underlying mechanism of GTSE1 in cervical cancer cell growth, migration, and aerobic glycolysis. METHODS GTSE1 expression levels in cervical cancer tissues and normal cervical tissues were determined by real time PCR and immunohistochemistry. Human short hairpin RNA was used to downregulate GTSE1 level in cervical cancer cells SiHa and HeLa cells. Colony formation, cell counting kit-8, and wound-healing assays were used for cell function evaluation. Lactate production, lactate dehydrogenase activity, and glucose concentration were tested to assess the Warburg effect. RESULTS GTSE1 expressions at both mRNA and protein levels were significantly elevated in cervical cancer tissues compared with normal tissues. Downregulation of GTSE1 induced significant repressions in cell colony formation, viability and migration, and Warburg effect, as well as reduced expression of lactate dehydrogenase isoform A (LDHA) at mRNA and protein levels. Additionally, downregulation of GTSE1 weakened the tumorigenesis of HeLa and SiHa cells in vivo. CONCLUSION This study demonstrated that downregulation of GTSE1 led to significant inhibitions in cell proliferation, migration, tumorigenesis, and Warburg effect in cervical cancer by blocking the expression of LHDA.
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Affiliation(s)
- Longyi Chen
- Department of Gynecology, First People's Hospital of Kashi, Kashi Prefecture, Xinjiang Uygur Autonomous Region, China
| | - Youwen Zhong
- School of Economics and Finance, Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Xiuwei Yang
- Department of Gynecology, First People's Hospital of Kashi, Kashi Prefecture, Xinjiang Uygur Autonomous Region, China
| | - Qingyue Zhang
- Department of Gynecology, First People's Hospital of Kashi, Kashi Prefecture, Xinjiang Uygur Autonomous Region, China
| | - Xiaoling Wu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
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Yin H, Zheng X, Tang X, Zang Z, Li B, He S, Shen R, Yang H, Li S. Potential biomarkers and lncRNA-mRNA regulatory networks in invasive growth hormone-secreting pituitary adenomas. J Endocrinol Invest 2021; 44:1947-1959. [PMID: 33559847 DOI: 10.1007/s40618-021-01510-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 01/15/2021] [Indexed: 02/06/2023]
Abstract
PURPOSE Growth hormone-secreting pituitary adenomas (GH-PAs) are common subtypes of functional PAs. Invasive GH-PAs play a key role in restricting poor outcomes. The transcriptional changes in GH-PAs were evaluated. METHODS In this study, the transcriptome analysis of six different GH-PA samples was performed. The functional roles, co-regulatory network, and chromosome location of differentially expressed (DE) genes in invasive GH-PAs were explored. RESULTS Bioinformatic analysis revealed 101 DE mRNAs and 70 DE long non-coding RNAs (lncRNAs) between invasive and non-invasive GH-PAs. Functional enrichment analysis showed that epithelial cell differentiation and development pathways were suppressed in invasive GH-PAs, whereas the pathways of olfactory transduction, retinol metabolism, drug metabolism-cytochrome P450, and metabolism of xenobiotics by cytochrome P450 had an active trend. In the protein-protein interaction network, 11 main communities were characterized by cell- adhesion, -motility, and -cycle; transport process; phosphorus and hormone metabolic processes. The SGK1 gene was suggested to play a role in the invasiveness of GH-PAs. Furthermore, the up-regulated genes OR51B6, OR52E4, OR52E8, OR52E6, OR52N2, MAGEA6, MAGEC1, ST8SIA6-AS1, and the down-regulated genes GAD1-AS1 and SPINT1-AS1 were identified in the competing endogenous RNA network. The RT-qPCR results further supported the aberrant expression of those genes. Finally, the enrichment of DE genes in chromosome 11p15 and 12p13 regions were detected. CONCLUSION Our findings provide a new perspective for studies evaluating the underlying mechanism of invasive GH-PAs.
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Affiliation(s)
- H Yin
- Department of Neurosurgery, Xinqiao Hospital, The Army Medical University, Chongqing, China
| | - X Zheng
- Department of Neurosurgery, Xinqiao Hospital, The Army Medical University, Chongqing, China
| | - X Tang
- Department of Neurosurgery, Xinqiao Hospital, The Army Medical University, Chongqing, China
| | - Z Zang
- Department of Neurosurgery, Xinqiao Hospital, The Army Medical University, Chongqing, China
| | - B Li
- College of Life Sciences, Chongqing Normal University, Chongqing, China
| | - S He
- Department of Neurosurgery, Xinqiao Hospital, The Army Medical University, Chongqing, China
| | - R Shen
- Department of Endocrinology, Xinqiao Hospital, The Army Medical University, Chongqing, China
| | - H Yang
- Department of Neurosurgery, Xinqiao Hospital, The Army Medical University, Chongqing, China.
| | - S Li
- Department of Neurosurgery, Xinqiao Hospital, The Army Medical University, Chongqing, China.
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Fan Y, Hu D, Li D, Ma C, Tang Y, Tao Q, Deng L, Tang D. UCHL3 promotes aerobic glycolysis of pancreatic cancer through upregulating LDHA expression. Clin Transl Oncol 2021; 23:1637-1645. [PMID: 33616859 DOI: 10.1007/s12094-021-02565-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 01/28/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Aerobic glycolysis has a pivotal role in the carcinogenic process. The current understanding of the functional role and mechanism of UCHL3-related aerobic glycolysis in pancreatic cancer is far from comprehensive, therefore requires an in-depth analysis on this aspect. METHODS In the present research, the expressions of ubiquitin carboxyl-terminal hydrolase L3 (UCHL3), lactate dehydrogenase A (LDHA) and Forkhead box protein M1 (FOXM1) were detected by qRT-PCR, Western blot and immunohistochemistry. The effects of UCHL3 knockdown or overexpression on pancreatic cancer cells were examined by determining cell viability and colony formation. Aerobic glycolysis was assessed according to glucose uptake, lactic acid production, and lactate dehydrogenase (LDH) activity. Dual-luciferase reporter assay was performed to detect LDHA promoter activity. RESULTS The results showed that UCHL3 expression was significantly increased in the pancreatic cancer tissues and cells, and that knocking down UCHL3 noticeably inhibited cell viability and aerobic glycolysis. Further investigations revealed that LDHA expression was promoted by UCHL3 and could be reduced by shFOXM1, and that low-expressed LDHA partly reversed the inhibition of aerobic glycolysis induced by overexpressed UCHL3. CONCLUSIONS To conclude, this study demonstrates that UCHL3 plays a carcinogenic role by promoting aerobic glycolysis in pancreatic cancer, suggesting that UCHL3 may be a potential diagnostic and therapeutic target for the treatment of cancer.
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Affiliation(s)
- Y Fan
- The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen City, 518107, Guangdong Province, China
| | - D Hu
- The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen City, 518107, Guangdong Province, China
| | - D Li
- The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen City, 518107, Guangdong Province, China
| | - C Ma
- The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen City, 518107, Guangdong Province, China
| | - Y Tang
- The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen City, 518107, Guangdong Province, China
| | - Q Tao
- The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen City, 518107, Guangdong Province, China
| | - L Deng
- The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen City, 518107, Guangdong Province, China
| | - D Tang
- The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen City, 518107, Guangdong Province, China.
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Sellitto A, Pecoraro G, Giurato G, Nassa G, Rizzo F, Saggese P, Martinez CA, Scafoglio C, Tarallo R. Regulation of Metabolic Reprogramming by Long Non-Coding RNAs in Cancer. Cancers (Basel) 2021; 13:cancers13143485. [PMID: 34298698 PMCID: PMC8308086 DOI: 10.3390/cancers13143485] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/08/2021] [Accepted: 07/09/2021] [Indexed: 01/10/2023] Open
Abstract
Metabolic reprogramming is a well described hallmark of cancer. Oncogenic stimuli and the microenvironment shape the metabolic phenotype of cancer cells, causing pathological modifications of carbohydrate, amino acid and lipid metabolism that support the uncontrolled growth and proliferation of cancer cells. Conversely, metabolic alterations in cancer can drive changes in genetic programs affecting cell proliferation and differentiation. In recent years, the role of non-coding RNAs in metabolic reprogramming in cancer has been extensively studied. Here, we review this topic, with a focus on glucose, glutamine, and lipid metabolism and point to some evidence that metabolic alterations occurring in cancer can drive changes in non-coding RNA expression, thus adding an additional level of complexity in the relationship between metabolism and genetic programs in cancer cells.
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Affiliation(s)
- Assunta Sellitto
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (G.P.); (G.G.); (G.N.); (F.R.)
| | - Giovanni Pecoraro
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (G.P.); (G.G.); (G.N.); (F.R.)
| | - Giorgio Giurato
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (G.P.); (G.G.); (G.N.); (F.R.)
- Genome Research Center for Health—CRGS, University of Salerno Campus of Medicine, 84081 Baronissi, Italy
| | - Giovanni Nassa
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (G.P.); (G.G.); (G.N.); (F.R.)
- Genome Research Center for Health—CRGS, University of Salerno Campus of Medicine, 84081 Baronissi, Italy
| | - Francesca Rizzo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (G.P.); (G.G.); (G.N.); (F.R.)
- Genome Research Center for Health—CRGS, University of Salerno Campus of Medicine, 84081 Baronissi, Italy
| | - Pasquale Saggese
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (P.S.); (C.A.M.); (C.S.)
| | - Cesar A. Martinez
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (P.S.); (C.A.M.); (C.S.)
| | - Claudio Scafoglio
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (P.S.); (C.A.M.); (C.S.)
| | - Roberta Tarallo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Italy; (A.S.); (G.P.); (G.G.); (G.N.); (F.R.)
- Genome Research Center for Health—CRGS, University of Salerno Campus of Medicine, 84081 Baronissi, Italy
- Correspondence: ; Tel.: +39-089-965067
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Huang P, Zhu S, Liang X, Zhang Q, Luo X, Liu C, Song L. Regulatory Mechanisms of LncRNAs in Cancer Glycolysis: Facts and Perspectives. Cancer Manag Res 2021; 13:5317-5336. [PMID: 34262341 PMCID: PMC8275123 DOI: 10.2147/cmar.s314502] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 06/19/2021] [Indexed: 12/24/2022] Open
Abstract
Cancer cells exhibit distinct metabolic characteristics that employ glycolysis to provide energy and intermediary metabolites. This aberrant metabolic phenotype favors cancer progression. LncRNAs are transcripts longer than 200 nucleotides that do not encode proteins. LncRNAs contribute to cancer progression and therapeutic resistance and affect aerobic glycolysis via multiple mechanisms, including modulating glycolytic transporters and enzymes. Further, dysregulated signaling pathways are vital for glycolysis. In this review, we highlight regulatory mechanisms for lncRNAs in aerobic glycolysis that provide novel insights into cancer development. Moreover, a comprehensive understanding of the regulatory mechanisms of lncRNAs in aerobic glycolysis can provide new strategies for clinical cancer management.
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Affiliation(s)
- Peng Huang
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China
| | - Shaomi Zhu
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China
| | - Xin Liang
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China
| | - Qinxiu Zhang
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China
| | - Xiaohong Luo
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China
| | - Chi Liu
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China
| | - Linjiang Song
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China
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Insulin-Like Growth Factor 1 (IGF-1) Signaling in Glucose Metabolism in Colorectal Cancer. Int J Mol Sci 2021; 22:ijms22126434. [PMID: 34208601 PMCID: PMC8234711 DOI: 10.3390/ijms22126434] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/04/2021] [Accepted: 06/14/2021] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common aggressive carcinoma types worldwide, characterized by unfavorable curative effect and poor prognosis. Epidemiological data re-vealed that CRC risk is increased in patients with metabolic syndrome (MetS) and its serum components (e.g., hyperglycemia). High glycemic index diets, which chronically raise post-prandial blood glucose, may at least in part increase colon cancer risk via the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. However, the underlying mechanisms linking IGF-1 and MetS are still poorly understood. Hyperactivated glucose uptake and aerobic glycolysis (the Warburg effect) are considered as a one of six hallmarks of cancer, including CRC. However, the role of insulin/IGF-1 signaling during the acquisition of the Warburg metabolic phenotypes by CRC cells is still poorly understood. It most likely results from the interaction of multiple processes, directly or indirectly regulated by IGF-1, such as activation of PI3K/Akt/mTORC, and Raf/MAPK signaling pathways, activation of glucose transporters (e.g., GLUT1), activation of key glycolytic enzymes (e.g., LDHA, LDH5, HK II, and PFKFB3), aberrant expression of the oncogenes (e.g., MYC, and KRAS) and/or overexpression of signaling proteins (e.g., HIF-1, TGF-β1, PI3K, ERK, Akt, and mTOR). This review describes the role of IGF-1 in glucose metabolism in physiology and colorectal carcinogenesis, including the role of the insulin/IGF system in the Warburg effect. Furthermore, current therapeutic strategies aimed at repairing impaired glucose metabolism in CRC are indicated.
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Abstract
Colorectal cancer (CRC) is characterized by genetic-environmental interplay leading to diffuse changes in the entire colonic mucosa (field carcinogenesis or field of injury) and to a pro-neoplastic genetic/epigenetic/physiological milieu. The clinical consequences are increased risk of synchronous and metachronous neoplasia. Factors such as genetics, race, ethnicity, age, and socioeconomic status are thought to influence neoplasia development. Here, we explore the potential improvement to CRC screening through exploiting field carcinogenesis, with particular focus on racial disparities and chemoprevention strategies. Also, we discuss future directions for field carcinogenesis/risk stratification using molecular and novel biophotonic techniques for personalized CRC screening.
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Zafari J, Zadehmodarres S, Javani Jouni F, Bagheri-Hosseinabadi Z, Najjar N, Asnaashari M. Investigation into the Effect of Photodynamic Therapy and Cisplatin on the Cervical Cancer Cell Line (A2780). J Lasers Med Sci 2020; 11:S85-S91. [PMID: 33995975 DOI: 10.34172/jlms.2020.s14] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Introduction: Cervical cancer is recognized as one of the major causes of mortality among elderly women. Although there are several different therapeutic worldwide guidelines, many researchers have focused on screening new methodologies and technologies to elevate the efficiency of cervical cancer treatment. The simultaneous use of photodynamic therapy (PDT) along with chemotherapy as cisplatin has achieved good aims in the treatment of cervical cancer. Methods: A2780 cells were treated with cisplatin, photodynamic progress (laser with methylene blue as a photosensitizer compound) and a combination of cisplatin and PDT. The lithic effect of the laser, methylene blue and their combination and the IC50 value of cisplatin were calculated for each group. The amount of malondialdehyde (MDA) as membrane lipid peroxidation product and released lactate dehydrogenase was measured in the medium. The toxicity of each agent was evaluated by the MTT technique. Results: The results show that a combination of PDT and chemotherapeutic agent cisplatin caused a twofold decrease in viable cervical cancer cells compared to each therapeutic progress. The combination of both laser therapy and cisplatin enhanced cancer cell membrane disruption by increased membrane lipid peroxidation and apoptotic enzyme activation by the elevation of lactate dehydrogenase activity. Conclusion: The results indicated that cisplatin combined with PDT had a greater therapeutic effect on A2780 as a cervical cancer cell line. Therefore, PDT in combination with chemotherapy enhances the effectiveness of chemotherapeutic agents by the disruption of the cancer cell membrane and switching the apoptosis progress with less adverse effects.
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Affiliation(s)
- Jaber Zafari
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahrzad Zadehmodarres
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Javani Jouni
- Department of Biomedical Engineering, Faculty of Health, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Zahra Bagheri-Hosseinabadi
- Department of Clinical Biochemistry, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Nabaa Najjar
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Asnaashari
- Department of Endodontic, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Zhu Z, Tang G, Yan J. MicroRNA-122 regulates docetaxel resistance of prostate cancer cells by regulating PKM2. Exp Ther Med 2020; 20:247. [PMID: 33178345 PMCID: PMC7651870 DOI: 10.3892/etm.2020.9377] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 02/25/2020] [Indexed: 02/06/2023] Open
Abstract
Prostate cancer (PCa), an epithelial malignancy that occurs in the prostate, is the second leading cause of cancer death worldwide. MicroRNAs (miRs/miRNAs) are reported to have important applications in the field of cancer diagnosis and treatment. The present study aimed to investigate the function of miRNA-122 in the chemoresistance of PCa cells and the underlying mechanism. Significantly decreased miR-122 and increased pyruvate kinase (PKM2) levels were observed in docetaxel-resistant PCa cells, and PKM2 was negatively correlated with miR-122. MiR-122 mimic transfection in docetaxel-resistant LNCaP cells significantly inhibited cell proliferation, promoted apoptosis and decreased glucose uptake and lactate production, which was counteracted by PKM2 overexpression. Inhibition of miR-122 in LNCaP cells had an opposite effect to miR-122 mimic transfection. In addition, miR-122 mimic transfection significantly increased the sensitivity of docetaxel-resistant LNCaP cells to docetaxel, while inhibition of miR-122 significantly decreased the sensitivity of LNCaP cells to docetaxel. Luciferase reporter assays showed that miR-122 regulated PKM2 expression by binding to the 3'-untranslated region of PKM2. The results suggest that upregulation of miR-122 could enhance docetaxel sensitivity, inhibit cell proliferation and promote apoptosis in PCa cells,possibly through the downregulation of its target protein PKM2.
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Affiliation(s)
- Zhirong Zhu
- Department of Urology, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang 312000, P.R. China
| | - Guiliang Tang
- Department of Urology, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang 312000, P.R. China
| | - Jiajun Yan
- Department of Urology, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang 312000, P.R. China
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Regulation of Glycolysis by Non-coding RNAs in Cancer: Switching on the Warburg Effect. MOLECULAR THERAPY-ONCOLYTICS 2020; 19:218-239. [PMID: 33251334 PMCID: PMC7666327 DOI: 10.1016/j.omto.2020.10.003] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The “Warburg effect” describes the reprogramming of glucose metabolism away from oxidative phosphorylation toward aerobic glycolysis, and it is one of the hallmarks of cancer cells. Several factors can be involved in this process, but in this review, the roles of non-coding RNAs (ncRNAs) are highlighted in several types of human cancer. ncRNAs, including microRNAs, long non-coding RNAs, and circular RNAs, can all affect metabolic enzymes and transcription factors to promote glycolysis and modulate glucose metabolism to enhance the progression of tumors. In particular, the 5′-AMP-activated protein kinase (AMPK) and the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathways are associated with alterations in ncRNAs. A better understanding of the roles of ncRNAs in the Warburg effect could ultimately lead to new therapeutic approaches for suppressing cancer.
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