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1
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Zhang F, Wu Z, Xiang Y, He Q, Li W, Yang K, Yang Y. SOX4 reprograms fatty acid metabolism through the CHREBP to inhibit ferroptosis in hepatocellular carcinoma. Cell Death Discov 2025; 11:246. [PMID: 40399256 PMCID: PMC12095664 DOI: 10.1038/s41420-025-02527-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 04/20/2025] [Accepted: 05/08/2025] [Indexed: 05/23/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality, characterized by aggressive progression and poor prognosis. Pathological angiogenesis in HCC is closely linked to metabolic reprogramming, particularly concerning fatty acid metabolism. The interplay between fatty acid metabolism and ferroptosis, a type of cell death driven by lipid peroxidation, is emerging as a crucial area of study. The transcription factor SOX4 is known to be overexpressed in various cancers, including HCC, and may play a key role in these processes. We assessed SOX4 expression in HCC using clinical samples and data from online databases. Next-generation RNA sequencing was employed to explore the effects of SOX4 on fatty acid metabolism, focusing on the CHREBP pathway. Functional assays, including lipid peroxidation and angiogenesis studies, were conducted to investigate the role of SOX4 in regulating ferroptosis and angiogenesis in HCC. SOX4 was found to be significantly upregulated in HCC and associated with enhanced angiogenesis. Mechanistically, SOX4 activated the CHREBP/SCD1 pathway, leading to increased production of monounsaturated fatty acids, which in turn inhibited ferroptosis. This suppression of ferroptosis contributed to the promotion of angiogenesis and tumor progression in HCC. In conclusion, SOX4 reprograms fatty acid metabolism via the CHREBP/SCD1 pathway, thereby inhibiting ferroptosis and promoting angiogenesis in HCC. These findings suggest that targeting the SOX4-CHREBP axis could represent a novel therapeutic strategy for HCC.
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Affiliation(s)
- Fan Zhang
- Department of Hepatobiliary Surgery, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, China
- Haikou Key Laboratory of Clinical Research and Transformation of Digestive Diseases, Haikou, China
| | - Zhiwei Wu
- Department of Organ Transplantation, Xiangya Hospital, Central South University, Changsha, China
| | - Yang Xiang
- Department of Hepatobiliary Surgery, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, China.
- Haikou Key Laboratory of Clinical Research and Transformation of Digestive Diseases, Haikou, China.
| | - Qing He
- Department of Organ Transplantation, Xiangya Hospital, Central South University, Changsha, China
| | - Wanqing Li
- Hunan Occupational Disease Prevention Hospital, Changsha, China
| | - Kaipeng Yang
- Department of Hepatobiliary Surgery, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, China
- Haikou Key Laboratory of Clinical Research and Transformation of Digestive Diseases, Haikou, China
| | - Yijun Yang
- Department of Hepatobiliary Surgery, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, China
- Haikou Key Laboratory of Clinical Research and Transformation of Digestive Diseases, Haikou, China
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2
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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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3
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Hamdy NM, Zaki MB, Abdelmaksoud NM, Ismail RA, Abd-Elmawla MA, Rizk NI, Fathi D, Abulsoud AI. Insights into the genetic and epigenetic mechanisms governing X-chromosome-linked-miRNAs expression in cancer; a step-toward ncRNA precision. Int J Biol Macromol 2025; 289:138773. [PMID: 39675615 DOI: 10.1016/j.ijbiomac.2024.138773] [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: 12/04/2024] [Revised: 12/09/2024] [Accepted: 12/11/2024] [Indexed: 12/17/2024]
Abstract
Sex chromosomes play a significant role in establishing sex-specific differences in gene expression, thereby contributing to phenotypic diversity and susceptibility to various diseases. MicroRNAs (miRNAs), which are small non-coding RNAs encoded by both the X and Y chromosomes, exhibit sex-specific regulatory characteristics. Computational analysis has identified several X-linked miRNAs differentially expressed in sex-specific cancers. This review aims to elucidate the genetic and epigenetic mechanisms that govern the sex-specific expression of X- and Y-linked miRNAs, with particular attention to their functional role in regulating diverse cellular processes in different cancer pathways. In addition, this review provides a comprehensive understanding of the targeted therapeutic interventions and critical insights into the potential clinical implications of targeting sex-specific miRNAs. In conclusion, this review opens new horizons for further research to effectively translate these findings into viable treatment options.
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Affiliation(s)
- Nadia M Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.
| | - Mohamed Bakr Zaki
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt
| | | | - Rehab A Ismail
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mai A Abd-Elmawla
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Kasr Al-Ainy, Cairo 11562, Egypt
| | - Nehal I Rizk
- Department of Biochemistry, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo 11786, Egypt
| | - Doaa Fathi
- Department of Biochemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21526, Egypt
| | - Ahmed I Abulsoud
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al Azhar University, Nasr City, Cairo 11231, Egypt
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4
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Liaghat M, Ferdousmakan S, Mortazavi SH, Yahyazadeh S, Irani A, Banihashemi S, Seyedi Asl FS, Akbari A, Farzam F, Aziziyan F, Bakhtiyari M, Arghavani MJ, Zalpoor H, Nabi-Afjadi M. The impact of epithelial-mesenchymal transition (EMT) induced by metabolic processes and intracellular signaling pathways on chemo-resistance, metastasis, and recurrence in solid tumors. Cell Commun Signal 2024; 22:575. [PMID: 39623377 PMCID: PMC11610171 DOI: 10.1186/s12964-024-01957-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 11/22/2024] [Indexed: 12/06/2024] Open
Abstract
The intricate cellular process, known as the epithelial-mesenchymal transition (EMT), significantly influences solid tumors development. Changes in cell shape, metabolism, and gene expression linked to EMT facilitate tumor cell invasion, metastasis, drug resistance, and recurrence. So, a better understanding of the intricate processes underlying EMT and its role in tumor growth may lead to the development of novel therapeutic approaches for the treatment of solid tumors. This review article focuses on the signals that promote EMT and metabolism, the intracellular signaling pathways leading to EMT, and the network of interactions between EMT and cancer cell metabolism. Furthermore, the functions of EMT in treatment resistance, recurrence, and metastasis of solid cancers are covered. Lastly, treatment approaches that focus on intracellular signaling networks and metabolic alterations brought on by EMT will be discussed.
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Affiliation(s)
- Mahsa Liaghat
- Department of Medical Laboratory Sciences, Faculty of Medical Sciences, Kazerun Branch, Islamic Azad University, Kazerun, Iran
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Saeid Ferdousmakan
- Department of Pharmacy Practice, Nargund College of Pharmacy, Bangalore, 560085, India
| | | | - Sheida Yahyazadeh
- Department of Immunology, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Asrin Irani
- Department of Biology, Faculty of Basic Sciences, University of Guilan, Rasht, Iran
| | - Sara Banihashemi
- Department of Bioscience, School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | | | - Abdullatif Akbari
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Farnoosh Farzam
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Fatemeh Aziziyan
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Maryam Bakhtiyari
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Mohammad Javad Arghavani
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Hamidreza Zalpoor
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran.
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Mohsen Nabi-Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
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5
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Jung DM, Lee S, Kim EM, Choi CW, Kim KK. Mangiferin, a component of Mangifera indica leaf extracts, inhibits lipid synthesis in human sebocytes. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2024; 26:1489-1501. [PMID: 38952150 DOI: 10.1080/10286020.2024.2369279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 06/12/2024] [Accepted: 06/13/2024] [Indexed: 07/03/2024]
Abstract
Inhibition of lipid synthesis in sebocytes is essential for acne treatments. The effects of natural product-derived substances on lipid synthesis are unknown. This study investigated the effects of water extract of Mangifera indica leaves (WEML) on lipid synthesis in human sebocytes. Sebocyte differentiation in low serum conditions increased lipid accumulation and proliferator-activated receptor γ expression. WEML treatment significantly inhibited lipid accumulation and adipogenic mRNA expression in sebocytes. Mangiferin, a bioactive compound in WEML, also reduced lipid accumulation and adipogenic mRNA expression via the AKT pathway. Thus, WEML and mangiferin effectively inhibit lipid synthesis in sebocytes, showing promise for acne treatment.
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Affiliation(s)
- Da-Min Jung
- Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon, Republic of Korea
| | - Sangsoo Lee
- Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon, Republic of Korea
| | - Eun-Mi Kim
- Department of Bio and Environmental Technology, College of Science and Convergence Technology, Seoul Women's University, Seoul, Republic of Korea
| | - Chong Won Choi
- Department of Dermatology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Gyeonggi-do, Republic of Korea
| | - Kee K Kim
- Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon, Republic of Korea
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6
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Rahman MA, Islam MM, Ripon MAR, Islam MM, Hossain MS. Regulatory Roles of MicroRNAs in the Pathogenesis of Metabolic Syndrome. Mol Biotechnol 2024; 66:1599-1620. [PMID: 37393414 DOI: 10.1007/s12033-023-00805-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 06/17/2023] [Indexed: 07/03/2023]
Abstract
Metabolic syndrome refers to a group of several disease conditions together with high glucose triglyceride levels, high blood pressure, lower high-density lipoprotein level, and large waist circumference. About 400 million people worldwide, one-third of the Euro-American population and 27% Chinese population over age 50 have it. microRNAs, an abundant novel class of endogenous small, non-coding RNAs in eukaryotic cells, act as negative controllers of gene expression by promoting either degradation/translational repression of target messenger RNA. More than 2000 microRNAs in the human genome have been identified and they are implicated in various biological & pathophysiological processes, including glucose homeostasis, inflammatory response, and angiogenesis. Destruction of microRNAs has a crucial role in the pathogenesis of obesity, cardiovascular disease, and diabetes. Recently the discovery of circulating microRNAs in human serum may help to promote metabolic crosstalk between organs and serves as a novel approach for the identification of various diseases, like Type 2 diabetes & atherosclerosis. In this review, we will discuss the most recent and up-to-date research on the pathophysiology and histopathology of metabolic syndrome besides their historical background and epidemiological highlight. As well as search the methodologies employed in this field of research and the potential role of microRNAs as novel biomarkers and therapeutic targets for metabolic syndrome in the human body. Furthermore, the significance of microRNAs in promising strategies, like stem cell therapy, which holds enormous promise for regenerative medicine in the treatment of metabolic disorders will also be discussed.
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Affiliation(s)
- Md Abdur Rahman
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh
| | - Md Mahmodul Islam
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh
| | - Md Abdur Rahman Ripon
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh
| | - Md Monirul Islam
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh
| | - Mohammad Salim Hossain
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh.
- Bangladesh Obesity Research Network (BORN), Noakhali, 3814, Bangladesh.
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7
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Zhou H, Shen Y, Zheng G, Zhang B, Wang A, Zhang J, Hu H, Lin J, Liu S, Luan X, Zhang W. Integrating single-cell and spatial analysis reveals MUC1-mediated cellular crosstalk in mucinous colorectal adenocarcinoma. Clin Transl Med 2024; 14:e1701. [PMID: 38778448 PMCID: PMC11111627 DOI: 10.1002/ctm2.1701] [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: 11/28/2023] [Revised: 04/26/2024] [Accepted: 04/29/2024] [Indexed: 05/25/2024] Open
Abstract
BACKGROUND Mucinous colorectal adenocarcinoma (MCA) is a distinct subtype of colorectal cancer (CRC) with the most aggressive pattern, but effective treatment of MCA remains a challenge due to its vague pathological characteristics. An in-depth understanding of transcriptional dynamics at the cellular level is critical for developing specialised MCA treatment strategies. METHODS We integrated single-cell RNA sequencing and spatial transcriptomics data to systematically profile the MCA tumor microenvironment (TME), particularly the interactome of stromal and immune cells. In addition, a three-dimensional bioprinting technique, canonical ex vivo co-culture system, and immunofluorescence staining were further applied to validate the cellular communication networks within the TME. RESULTS This study identified the crucial intercellular interactions that engaged in MCA pathogenesis. We found the increased infiltration of FGF7+/THBS1+ myofibroblasts in MCA tissues with decreased expression of genes associated with leukocyte-mediated immunity and T cell activation, suggesting a crucial role of these cells in regulating the immunosuppressive TME. In addition, MS4A4A+ macrophages that exhibit M2-phenotype were enriched in the tumoral niche and high expression of MS4A4A+ was associated with poor prognosis in the cohort data. The ligand-receptor-based intercellular communication analysis revealed the tight interaction of MUC1+ malignant cells and ZEB1+ endothelial cells, providing mechanistic information for MCA angiogenesis and molecular targets for subsequent translational applications. CONCLUSIONS Our study provides novel insights into communications among tumour cells with stromal and immune cells that are significantly enriched in the TME during MCA progression, presenting potential prognostic biomarkers and therapeutic strategies for MCA. KEY POINTS Tumour microenvironment profiling of MCA is developed. MUC1+ tumour cells interplay with FGF7+/THBS1+ myofibroblasts to promote MCA development. MS4A4A+ macrophages exhibit M2 phenotype in MCA. ZEB1+ endotheliocytes engage in EndMT process in MCA.
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Affiliation(s)
- Haiyang Zhou
- Shanghai Frontiers Science Center of TCM Chemical BiologyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghaiChina
- Department of Colorectal SurgeryChangzheng HospitalNaval Medical UniversityShanghaiChina
| | - Yiwen Shen
- Shanghai Frontiers Science Center of TCM Chemical BiologyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Guangyong Zheng
- Shanghai Frontiers Science Center of TCM Chemical BiologyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Beibei Zhang
- Department of DermatologyTongren HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Anqi Wang
- Department of Colorectal SurgeryChangzheng HospitalNaval Medical UniversityShanghaiChina
| | - Jing Zhang
- Department of PathologyChangzheng HospitalNaval Medical UniversityShanghaiChina
| | - Hao Hu
- Department of PathologyChanghai HospitalNaval Medical UniversityShanghaiChina
| | - Jiayi Lin
- Shanghai Frontiers Science Center of TCM Chemical BiologyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Sanhong Liu
- Shanghai Frontiers Science Center of TCM Chemical BiologyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Xin Luan
- Shanghai Frontiers Science Center of TCM Chemical BiologyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Weidong Zhang
- Shanghai Frontiers Science Center of TCM Chemical BiologyInstitute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- School of PharmacyNaval Medical UniversityShanghaiChina
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8
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Mohajeri Khorasani A, Mohammadi S, Raghibi A, Haj Mohammad Hassani B, Bazghandi B, Mousavi P. miR-17-92a-1 cluster host gene: a key regulator in colorectal cancer development and progression. Clin Exp Med 2024; 24:85. [PMID: 38662056 PMCID: PMC11045601 DOI: 10.1007/s10238-024-01331-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 03/14/2024] [Indexed: 04/26/2024]
Abstract
Colorectal cancer (CRC), recognized among the five most prevalent malignancies and most deadly cancers, manifests multifactorial influences stemming from environmental exposures, dietary patterns, age, and genetic predisposition. Although substantial progress has been made in comprehending the etiology of CRC, the precise genetic components driving its pathogenesis remain incompletely elucidated. Within the expansive repertoire of non-coding RNAs, particular focus has centered on the miR-17-92a-1 cluster host gene (MIR17HG) and its associated miRNAs, which actively participate in diverse cellular processes and frequently exhibit heightened expression in various solid tumors, notably CRC. Therefore, the primary objective of this research is to undertake an extensive inquiry into the regulatory mechanisms, structural features, functional attributes, and potential diagnostic and therapeutic implications associated with this cluster in CRC. Furthermore, the intricate interplay between this cluster and the development and progression of CRC will be explored. Our findings underscore the upregulation of the miR-17-92a-1 cluster host gene (MIR17HG) and its associated miRNAs in CRC compared to normal tissues, thus implying their profound involvement in the progression of CRC. Collectively, these molecules are implicated in critical oncogenic processes, encompassing metastatic activity, regulation of apoptotic pathways, cellular proliferation, and drug resistance. Consequently, these findings shed illuminating insights into the potential of MIR17HG and its associated miRNAs as promising targets for therapeutic interventions in the management of CRC.
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Affiliation(s)
- Amirhossein Mohajeri Khorasani
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
- Student Research Committee, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Samane Mohammadi
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
- Student Research Committee, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Alireza Raghibi
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Behzad Haj Mohammad Hassani
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
- Student Research Committee, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Behina Bazghandi
- Protein Research Center, Shahid Beheshti University, Tehran, Iran
| | - Pegah Mousavi
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
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9
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Wang K, Lu Y, Li H, Zhang J, Ju Y, Ouyang M. Role of long non-coding RNAs in metabolic reprogramming of gastrointestinal cancer cells. Cancer Cell Int 2024; 24:15. [PMID: 38184562 PMCID: PMC10770979 DOI: 10.1186/s12935-023-03194-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 12/26/2023] [Indexed: 01/08/2024] Open
Abstract
Metabolic reprogramming, which is recognized as a hallmark of cancer, refers to the phenomenon by which cancer cells change their metabolism to support their increased biosynthetic demands. Tumor cells undergo substantial alterations in metabolic pathways, such as glycolysis, oxidative phosphorylation, pentose phosphate pathway, tricarboxylic acid cycle, fatty acid metabolism, and amino acid metabolism. Latest studies have revealed that long non-coding RNAs (lncRNAs), a group of non-coding RNAs over 200 nucleotides long, mediate metabolic reprogramming in tumor cells by regulating the transcription, translation and post-translational modification of metabolic-related signaling pathways and metabolism-related enzymes through transcriptional, translational, and post-translational modifications of genes. In addition, lncRNAs are closely related to the tumor microenvironment, and they directly or indirectly affect the proliferation and migration of tumor cells, drug resistance and other processes. Here, we review the mechanisms of lncRNA-mediated regulation of glucose, lipid, amino acid metabolism and tumor immunity in gastrointestinal tumors, aiming to provide more information on effective therapeutic targets and drug molecules for gastrointestinal tumors.
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Affiliation(s)
- Kang Wang
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, The First People's Hospital of Shunde Foshan), Shunde, Foshan, 528300, Guangdong, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510080, Guangdong, China
| | - Yan Lu
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, The First People's Hospital of Shunde Foshan), Shunde, Foshan, 528300, Guangdong, China
| | - Haibin Li
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, The First People's Hospital of Shunde Foshan), Shunde, Foshan, 528300, Guangdong, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510080, Guangdong, China
| | - Jun Zhang
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, The First People's Hospital of Shunde Foshan), Shunde, Foshan, 528300, Guangdong, China
- Guangdong Medical University, Dongguan, 523808, China
| | - Yongle Ju
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, The First People's Hospital of Shunde Foshan), Shunde, Foshan, 528300, Guangdong, China.
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510080, Guangdong, China.
| | - Manzhao Ouyang
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, The First People's Hospital of Shunde Foshan), Shunde, Foshan, 528300, Guangdong, China.
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510080, Guangdong, China.
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10
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Sardari A, Usefi H. Machine learning-based meta-analysis of colorectal cancer and inflammatory bowel disease. PLoS One 2023; 18:e0290192. [PMID: 38134011 PMCID: PMC10745176 DOI: 10.1371/journal.pone.0290192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 11/30/2023] [Indexed: 12/24/2023] Open
Abstract
Colorectal cancer (CRC) is a major global health concern, resulting in numerous cancer-related deaths. CRC detection, treatment, and prevention can be improved by identifying genes and biomarkers. Despite extensive research, the underlying mechanisms of CRC remain elusive, and previously identified biomarkers have not yielded satisfactory insights. This shortfall may be attributed to the predominance of univariate analysis methods, which overlook potential combinations of variants and genes contributing to disease development. Here, we address this knowledge gap by presenting a novel multivariate machine-learning strategy to pinpoint genes associated with CRC. Additionally, we applied our analysis pipeline to Inflammatory Bowel Disease (IBD), as IBD patients face substantial CRC risk. The importance of the identified genes was substantiated by rigorous validation across numerous independent datasets. Several of the discovered genes have been previously linked to CRC, while others represent novel findings warranting further investigation. A Python implementation of our pipeline can be accessed publicly at https://github.com/AriaSar/CRCIBD-ML.
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Affiliation(s)
- Aria Sardari
- Department of Computer Science, Memorial University of Newfoundland, St. John’s, NL, Canada
| | - Hamid Usefi
- Department of Computer Science, Memorial University of Newfoundland, St. John’s, NL, Canada
- Department of Mathematics & Statistics, Memorial University of Newfoundland, St. John’s, NL, Canada
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Guo Z, Huo X, Li X, Jiang C, Xue L. Advances in regulation and function of stearoyl-CoA desaturase 1 in cancer, from bench to bed. SCIENCE CHINA. LIFE SCIENCES 2023; 66:2773-2785. [PMID: 37450239 DOI: 10.1007/s11427-023-2352-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 04/23/2023] [Indexed: 07/18/2023]
Abstract
Stearoyl-CoA desaturase 1 (SCD1) converts saturated fatty acids to monounsaturated fatty acids. The expression of SCD1 is increased in many cancers, and the altered expression contributes to the proliferation, invasion, sternness and chemoresistance of cancer cells. Recently, more evidence has been reported to further support the important role of SCD1 in cancer, and the regulation mechanism of SCD1 has also been focused. Multiple factors are involved in the regulation of SCD1, including metabolism, diet, tumor microenvironment, transcription factors, non-coding RNAs, and epigenetics modification. Moreover, SCD1 is found to be involved in regulating ferroptosis resistance. Based on these findings, SCD1 has been considered as a potential target for cancer treatment. However, the resistance of SCD1 inhibition may occur in certain tumors due to tumor heterogeneity and metabolic plasticity. This review summarizes recent advances in the regulation and function of SCD1 in tumors and discusses the potential clinical application of targeting SCD1 for cancer treatment.
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Affiliation(s)
- Zhengyang Guo
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China
| | - Xiao Huo
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China
| | - Xianlong Li
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China
| | - Changtao Jiang
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China.
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University and the Key Laboratory of Molecular Cardiovascular Science (Peking University), Ministry of Education, Beijing, 100191, China.
| | - Lixiang Xue
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China.
- Peking University Third Hospital Cancer Center, Department of Radiation Oncology, Peking University Third Hospital, Beijing, 100191, China.
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12
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Tariq L, Arafah A, Sehar N, Ali A, Khan A, Rasool I, Rashid SM, Ahmad SB, Beigh S, Dar TUH, Rehman MU. Novel insights on perils and promises of miRNA in understanding colon cancer metastasis and progression. Med Oncol 2023; 40:282. [PMID: 37639075 DOI: 10.1007/s12032-023-02099-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 06/19/2023] [Indexed: 08/29/2023]
Abstract
Colorectal cancer (CRC) is the third highest frequent malignancy and ultimate critical source of cancer-associated mortality around the world. Regardless of latest advances in molecular and surgical targeted medicines that have increased remedial effects in CRC patients, the 5-year mortality rate for CRC patients remains dismally low. Evidence suggests that microRNAs (miRNAs) execute an essential part in the development and spread of CRC. The miRNAs are a type of short non-coding RNA that exhibited to control the appearance of tumor suppressor genes and oncogenes. miRNA expression profiling is already being utilized in clinical practice as analytical and prognostic biomarkers to evaluate cancer patients' tumor genesis, advancement, and counteraction to drugs. By modulating their target genes, dysregulated miRNAs are linked to malignant characteristics (e.g., improved proliferative and invasive capabilities, cell cycle aberration, evasion of apoptosis, and promotion of angiogenesis). This review presents an updated summary of circulatory miRNAs, tumor-suppressive and oncogenic miRNAs, and the potential reasons for dysregulated miRNAs in CRC. Further we will explore the critical role of miRNAs in CRC drug resistance.
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Affiliation(s)
- Lubna Tariq
- Department of Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, 183254, India
| | - Azher Arafah
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Nouroz Sehar
- Centre for Translational and Clinical Research, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Aarif Ali
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Andleeb Khan
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, 45142, Jazan, Saudi Arabia
| | - Iyman Rasool
- Department of Pathology, Government Medical College (GMC-Srinagar), Karanagar, Srinagar, Jammu and Kashmir, 190006, India
| | - Shahzada Mudasir Rashid
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Sheikh Bilal Ahmad
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Alusteng, Shuhama, Srinagar, Jammu and Kashmir, 190006, India
| | - Saba Beigh
- Department of Public Health, Faculty of Applied Medical Science, Al Baha University, 65431, Al Baha, Saudi Arabia
| | - Tanveer Ul Hassan Dar
- Department of Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, 183254, India
| | - Muneeb U Rehman
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, 11451, Riyadh, Saudi Arabia.
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13
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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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14
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Safi A, Saberiyan M, Sanaei MJ, Adelian S, Davarani Asl F, Zeinaly M, Shamsi M, Ahmadi R. The role of noncoding RNAs in metabolic reprogramming of cancer cells. Cell Mol Biol Lett 2023; 28:37. [PMID: 37161350 PMCID: PMC10169341 DOI: 10.1186/s11658-023-00447-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 04/11/2023] [Indexed: 05/11/2023] Open
Abstract
Metabolic reprogramming is a well-known feature of cancer that allows malignant cells to alter metabolic reactions and nutrient uptake, thereby promoting tumor growth and spread. It has been discovered that noncoding RNAs (ncRNAs), including microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA), have a role in a variety of biological functions, control physiologic and developmental processes, and even influence disease. They have been recognized in numerous cancer types as tumor suppressors and oncogenic agents. The role of ncRNAs in the metabolic reprogramming of cancer cells has recently been noticed. We examine this subject, with an emphasis on the metabolism of glucose, lipids, and amino acids, and highlight the therapeutic use of targeting ncRNAs in cancer treatment.
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Affiliation(s)
- Amir Safi
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mohammadreza Saberiyan
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mohammad-Javad Sanaei
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samaneh Adelian
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Fateme Davarani Asl
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mahsa Zeinaly
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
| | - Mahdi Shamsi
- Department of Cell and Molecular Biology, Najafabad Branch, Islamic Azad University, Najafabad, Iran
| | - Reza Ahmadi
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Rahmatiyeh Region, Shahrekord, Iran.
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15
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Abdelmaksoud NM, Abulsoud AI, Abdelghany TM, Elshaer SS, Rizk SM, Senousy MA. Mitochondrial remodeling in colorectal cancer initiation, progression, metastasis, and therapy: A review. Pathol Res Pract 2023; 246:154509. [PMID: 37182313 DOI: 10.1016/j.prp.2023.154509] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 04/25/2023] [Accepted: 05/05/2023] [Indexed: 05/16/2023]
Abstract
Colorectal cancer (CRC) is a major health concern with multifactorial pathophysiology representing intense therapeutic challenges. It is well known that deregulation of spatiotemporally-controlled signaling pathways and their metabolic reprogramming effects play a pivotal role in the development and progression of CRC. As such, the mitochondrial role in CRC initiation gained a lot of attention recently, as it is considered the powerhouse that regulates the bioenergetics in CRC. In addition, the crosstalk between microRNAs (miRNAs) and mitochondrial dysfunction has become a newfangled passion for deciphering CRC molecular mechanisms. This review sheds light on the relationship between different signaling pathways involved in metabolic reprogramming and their therapeutic targets, alterations in mitochondrial DNA content, mitochondrial biogenesis, and mitophagy, and the role of polymorphisms in mitochondrial genes as well as miRNAs regulating mitochondrial proteins in CRC initiation, progression, metastasis, and resistance to various therapies.
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Affiliation(s)
- Nourhan M Abdelmaksoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020 El Salam, 11785 Cairo, Egypt
| | - Ahmed I Abulsoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020 El Salam, 11785 Cairo, Egypt; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11823, Egypt.
| | - Tamer M Abdelghany
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11884, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020 El Salam, 11785 Cairo, Egypt
| | - Shereen Saeid Elshaer
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020 El Salam, 11785 Cairo, Egypt; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo 11823, Egypt
| | - Sherine Maher Rizk
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
| | - Mahmoud A Senousy
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; Department of Biochemistry, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo 11786, Egypt
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16
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Mokhtari K, Peymani M, Rashidi M, Hushmandi K, Ghaedi K, Taheriazam A, Hashemi M. Colon cancer transcriptome. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2023; 180-181:49-82. [PMID: 37059270 DOI: 10.1016/j.pbiomolbio.2023.04.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/31/2023] [Accepted: 04/06/2023] [Indexed: 04/16/2023]
Abstract
Over the last four decades, methodological innovations have continuously changed transcriptome profiling. It is now feasible to sequence and quantify the transcriptional outputs of individual cells or thousands of samples using RNA sequencing (RNA-seq). These transcriptomes serve as a connection between cellular behaviors and their underlying molecular mechanisms, such as mutations. This relationship, in the context of cancer, provides a chance to unravel tumor complexity and heterogeneity and uncover novel biomarkers or treatment options. Since colon cancer is one of the most frequent malignancies, its prognosis and diagnosis seem to be critical. The transcriptome technology is developing for an earlier and more accurate diagnosis of cancer which can provide better protectivity and prognostic utility to medical teams and patients. A transcriptome is a whole set of expressed coding and non-coding RNAs in an individual or cell population. The cancer transcriptome includes RNA-based changes. The combined genome and transcriptome of a patient may provide a comprehensive picture of their cancer, and this information is beginning to affect treatment decision-making in real-time. A full assessment of the transcriptome of colon (colorectal) cancer has been assessed in this review paper based on risk factors such as age, obesity, gender, alcohol use, race, and also different stages of cancer, as well as non-coding RNAs like circRNAs, miRNAs, lncRNAs, and siRNAs. Similarly, they have been examined independently in the transcriptome study of colon cancer.
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Affiliation(s)
- Khatere Mokhtari
- Department of Modern Biology, ACECR Institute of Higher Education (Isfahan Branch), Isfahan, Iran
| | - Maryam Peymani
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, 4815733971, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, 4815733971, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Kamran Ghaedi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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17
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Fernández LP, Deleyto-Seldas N, Colmenarejo G, Sanz A, Wagner S, Plata-Gómez AB, Gómez-Patiño M, Molina S, Espinosa-Salinas I, Aguilar-Aguilar E, Ortega S, Graña-Castro O, Loria-Kohen V, Fernández-Marcos PJ, Efeyan A, Ramírez de Molina A. Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3' untranslated region. Genome Biol 2022; 23:230. [PMID: 36316722 PMCID: PMC9620695 DOI: 10.1186/s13059-022-02798-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 10/19/2022] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND Overweight and obesity are defined by an anomalous or excessive fat accumulation that may compromise health. To find single-nucleotide polymorphisms (SNPs) influencing metabolic phenotypes associated with the obesity state, we analyze multiple anthropometric and clinical parameters in a cohort of 790 healthy volunteers and study potential associations with 48 manually curated SNPs, in metabolic genes functionally associated with the mechanistic target of rapamycin (mTOR) pathway. RESULTS We identify and validate rs2291007 within a conserved region in the 3'UTR of folliculin-interacting protein FNIP2 that correlates with multiple leanness parameters. The T-to-C variant represents the major allele in Europeans and disrupts an ancestral target sequence of the miRNA miR-181b-5p, thus resulting in increased FNIP2 mRNA levels in cancer cell lines and in peripheral blood from carriers of the C allele. Because the miRNA binding site is conserved across vertebrates, we engineered the T-to-C substitution in the endogenous Fnip2 allele in mice. Primary cells derived from Fnip2 C/C mice show increased mRNA stability, and more importantly, Fnip2 C/C mice replicate the decreased adiposity and increased leanness observed in human volunteers. Finally, expression levels of FNIP2 in both human samples and mice negatively associate with leanness parameters, and moreover, are the most important contributor in a multifactorial model of body mass index prediction. CONCLUSIONS We propose that rs2291007 influences human leanness through an evolutionarily conserved modulation of FNIP2 mRNA levels.
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Affiliation(s)
- Lara P Fernández
- Molecular Oncology Group, IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain
| | | | - Gonzalo Colmenarejo
- Biostatistics and Bioinformatics Unit, IMDEA-Food Institute, CEI UAM+CSIC, Madrid, Spain
| | - Alba Sanz
- Spanish National Cancer Research Center, Madrid, Spain
| | - Sonia Wagner
- Molecular Oncology Group, IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain
| | | | - Mónica Gómez-Patiño
- GENYAL Platform on Nutrition and Health, IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain
| | - Susana Molina
- GENYAL Platform on Nutrition and Health, IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain
| | - Isabel Espinosa-Salinas
- GENYAL Platform on Nutrition and Health, IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain
| | - Elena Aguilar-Aguilar
- GENYAL Platform on Nutrition and Health, IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain
| | - Sagrario Ortega
- Mouse Genome Editing Unit, Spanish National Cancer Research Center, Madrid, Spain
| | - Osvaldo Graña-Castro
- Bioinformatics Unit, Spanish National Cancer Research Center, Madrid, Spain
- Institute of Applied Molecular Medicine (IMMA-Nemesio Díez), Department of Basic Medical Sciences, School of Medicine, San Pablo-CEU University, CEU Universities, Boadilla del Monte, Madrid, Spain
| | - Viviana Loria-Kohen
- GENYAL Platform on Nutrition and Health, IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain
| | | | - Alejo Efeyan
- Spanish National Cancer Research Center, Madrid, Spain.
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Inhibition of Aryl Hydrocarbon Receptor (AhR) Expression Disrupts Cell Proliferation and Alters Energy Metabolism and Fatty Acid Synthesis in Colon Cancer Cells. Cancers (Basel) 2022; 14:cancers14174245. [PMID: 36077780 PMCID: PMC9454859 DOI: 10.3390/cancers14174245] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/12/2022] [Accepted: 08/25/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Cancer cells undergo metabolic modifications in order to meet their high energetic demand. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcriptional factor primarily known as a xenobiotic sensor. However, this receptor seems to have a wide range of physiological roles in many processes including cell proliferation, migration or control of immune responses. AhR is often overexpressed in tumor cells of various tissue origin, and several studies have indicated that AhR may also contribute to regulation of cellular metabolism, including synthesis of fatty acids (FA), one of the major steps in metabolic transition. Potential links between the AhR and the control of tumor cell proliferation and metabolism thus deserve more attention. Abstract The aryl hydrocarbon receptor (AhR) plays a wide range of physiological roles in cellular processes such as proliferation, migration or control of immune responses. Several studies have also indicated that AhR might contribute to the regulation of energy balance or cellular metabolism. We observed that the AhR is upregulated in tumor epithelial cells derived from colon cancer patients. Using wild-type and the corresponding AhR knockout (AhR KO) variants of human colon cancer cell lines HCT116 and HT-29, we analyzed possible role(s) of the AhR in cell proliferation and metabolism, with a focus on regulation of the synthesis of fatty acids (FAs). We observed a decreased proliferation rate in the AhR KO cells, which was accompanied with altered cell cycle progression, as well as a decreased ATP production. We also found reduced mRNA levels of key enzymes of the FA biosynthetic pathway in AhR KO colon cancer cells, in particular of stearoyl-CoA desaturase 1 (SCD1). The loss of AhR was also associated with reduced expression and/or activity of components of the PI3K/Akt pathway, which controls lipid metabolism, and other lipogenic transcriptional regulators, such as sterol regulatory element binding transcription factor 1 (SREBP1). Together, our data indicate that disruption of AhR activity in colon tumor cells may, likely in a cell-specific manner, limit their proliferation, which could be linked with a suppressive effect on their endogenous FA metabolism. More attention should be paid to potential mechanistic links between overexpressed AhR and colon tumor cell metabolism.
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Wang G, Wang JJ, Xu XN, Shi F, Fu XL. Targeting cellular energy metabolism- mediated ferroptosis by small molecule compounds for colorectal cancer therapy. J Drug Target 2022; 30:819-832. [PMID: 35481396 DOI: 10.1080/1061186x.2022.2071909] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Alterations in cellular energy metabolism, including glycolysis, glutamine and lipid metabolism that affects ferroptosis in the tumour microenvironment (TME), play a critical role in the development and progression of colorectal cancer (CRC) and offer evolutionary advantages to tumour cells and even enhance their aggressive phenotype. This review summarises the findings on the dysregulated energy metabolism pathways, including lipid and fatty acid metabolism especially for regulating the ferroptosis in TME. Moreover, the cellular energy metabolism and tumour ferroptosis to be regulated by small molecule compounds, which targeting the different aspects of metabolic pathways of energy production as well as metabolic enzymes that connect with the tumour cell growth and ferroptosis in CRC are also discussed. In this review, we will provide a comprehensive summary on small molecule compounds regulatory function of different energy metabolic routes on ferroptosis in tumour cells and discuss those metabolic vulnerabilities for the development of potential ferroptosis-based tumour therapies for colorectal cancer.
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Affiliation(s)
- Gang Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai, China
| | - Jun-Jie Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai, China
| | - Xiao-Na Xu
- Department of Medicine, Jiangsu University, Zhenjiang City, China
| | - Feng Shi
- Department of Medicine, Jiangsu University, Zhenjiang City, China
| | - Xing-Li Fu
- Department of Medicine, Jiangsu University, Zhenjiang City, China
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20
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Gregorio JD, Petricca S, Iorio R, Toniato E, Flati V. MITOCHONDRIAL AND METABOLIC ALTERATIONS IN CANCER CELLS. Eur J Cell Biol 2022; 101:151225. [DOI: 10.1016/j.ejcb.2022.151225] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 04/11/2022] [Accepted: 04/11/2022] [Indexed: 02/07/2023] Open
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21
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Song S, Wen F, Gu S, Gu P, Huang W, Ruan S, Chen X, Zhou J, Li Y, Liu J, Shu P. Network Pharmacology Study and Experimental Validation of Yiqi Huayu Decoction Inducing Ferroptosis in Gastric Cancer. Front Oncol 2022; 12:820059. [PMID: 35237519 PMCID: PMC8883049 DOI: 10.3389/fonc.2022.820059] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 01/17/2022] [Indexed: 12/24/2022] Open
Abstract
ObjectiveThis study aimed to identify the mechanism of Yiqi Huayu Decoction (YQHY) induced ferroptosis in gastric cancer (GC) by using network pharmacology and experimental validation.MethodsThe targets of YQHY, ferroptosis-related targets, and targets related to GC were derived from databases. Following the protein–protein interaction (PPI) network, the hub targets for YQHY induced ferroptosis in GC were identified. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were used to analyze the hub targets from a macro perspective. We verified the hub targets by molecular docking, GEPIA, HPA, and the cBioPortal database. Finally, we performed cell viability assays, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, lipid peroxidation, and GSH assays to explore the mechanism of YQHY induced ferroptosis in GC.ResultsWe identified the main active compounds and hub targets: Quercetin, DIBP, DBP, Mipax, Phaseol and TP53, ATM, SMAD4, PTGS2, and ACSL4. KEGG enrichment analyses indicated that the JAK2-STAT3 signaling pathway may be a significant pathway. Molecular docking results showed that the main active compounds had a good binding activity with the hub targets. The experimental results proved that YQHY could induce ferroptosis in AGS by increasing the MDA content and reducing the GSH content. qRT–PCR and Western blot results showed that YQHY can induce ferroptosis in GC by affecting the JAK2-STAT3 pathway and the expression of ACSL4.ConclusionsThis study indicated that YQHY can induce ferroptosis in GC by affecting the JAK2–STAT3 pathway and the expression of ACSL4, and induction of ferroptosis may be one of the possible mechanisms of YQHY’s anti-recurrence and metastasis of GC.
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Affiliation(s)
- Siyuan Song
- Department of Medical Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- The First College for Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Medical Oncology, Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, China
| | - Fang Wen
- The First College for Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Suping Gu
- The First College for Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Peixin Gu
- The First College for Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenjie Huang
- Department of Medical Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- The First College for Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Medical Oncology, Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, China
| | - Shuai Ruan
- Department of Medical Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- The First College for Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Medical Oncology, Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, China
| | - Xiaoxue Chen
- Department of Medical Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- The First College for Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Medical Oncology, Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, China
| | - Jiayu Zhou
- Department of Medical Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- The First College for Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Medical Oncology, Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, China
| | - Ye Li
- Department of Medical Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- The First College for Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Medical Oncology, Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, China
| | - Jiatong Liu
- The First College for Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Peng Shu
- Department of Medical Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- The First College for Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Medical Oncology, Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, China
- *Correspondence: Peng Shu,
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22
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Xu YJ, Wei RS, Li XH, Li Q, Yu JR, Zhuang XF. MiR-421 promotes lipid metabolism by targeting PTEN via activating PI3K/AKT/mTOR pathway in non-small cell lung cancer. Epigenomics 2022; 14:121-138. [PMID: 35045733 DOI: 10.2217/epi-2021-0229] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Aims: We aim to investigate the effects of miR-421 on lipid metabolism in non-small cell lung cancer (NSCLC). Methods: The miR-421 expression and PTEN mRNA level in tumor tissues, adjacent normal tissues, human lung epithelial cells and NSCLC cell lines were detected with reverse transcription quantitative real-time PCR. Results: MiR-421 was increased, and PTEN was reduced remarkably in tumor tissues and NSCLC cell lines. Down-regulated miR-421 suppressed lipid accumulation, cell proliferation, migration and invasion, whereas overexpression of miR-421 had the opposite effects. MiR-421 directly targeted PTEN and negatively regulated PTEN expression. MiR-421 activated PI3K/AKT/mTOR pathway through regulating PTEN. Conclusion: MiR-421 promotes lipid metabolism through targeting PTEN via PI3K/AKT/mTOR pathway activation in NSCLC, indicating that miR-421 can be a latent therapeutic target for NSCLC.
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Affiliation(s)
- Yong-Jie Xu
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, 030000, Shanxi Province, China
| | - Rui-Shi Wei
- Department of Thoracic Surgery, Changzhou Cancer Hospital Affiliated to Soochow University, Changzhou, 213001, Jiangsu Province, China
| | - Xin-Hua Li
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, 030000, Shanxi Province, China
| | - Qiang Li
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, 030000, Shanxi Province, China
| | - Jian-Rong Yu
- Department of Thoracic Surgery, Changzhou Cancer Hospital Affiliated to Soochow University, Changzhou, 213001, Jiangsu Province, China
| | - Xiao-Fei Zhuang
- Department of Thoracic Surgery, Shanxi Cancer Hospital, Taiyuan, 030000, Shanxi Province, China
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23
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The Epithelial-Mesenchymal Transition at the Crossroads between Metabolism and Tumor Progression. Int J Mol Sci 2022; 23:ijms23020800. [PMID: 35054987 PMCID: PMC8776206 DOI: 10.3390/ijms23020800] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/04/2022] [Accepted: 01/05/2022] [Indexed: 12/12/2022] Open
Abstract
The transition between epithelial and mesenchymal phenotype is emerging as a key determinant of tumor cell invasion and metastasis. It is a plastic process in which epithelial cells first acquire the ability to invade the extracellular matrix and migrate into the bloodstream via transdifferentiation into mesenchymal cells, a phenomenon known as epithelial–mesenchymal transition (EMT), and then reacquire the epithelial phenotype, the reverse process called mesenchymal–epithelial transition (MET), to colonize a new organ. During all metastatic stages, metabolic changes, which give cancer cells the ability to adapt to increased energy demand and to withstand a hostile new environment, are also important determinants of successful cancer progression. In this review, we describe the complex interaction between EMT and metabolism during tumor progression. First, we outline the main connections between the two processes, with particular emphasis on the role of cancer stem cells and LncRNAs. Then, we focus on some specific cancers, such as breast, lung, and thyroid cancer.
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24
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Ma Y, Nenkov M, Chen Y, Press AT, Kaemmerer E, Gassler N. Fatty acid metabolism and acyl-CoA synthetases in the liver-gut axis. World J Hepatol 2021; 13:1512-1533. [PMID: 34904027 PMCID: PMC8637682 DOI: 10.4254/wjh.v13.i11.1512] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 06/28/2021] [Accepted: 10/11/2021] [Indexed: 02/06/2023] Open
Abstract
Fatty acids are energy substrates and cell components which participate in regulating signal transduction, transcription factor activity and secretion of bioactive lipid mediators. The acyl-CoA synthetases (ACSs) family containing 26 family members exhibits tissue-specific distribution, distinct fatty acid substrate preferences and diverse biological functions. Increasing evidence indicates that dysregulation of fatty acid metabolism in the liver-gut axis, designated as the bidirectional relationship between the gut, microbiome and liver, is closely associated with a range of human diseases including metabolic disorders, inflammatory disease and carcinoma in the gastrointestinal tract and liver. In this review, we depict the role of ACSs in fatty acid metabolism, possible molecular mechanisms through which they exert functions, and their involvement in hepatocellular and colorectal carcinoma, with particular attention paid to long-chain fatty acids and small-chain fatty acids. Additionally, the liver-gut communication and the liver and gut intersection with the microbiome as well as diseases related to microbiota imbalance in the liver-gut axis are addressed. Moreover, the development of potentially therapeutic small molecules, proteins and compounds targeting ACSs in cancer treatment is summarized.
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Affiliation(s)
- Yunxia Ma
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Miljana Nenkov
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Yuan Chen
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Adrian T Press
- Department of Anesthesiology and Intensive Care Medicine and Center for Sepsis Control and Care, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Elke Kaemmerer
- Department of Pediatrics, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Nikolaus Gassler
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany.
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25
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Complex Alterations of Fatty Acid Metabolism and Phospholipidome Uncovered in Isolated Colon Cancer Epithelial Cells. Int J Mol Sci 2021; 22:ijms22136650. [PMID: 34206240 PMCID: PMC8268957 DOI: 10.3390/ijms22136650] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/16/2021] [Accepted: 06/18/2021] [Indexed: 12/15/2022] Open
Abstract
The development of colon cancer, one of the most common malignancies, is accompanied with numerous lipid alterations. However, analyses of whole tumor samples may not always provide an accurate description of specific changes occurring directly in tumor epithelial cells. Here, we analyzed in detail the phospholipid (PL), lysophospholipid (lysoPL), and fatty acid (FA) profiles of purified EpCAM+ cells, isolated from tumor and adjacent non-tumor tissues of colon cancer patients. We found that a number of FAs increased significantly in isolated tumor cells, which also included a number of long polyunsaturated FAs. Higher levels of FAs were associated with increased expression of FA synthesis genes, as well as with altered expression of enzymes involved in FA elongation and desaturation, including particularly fatty acid synthase, stearoyl-CoA desaturase, fatty acid desaturase 2 and ELOVL5 fatty acid elongase 5 We identified significant changes in ratios of specific lysoPLs and corresponding PLs. A number of lysophosphatidylcholine and lysophosphatidylethanolamine species, containing long-chain and very-long chain FAs, often with high numbers of double bonds, were significantly upregulated in tumor cells. Increased de novo synthesis of very long-chain FAs, or, altered uptake or incorporation of these FAs into specific lysoPLs in tumor cells, may thus contribute to reprogramming of cellular phospholipidome and membrane alterations observed in colon cancer.
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26
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Pidíková P, Herichová I. miRNA Clusters with Up-Regulated Expression in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13122979. [PMID: 34198662 PMCID: PMC8232258 DOI: 10.3390/cancers13122979] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/05/2021] [Accepted: 06/09/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary As miRNAs show the capacity to be used as CRC biomarkers, we analysed experimentally validated data about frequently up-regulated miRNA clusters in CRC tissue. We identified 15 clusters that showed increased expression in CRC: miR-106a/363, miR-106b/93/25, miR-17/92a-1, miR-181a-1/181b-1, miR-181a-2/181b-2, miR-181c/181d, miR-183/96/182, miR-191/425, miR-200c/141, miR-203a/203b, miR-222/221, mir-23a/27a/24-2, mir-29b-1/29a, mir-301b/130b and mir-452/224. Cluster positions in the genome are intronic or intergenic. Most clusters are regulated by several transcription factors, and by long non-coding RNAs. In some cases, co-expression of miRNA with other cluster members or host gene has been proven. miRNA expression patterns in cancer tissue, blood and faeces were compared. The members of the selected clusters target 181 genes. Their functions and corresponding pathways were revealed with the use of Panther analysis. Clusters miR-17/92a-1, miR-106a/363, miR-106b/93/25 and miR-183/96/182 showed the strongest association with metastasis occurrence and poor patient survival, implicating them as the most promising targets of translational research. Abstract Colorectal cancer (CRC) is one of the most common malignancies in Europe and North America. Early diagnosis is a key feature of efficient CRC treatment. As miRNAs can be used as CRC biomarkers, the aim of the present study was to analyse experimentally validated data on frequently up-regulated miRNA clusters in CRC tissue and investigate their members with respect to clinicopathological characteristics of patients. Based on available data, 15 up-regulated clusters, miR-106a/363, miR-106b/93/25, miR-17/92a-1, miR-181a-1/181b-1, miR-181a-2/181b-2, miR-181c/181d, miR-183/96/182, miR-191/425, miR-200c/141, miR-203a/203b, miR-222/221, mir-23a/27a/24-2, mir-29b-1/29a, mir-301b/130b and mir-452/224, were selected. The positions of such clusters in the genome can be intronic or intergenic. Most clusters are regulated by several transcription factors, and miRNAs are also sponged by specific long non-coding RNAs. In some cases, co-expression of miRNA with other cluster members or host gene has been proven. miRNA expression patterns in cancer tissue, blood and faeces were compared. Based on experimental evidence, 181 target genes of selected clusters were identified. Panther analysis was used to reveal the functions of the target genes and their corresponding pathways. Clusters miR-17/92a-1, miR-106a/363, miR-106b/93/25 and miR-183/96/182 showed the strongest association with metastasis occurrence and poor patient survival, implicating them as the most promising targets of translational research.
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27
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Paul S, Bravo Vázquez LA, Uribe SP, Manzanero Cárdenas LA, Ruíz Aguilar MF, Chakraborty S, Sharma A. Roles of microRNAs in carbohydrate and lipid metabolism disorders and their therapeutic potential. Biochimie 2021; 187:83-93. [PMID: 34082043 DOI: 10.1016/j.biochi.2021.05.015] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/19/2021] [Accepted: 05/25/2021] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRNAs) are small (∼21 nucleotides), endogenous, non-coding RNA molecules implicated in the post-transcriptional gene regulation performed through target mRNA cleavage or translational inhibition. In recent years, several investigations have demonstrated that miRNAs are involved in regulating both carbohydrate and lipid homeostasis in humans and other organisms. Moreover, it has been observed that the dysregulation of these metabolism-related miRNAs leads to the development of several metabolic disorders, such as type 2 diabetes, obesity, nonalcoholic fatty liver, insulin resistance, and hyperlipidemia. Hence, in this current review, with the aim to impulse the research arena of the micro-transcriptome implications in vital metabolic pathways as well as to highlight the remarkable potential of miRNAs as therapeutic targets for metabolic disorders in humans, we provide an overview of the regulatory roles of metabolism-associated miRNAs in humans and murine models.
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Affiliation(s)
- Sujay Paul
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Queretaro, Av. Epigmenio Gonzalez, No. 500 Fracc, San Pablo, CP 76130, Querétaro, Mexico.
| | - Luis Alberto Bravo Vázquez
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Queretaro, Av. Epigmenio Gonzalez, No. 500 Fracc, San Pablo, CP 76130, Querétaro, Mexico
| | - Samantha Pérez Uribe
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Queretaro, Av. Epigmenio Gonzalez, No. 500 Fracc, San Pablo, CP 76130, Querétaro, Mexico
| | - Luis Aarón Manzanero Cárdenas
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Ciudad de Mexico, Calle del Puente, No. 222 Col. Ejidos de Huipulco, Tlalpan, CP 14380, Mexico City, Mexico
| | - María Fernanda Ruíz Aguilar
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Ciudad de Mexico, Calle del Puente, No. 222 Col. Ejidos de Huipulco, Tlalpan, CP 14380, Mexico City, Mexico
| | - Samik Chakraborty
- Division of Nephrology, Boston Children's Hospital, Harvard Medical School, MA, 02115, USA
| | - Ashutosh Sharma
- Tecnologico de Monterrey, School of Engineering and Sciences, Campus Queretaro, Av. Epigmenio Gonzalez, No. 500 Fracc, San Pablo, CP 76130, Querétaro, Mexico.
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28
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Venosa A, Smith LC, Gow AJ, Zarbl H, Laskin JD, Laskin DL. Macrophage activation in the lung during the progression of nitrogen mustard induced injury is associated with histone modifications and altered miRNA expression. Toxicol Appl Pharmacol 2021; 423:115569. [PMID: 33971176 DOI: 10.1016/j.taap.2021.115569] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 04/30/2021] [Accepted: 05/05/2021] [Indexed: 12/11/2022]
Abstract
Activated macrophages have been implicated in lung injury and fibrosis induced by the cytotoxic alkylating agent, nitrogen mustard (NM). Herein, we determined if macrophage activation is associated with histone modifications and altered miRNA expression. Treatment of rats with NM (0.125 mg/kg, i.t.) resulted in increases in phosphorylation of H2A.X in lung macrophages at 1 d and 3 d post-exposure. This DNA damage response was accompanied by methylation of histone (H) 3 lysine (K) 4 and acetylation of H3K9, marks of transcriptional activation, and methylation of H3K36 and H3K9, marks associated with transcriptional repression. Increases in histone acetyl transferase and histone deacetylase were also observed in macrophages 1 d and 28 d post-NM exposure. PCR array analysis of miRNAs (miR)s involved in inflammation and fibrosis revealed unique and overlapping expression profiles in macrophages isolated 1, 3, 7, and 28 d post-NM. An IPA Core Analysis of predicted mRNA targets of differentially expressed miRNAs identified significant enrichment of Diseases and Functions related to cell cycle arrest, apoptosis, cell movement, cell adhesion, lipid metabolism, and inflammation 1 d and 28 d post NM. miRNA-mRNA interaction network analysis revealed highly connected miRNAs representing key upstream regulators of mRNAs involved in significantly enriched pathways including miR-34c-5p and miR-27a-3p at 1 d post NM and miR-125b-5p, miR-16-5p, miR-30c-5p, miR-19b-3p and miR-148b-3p at 28 d post NM. Collectively, these data show that NM promotes histone remodeling and alterations in miRNA expression linked to lung macrophage responses during inflammatory injury and fibrosis.
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Affiliation(s)
- Alessandro Venosa
- Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA
| | - L Cody Smith
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, NJ 08854, USA
| | - Andrew J Gow
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, NJ 08854, USA; Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA
| | - Helmut Zarbl
- Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA; Department of Environmental and Occupational Health and Justice, Rutgers University School of Public Health, Piscataway, NJ 08854, USA
| | - Jeffrey D Laskin
- Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA; Department of Environmental and Occupational Health and Justice, Rutgers University School of Public Health, Piscataway, NJ 08854, USA
| | - Debra L Laskin
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, NJ 08854, USA; Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ 08854, USA.
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29
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Rubio J, Cristóbal I, Santos A, Caramés C, Luque M, Sanz-Alvarez M, Zazo S, Madoz-Gúrpide J, Rojo F, García-Foncillas J. Low MicroRNA-19b Expression Shows a Promising Clinical Impact in Locally Advanced Rectal Cancer. Cancers (Basel) 2021; 13:cancers13061456. [PMID: 33810186 PMCID: PMC8005118 DOI: 10.3390/cancers13061456] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 03/08/2021] [Accepted: 03/19/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary The establishment of molecular markers to predict response to neoadjuvant chemoradiotherapy (CRT) would help to avoid unnecessary toxicities and surgery delays in the clinical management of locally advanced rectal cancer (LARC) patients. Our aim here was to in-vestigate the clinical impact of miR-19b in this disease. Interestingly, our findings highlight the potential usefulness of miR-19b as a predictor of response to neoadjuvant CRT and outcome, and suggest PPP2R5E as a relevant miR-19b target in LARC. Abstract The standard treatment for patients with locally advanced colorectal cancer (LARC) is neoadjuvant 5-fluorouracil (5-FU) based chemoradiotherapy (CRT) followed by surgical mesorectal excision. However, the lack of response to this preoperative treatment strongly compromises patient outcomes and leads to surgical delays and undesired toxicities in those non-responder cases. Thus, the identification of effective and robust biomarkers to predict response to preoperative CRT represents an urgent need in the current clinical management of LARC. The oncomiR microRNA-19b (miR-19b) has been reported to functionally play oncogenic roles in colorectal cancer (CRC) cells as well as regulate 5-FU sensitivity and determine outcome in CRC patients. However, its clinical impact in LARC has not been previously investigated. Here, we show that miR-19b deregulation is a common event in this disease, and its decreased expression significantly associates with lower tumor size after CRT (p = 0.003), early pathological stage (p = 0.003), and absence of recurrence (p = 0.001) in LARC patients. Interestingly, low miR-19b expression shows a predictive value of better response to neoajuvant CRT (p < 0.001), and the subgroup of LARC patients with low miR-19b levels have a markedly longer overall (p = 0.003) and event-free survival (p = 0.023). Finally, multivariate analyses determined that miR-19b independently predicts both patient outcome and response to preoperative CRT, highlighting its potential clinical usefulness in the management of LARC patients.
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Affiliation(s)
- Jaime Rubio
- Cancer Unit for Research on Novel Therapeutic Targets, Oncohealth Institute, IIS- Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain; (J.R.); (A.S.); (C.C.)
- Translational Oncology Division, Oncohealth Institute, IIS- Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain
- Medical Oncology Department, University Hospital “Fundación Jiménez Díaz”, UAM, E-28040 Madrid, Spain
| | - Ion Cristóbal
- Cancer Unit for Research on Novel Therapeutic Targets, Oncohealth Institute, IIS- Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain; (J.R.); (A.S.); (C.C.)
- Translational Oncology Division, Oncohealth Institute, IIS- Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain
- Correspondence: (I.C.); (J.G.-F.); Tel.: +34-915504800 (I.C. & J.G-F.)
| | - Andrea Santos
- Cancer Unit for Research on Novel Therapeutic Targets, Oncohealth Institute, IIS- Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain; (J.R.); (A.S.); (C.C.)
- Translational Oncology Division, Oncohealth Institute, IIS- Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain
| | - Cristina Caramés
- Cancer Unit for Research on Novel Therapeutic Targets, Oncohealth Institute, IIS- Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain; (J.R.); (A.S.); (C.C.)
- Translational Oncology Division, Oncohealth Institute, IIS- Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain
- Medical Oncology Department, University Hospital “Fundación Jiménez Díaz”, UAM, E-28040 Madrid, Spain
| | - Melani Luque
- Pathology Department, IIS- Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain; (M.L.); (M.S.-A.); (S.Z.); (J.M.-G.); (F.R.)
| | - Marta Sanz-Alvarez
- Pathology Department, IIS- Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain; (M.L.); (M.S.-A.); (S.Z.); (J.M.-G.); (F.R.)
| | - Sandra Zazo
- Pathology Department, IIS- Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain; (M.L.); (M.S.-A.); (S.Z.); (J.M.-G.); (F.R.)
| | - Juan Madoz-Gúrpide
- Pathology Department, IIS- Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain; (M.L.); (M.S.-A.); (S.Z.); (J.M.-G.); (F.R.)
| | - Federico Rojo
- Pathology Department, IIS- Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain; (M.L.); (M.S.-A.); (S.Z.); (J.M.-G.); (F.R.)
| | - Jesús García-Foncillas
- Translational Oncology Division, Oncohealth Institute, IIS- Fundación Jiménez Díaz-UAM, E-28040 Madrid, Spain
- Medical Oncology Department, University Hospital “Fundación Jiménez Díaz”, UAM, E-28040 Madrid, Spain
- Correspondence: (I.C.); (J.G.-F.); Tel.: +34-915504800 (I.C. & J.G-F.)
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30
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Kumar P, Kumar V. Role of NMR Metabolomics and MR Imaging in Colon Cancer. COLON CANCER DIAGNOSIS AND THERAPY 2021:43-66. [DOI: 10.1007/978-3-030-63369-1_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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31
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Wang G, Yu Y, Wang YZ, Zhu ZM, Yin PH, Xu K. Effects and mechanisms of fatty acid metabolism‑mediated glycolysis regulated by betulinic acid‑loaded nanoliposomes in colorectal cancer. Oncol Rep 2020; 44:2595-2609. [PMID: 33125108 PMCID: PMC7640364 DOI: 10.3892/or.2020.7787] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 06/03/2020] [Indexed: 01/05/2023] Open
Abstract
Although previous studies have demonstrated that triterpenoids, such as betulinic acid (BA), can inhibit tumor cell growth, their potential targets in colorectal cancer (CRC) metabolism have not been systematically investigated. In the present study, BA‑loaded nanoliposomes (BA‑NLs) were prepared, and their effects on CRC cell lines were evaluated. The aim of the present study was to determine the anticancer mechanisms of action of BA‑NLs in fatty acid metabolism‑mediated glycolysis, and investigate the role of key targets, such as acyl‑CoA synthetase (ACSL), carnitine palmitoyltransferase (CPT) and acetyl CoA, in promoting glycolysis, which is activated by inducing hexokinase (HK), phosphofructokinase‑1 (PFK‑1), phosphoenolpyruvate (PEP) and pyruvate kinase (PK) expression. The results demonstrated that BA‑NLs significantly suppressed the proliferation and glucose uptake of CRC cells by regulating potential glycolysis and fatty acid metabolism targets and pathways, which forms the basis of the anti‑CRC function of BA‑NLs. Moreover, the effects of BA‑NLs were further validated by demonstrating that the key targets of HK2, PFK‑1, PEP and PK isoenzyme M2 (PKM2) in glycolysis, and of ACSL1, CPT1a and PEP in fatty acid metabolism, were blocked by BA‑NLs, which play key roles in the inhibition of glycolysis and fatty acid‑mediated production of pyruvate and lactate. The results of the present study may provide a deeper understanding supporting the hypothesis that liposomal BA may regulate alternative metabolic pathways implicated in CRC adjuvant therapy.
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Affiliation(s)
- Gang Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai 200235, P.R. China
| | - Yang Yu
- Jiangsu University School of Pharmacy, Zhenjiang, Jiangsu 212001, P.R. China
| | - Yu-Zhu Wang
- Jiangsu University School of Pharmacy, Zhenjiang, Jiangsu 212001, P.R. China
| | - Zhi-Min Zhu
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai 200235, P.R. China
| | - Pei-Hao Yin
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Ke Xu
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
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32
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Cruz-Gil S, Fernández LP, Sánchez-Martínez R, Gómez de Cedrón M, Ramírez de Molina A. Non-Coding and Regulatory RNAs as Epigenetic Remodelers of Fatty Acid Homeostasis in Cancer. Cancers (Basel) 2020; 12:E2890. [PMID: 33050166 PMCID: PMC7599548 DOI: 10.3390/cancers12102890] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/05/2020] [Accepted: 10/07/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer cells commonly display metabolic fluctuations. Together with the Warburg effect and the increased glutaminolysis, alterations in lipid metabolism homeostasis have been recognized as a hallmark of cancer. Highly proliferative cancer cells upregulate de novo synthesis of fatty acids (FAs) which are required to support tumor progression by exerting multiple roles including structural cell membrane composition, regulators of the intracellular redox homeostasis, ATP synthesis, intracellular cell signaling molecules, and extracellular mediators of the tumor microenvironment. Epigenetic modifications have been shown to play a crucial role in human development, but also in the initiation and progression of complex diseases. The study of epigenetic processes could help to design new integral strategies for the prevention and treatment of metabolic disorders including cancer. Herein, we first describe the main altered intracellular fatty acid processes to support cancer initiation and progression. Next, we focus on the most important regulatory and non-coding RNAs (small noncoding RNA-sncRNAs-long non-coding RNAs-lncRNAs-and other regulatory RNAs) which may target the altered fatty acids pathway in cancer.
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Affiliation(s)
| | | | | | - Marta Gómez de Cedrón
- Correspondence: (M.G.d.C.); (A.R.d.M.); Tel.: +34-67-213-49-21 (A.R.d.M.); Fax: +34-91-830-59-61 (A.R.d.M.)
| | - Ana Ramírez de Molina
- Laboratory of Molecular Oncology, IMDEA-Food Institute, CEI UAM + CSIC, 28049 Madrid, Spain; (S.C.-G.); (L.P.F.); (R.S.-M.)
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miR-19 Is a Potential Clinical Biomarker for Gastrointestinal Malignancy: A Systematic Review and Meta-analysis. BIOMED RESEARCH INTERNATIONAL 2020; 2020:2810150. [PMID: 32964023 PMCID: PMC7501555 DOI: 10.1155/2020/2810150] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 06/15/2020] [Accepted: 06/26/2020] [Indexed: 02/07/2023]
Abstract
Objectives To assess the expression and clinical value of miR-19 in gastrointestinal malignancy. Setting. Embase, Web of Science, PubMed, and other databases were retrieved to screen out relevant studies until December 31, 2019. Participants. Gastrointestinal cancer patients with the description of miR-19 expression, as well as the correlation between miR-19 and clinicopathological characteristics or prognosis. Main Outcome Measures. Pooled odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) was obtained to determine miR-19 expression in gastrointestinal malignancy and the association between miR-19 and patients' clinical characteristics and survival. Results Thirty-seven studies were included in this study. miR-19 levels in gastrointestinal malignancy, especially in hepatocellular (OR = 4.88, 95% CI = 2.38‐9.99), colorectal (OR = 4.81, 95% CI = 2.38‐9.72), and pancreatic (OR = 5.12, 95% CI = 2.43‐10.78) cancers, were significantly overexpressed, and miR-19 was tightly related to some clinicopathological characteristics, such as lymph node metastasis (OR = 1.74, 95% CI = 1.05‐2.86). Although gastrointestinal cancer patients with low and high miR-19 expression had comparable OS (overall survival) and DFS (disease-free survival), subgroup analyses showed that patients with high miR-19 presented better DFS than those with low miR-19 in liver cancer (HR = 0.46, 95% CI = 0.30‐0.71). Conclusions miR-19 might be a potential progression and prognostic biomarker for gastrointestinal malignancy.
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Wai Hon K, Zainal Abidin SA, Othman I, Naidu R. Insights into the Role of microRNAs in Colorectal Cancer (CRC) Metabolism. Cancers (Basel) 2020; 12:cancers12092462. [PMID: 32878019 PMCID: PMC7565715 DOI: 10.3390/cancers12092462] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 08/26/2020] [Accepted: 08/27/2020] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most frequently diagnosed cancers, with a high mortality rate globally. The pathophysiology of CRC is mainly initiated by alteration in gene expression, leading to dysregulation in multiple signalling pathways and cellular processes. Metabolic reprogramming is one of the important cancer hallmarks in CRC, which involves the adaptive changes in tumour cell metabolism to sustain the high energy requirements for rapid cell proliferation. There are several mechanisms in the metabolic reprogramming of cancer cells, such as aerobic glycolysis, oxidative phosphorylation, lactate and fatty acids metabolism. MicroRNAs (miRNAs) are a class of non-coding RNAs that are responsible for post-transcriptional regulation of gene expression. Differential expression of miRNAs has been shown to play an important role in different aspects of tumorigenesis, such as proliferation, apoptosis, and drug resistance, as well as metabolic reprogramming. Increasing evidence also reports that miRNAs could function as potential regulators of metabolic reprogramming in CRC cells. This review provides an insight into the role of different miRNAs in regulating the metabolism of CRC cells as well as to discuss the potential role of miRNAs as biomarkers or therapeutic targets in CRC tumour metabolism.
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Georgakopoulos-Soares I, Chartoumpekis DV, Kyriazopoulou V, Zaravinos A. EMT Factors and Metabolic Pathways in Cancer. Front Oncol 2020; 10:499. [PMID: 32318352 PMCID: PMC7154126 DOI: 10.3389/fonc.2020.00499] [Citation(s) in RCA: 223] [Impact Index Per Article: 44.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 03/19/2020] [Indexed: 12/11/2022] Open
Abstract
The epithelial-mesenchymal transition (EMT) represents a biological program during which epithelial cells lose their cell identity and acquire a mesenchymal phenotype. EMT is normally observed during organismal development, wound healing and tissue fibrosis. However, this process can be hijacked by cancer cells and is often associated with resistance to apoptosis, acquisition of tissue invasiveness, cancer stem cell characteristics, and cancer treatment resistance. It is becoming evident that EMT is a complex, multifactorial spectrum, often involving episodic, transient or partial events. Multiple factors have been causally implicated in EMT including transcription factors (e.g., SNAIL, TWIST, ZEB), epigenetic modifications, microRNAs (e.g., miR-200 family) and more recently, long non-coding RNAs. However, the relevance of metabolic pathways in EMT is only recently being recognized. Importantly, alterations in key metabolic pathways affect cancer development and progression. In this review, we report the roles of key EMT factors and describe their interactions and interconnectedness. We introduce metabolic pathways that are involved in EMT, including glycolysis, the TCA cycle, lipid and amino acid metabolism, and characterize the relationship between EMT factors and cancer metabolism. Finally, we present therapeutic opportunities involving EMT, with particular focus on cancer metabolic pathways.
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Affiliation(s)
- Ilias Georgakopoulos-Soares
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, United States.,Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, United States
| | - Dionysios V Chartoumpekis
- Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.,Division of Endocrinology, Department of Internal Medicine, School of Medicine, University of Patras, Patras, Greece
| | - Venetsana Kyriazopoulou
- Division of Endocrinology, Department of Internal Medicine, School of Medicine, University of Patras, Patras, Greece
| | - Apostolos Zaravinos
- College of Medicine, Member of QU Health, Qatar University, Doha, Qatar.,Department of Life Sciences European University Cyprus, Nicosia, Cyprus
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Wang G, Li Z, Li X, Zhang C, Peng L. RASAL1 induces to downregulate the SCD1, leading to suppression of cell proliferation in colon cancer via LXRα/SREBP1c pathway. Biol Res 2019; 52:60. [PMID: 31847887 PMCID: PMC6918686 DOI: 10.1186/s40659-019-0268-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 12/09/2019] [Indexed: 12/18/2022] Open
Abstract
Background Recent studies have confirmed that RASAL1 has an antitumor effect in many cancers, but its functional role and the molecular mechanism underlying in colon cancer has not been investigated. Results We collected human colon cancer tissues and adjacent non-tumor tissues, human colon cancer cell lines LoVo, CaCo2, SW1116, SW480 and HCT-116, and normal colonic mucosa cell line NCM460. RT-qPCR was used to detect the RASAL1 level in the clinical tissues and cell lines. In LoVo and HCT-116, RASAL1 was artificially overexpressed. Cell viability and proliferation were measured using CCK-8 assays, and cell cycle was detected via PI staining and flow cytometry analysis. RASAL1 significantly inhibited the cell proliferation via inducing cell cycle arrest, suppressed cell cycle associated protein expression, and decreased the lipid content and inhibited the SCD1 expression. Moreover, SCD1 overexpression induced and downregulation repressed cell proliferation by causing cell cycle arrest. Additionally, luciferase reporter assays were performed to confirm the direct binding between SREBP1c, LXRα and SCD1 promoter, we also demonstrated that RASAL1 inhibit SCD1 3′-UTR activity. RASAL1 inhibited tumor growth in xenograft nude mice models and shows inhibitory effect of SCD1 expression in vivo. Conclusion Taken together, we concluded that RASAL1 inhibited colon cancer cell proliferation via modulating SCD1 activity through LXRα/SREBP1c pathway.
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Affiliation(s)
- Guangchuan Wang
- Department of Gastroenterology and Hepatology, Shandong Provincial Hospital Affiliated to Shandong University, 324 JingwuWeiqi Road, Jinan, Shandong, 250021, People's Republic of China
| | - Zhen Li
- Department of Gastroenterology and Hepatology, Shandong Provincial Hospital Affiliated to Shandong University, 324 JingwuWeiqi Road, Jinan, Shandong, 250021, People's Republic of China
| | - Xiao Li
- Department of Gastroenterology and Hepatology, Shandong Provincial Hospital Affiliated to Shandong University, 324 JingwuWeiqi Road, Jinan, Shandong, 250021, People's Republic of China
| | - Chunqing Zhang
- Department of Gastroenterology and Hepatology, Shandong Provincial Hospital Affiliated to Shandong University, 324 JingwuWeiqi Road, Jinan, Shandong, 250021, People's Republic of China
| | - Lipan Peng
- Department of General Surgery, Shandong Provincial Hospital Affiliated to Shandong University, 324 JingwuWeiqi Road, Jinan, Shandong, 250021, People's Republic of China.
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Reglero C, Reglero G. Precision Nutrition and Cancer Relapse Prevention: A Systematic Literature Review. Nutrients 2019; 11:E2799. [PMID: 31744117 PMCID: PMC6893579 DOI: 10.3390/nu11112799] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 11/09/2019] [Accepted: 11/14/2019] [Indexed: 02/07/2023] Open
Abstract
Cancer mortality rates are undergoing a global downward trend; however, metastasis and relapse after surgery and adjuvant treatments still correlate with poor prognosis and represent the most significant challenges in the treatment of this disease. Advances in genomics, metabolomics, and proteomics are improving our understanding regarding cancer metabolic diversity, resulting in detailed classifications of tumors and raising the effectiveness of precision medicine. Likewise, the growing knowledge of interactions between nutrients and the expression of certain genes could lead to cancer therapies based on precision nutrition strategies. This review aims to identify the recent advances in the knowledge of the mechanistic role of bioactive phytochemicals in foodstuffs in tumor progression, metastasis, and chemo-resistance in order to assess their potential use in precision nutrition therapies targeting relapse in lung, breast, colon, and prostate cancer, and leukemia. A considerable number of bioactive phytochemicals in foodstuffs were identified in the literature with proven effects modulating tumor growth, progression, and metastasis. In addition, the use of foodstuffs in cancer, and specifically in relapse therapies, is being reinforced by the development of different formulations that significantly increase the therapeutic efficiency of these products. This can open the possibility for testing combinations of bioactive phytochemicals with cancer relapse treatments as a potential prevention strategy.
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Affiliation(s)
- Clara Reglero
- Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA
| | - Guillermo Reglero
- IMDEA Food Institute, 28049 Madrid, Spain;
- Institute of Food Science Research (CIAL), Autónoma de Madrid University, 28049 Madrid, Spain
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Ni K, Wang D, Xu H, Mei F, Wu C, Liu Z, Zhou B. miR-21 promotes non-small cell lung cancer cells growth by regulating fatty acid metabolism. Cancer Cell Int 2019; 19:219. [PMID: 31462892 PMCID: PMC6708160 DOI: 10.1186/s12935-019-0941-8] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 08/18/2019] [Indexed: 12/11/2022] Open
Abstract
Background Lung cancer is one of the most common malignant tumors worldwide. CD36 is a receptor for fatty acids and plays an important role in regulating fatty acid metabolism, which is closely related to tumorigenesis and development. The regulation of miR-21 and its role in tumorigenesis have been extensively studied in recent years. However, the relationship between miR-21 and CD36 regulated fatty acid metabolism in human non-small cell lung cancer remains unknown. Methods In this study, lentivirus transfection, qRT-PCR, cell migration, immunofluorescence, and western blot were used to examine the relationship between miR-21 and CD36 regulated fatty acid metabolism and the regulation role of miR-21 in human non-small cell lung cancer. Results This study demonstrated that up-regulation of miR-21 promoted cell migration and cell growth in human non-small cell lung cancer cells. Moreover, the intracellular contents of lipids including cellular content of phospholipids, neutral lipids content, cellular content of triglycerides were significantly increased following miR-21 mimic treatment compared with control, and the levels of key lipid metabolic enzymes FASN, ACC1 and FABP5 were obviously enhanced in human non-small cell lung cancer cells. Furthermore, down-regulation of CD36 suppressed miR-21 regulated cell growth, migration and intracellular contents of lipids in human non-small cell lung cancer cells, which suggested that miR-21 promoted cell growth and migration of human non-small cell lung cancer cells through CD36 mediated fatty acid metabolism. Inhibition of miR-21 was revealed to inhibit cell growth, migration, intracellular contents of lipids, and CD36 protein expression level in human non-small cell lung cancer cells. In addition, PPARGC1B was a direct target of miR-21, and down-regulation of PPARGC1B reversed the inhibition of CD36 expression induced by miR-21 inhibitor. Conclusions These results explored the mechanism of miR-21 promoted non-small cell lung cancer and might provide a novel therapeutic method in treating non-small cell lung cancer in clinic.
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Affiliation(s)
- Kewei Ni
- Department of Cardiothoracic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014 Zhejiang People's Republic of China
| | - Dimin Wang
- 2College of Basic Medical Sciences, Second Military Medical University, Shanghai, China
| | - Heyun Xu
- Department of Cardiothoracic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014 Zhejiang People's Republic of China
| | - Fuyang Mei
- Department of Cardiothoracic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014 Zhejiang People's Republic of China
| | - Changhao Wu
- Department of Cardiothoracic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014 Zhejiang People's Republic of China
| | - Zhifang Liu
- Department of Cardiothoracic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014 Zhejiang People's Republic of China
| | - Bing Zhou
- Department of Cardiothoracic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014 Zhejiang People's Republic of China
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Rossi Sebastiano M, Konstantinidou G. Targeting Long Chain Acyl-CoA Synthetases for Cancer Therapy. Int J Mol Sci 2019; 20:E3624. [PMID: 31344914 PMCID: PMC6696099 DOI: 10.3390/ijms20153624] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 07/22/2019] [Accepted: 07/22/2019] [Indexed: 12/14/2022] Open
Abstract
The deregulation of cancer cell metabolic networks is now recognized as one of the hallmarks of cancer. Abnormal lipid synthesis and extracellular lipid uptake are advantageous modifications fueling the needs of uncontrolled cancer cell proliferation. Fatty acids are placed at the crossroads of anabolic and catabolic pathways, as they are implicated in the synthesis of phospholipids and triacylglycerols, or they can undergo β-oxidation. Key players to these decisions are the long-chain acyl-CoA synthetases, which are enzymes that catalyze the activation of long-chain fatty acids of 12-22 carbons. Importantly, the long-chain acyl-CoA synthetases are deregulated in many types of tumors, providing a rationale for anti-tumor therapeutic opportunities. The purpose of this review is to summarize the last up-to-date findings regarding their role in cancer, and to discuss the related emerging tumor targeting opportunities.
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Cruz-Gil S, Sánchez-Martínez R, Wagner-Reguero S, Stange D, Schölch S, Pape K, Ramírez de Molina A. A more physiological approach to lipid metabolism alterations in cancer: CRC-like organoids assessment. PLoS One 2019; 14:e0219944. [PMID: 31339921 PMCID: PMC6655698 DOI: 10.1371/journal.pone.0219944] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 07/03/2019] [Indexed: 12/17/2022] Open
Abstract
Precision medicine might be the response to the recent questioning of the use of metformin as an anticancer drug in colorectal cancer (CRC). Thus, in order to establish properly its benefits, metformin application needs to be assayed on the different progression stages of CRC. In this way, intestinal organoids imply a more physiological tool, representing a new therapeutic opportunity for CRC personalized treatment to assay tumor stage-dependent drugs. The previously reported lipid metabolism-related axis, Acyl-CoA synthetases/ Stearoyl-CoA desaturase (ACSLs/SCD), stimulates colon cancer progression and metformin is able to rescue the invasive and migratory phenotype conferred to cancer cells upon this axis overexpression. Therefore, we checked ACSL/SCD axis status, its regulatory miRNAs and the effect of metformin treatment in intestinal organoids with the most common acquired mutations in a sporadic CRC (CRC-like organoids) as a model for specific and personalized treatment. Despite ACSL4 expression is upregulated progressively in CRC-like organoids, metformin is able to downregulate its expression, especially in the first two stages (I, II). Besides, organoids are clearly more sensitive in the first stage (Apc mutated) to metformin than current chemotherapeutic drugs such as fluorouracil (5-FU). Metformin performs an independent "Warburg effect" blockade to cancer progression and is able to reduce crypt stem cell markers expression such as LGR5+. These results suggest a putative increased efficiency of the use of metformin in early stages of CRC than in advanced disease.
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Affiliation(s)
- Silvia Cruz-Gil
- Molecular Oncology Group/ IMDEA Food Institute, CEI UAM + CSIC, Ctra, De Cantoblanco, Madrid, Spain
| | - Ruth Sánchez-Martínez
- Molecular Oncology Group/ IMDEA Food Institute, CEI UAM + CSIC, Ctra, De Cantoblanco, Madrid, Spain
| | - Sonia Wagner-Reguero
- Molecular Oncology Group/ IMDEA Food Institute, CEI UAM + CSIC, Ctra, De Cantoblanco, Madrid, Spain
| | - Daniel Stange
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Sebastian Schölch
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- German Cancer Consortium (DKTK), Dresden, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Kristin Pape
- Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Ana Ramírez de Molina
- Molecular Oncology Group/ IMDEA Food Institute, CEI UAM + CSIC, Ctra, De Cantoblanco, Madrid, Spain
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Non-coding RNAs derailed: The many influences on the fatty acid reprogramming of cancer. Life Sci 2019; 231:116509. [PMID: 31152812 DOI: 10.1016/j.lfs.2019.05.065] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/19/2019] [Accepted: 05/24/2019] [Indexed: 02/05/2023]
Abstract
Non-coding RNAs (NcRNAs), a family of functional RNA molecules that cannot translate into proteins but control specific gene expression programs, have been shown to be implicated in various biological processes, including fatty acid metabolism. Fast-growing tumor cells rewire their fatty acid metabolic circuitry in order to meet the needs of energy storage, membrane proliferation, and the generation of signaling molecules, which is achieved by regulating a variety of key enzymes along with related signaling pathways in fatty acid metabolism. This review presents an update of our knowledge about the regulatory network of ncRNAs-specifically, microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs)-in this metabolic shift and discusses the possibility of ncRNA-based therapeutics being applied to the restoration of cancer-related fatty acid metabolism.
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Wang G, Wang JJ, Yin PH, Xu K, Wang YZ, Shi F, Gao J, Fu XL. Strategies for targeting energy metabolism in Kirsten rat sarcoma viral oncogene homolog -mutant colorectal cancer. J Cell Biochem 2019; 120:1106-1121. [PMID: 30362665 DOI: 10.1002/jcb.27558] [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: 04/20/2018] [Accepted: 08/06/2018] [Indexed: 01/24/2023]
Abstract
Alterations in cellular energy metabolism play critical roles in colorectal cancer (CRC). These alterations, which correlate to KRAS mutations, have been identified as energy metabolism signatures. This review summarizes the relationship between colorectal tumors associated with mutated KRAS and energy metabolism, especially for the deregulated energy metabolism that affects tumor cell proliferation, invasion, and migration. Furthermore, this review will concentrate on the role of metabolic genes, factors and signaling pathways, which are coupled with the primary energy source connected with the KRAS mutation that induces metabolic alterations. Strategies for targeting energy metabolism in mutated KRAS CRC are also introduced. In conclusion, deregulated energy metabolism has a close relationship with KRAS mutations in colorectal tumors. Therefore, selective inhibitors, agents against metabolic targets or KRAS signaling, may be clinically useful for colorectal tumor treatment through a patient-personalized approach.
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Affiliation(s)
- Gang Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai, China
| | - Jun-Jie Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai, China
| | - Pei-Hao Yin
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ke Xu
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu-Zhu Wang
- Department of Medicine, Jiangsu University, Zhenjiang City, Jiangsu Province, China
| | - Feng Shi
- Department of Medicine, Jiangsu University, Zhenjiang City, Jiangsu Province, China
| | - Jing Gao
- Department of Medicine, Jiangsu University, Zhenjiang City, Jiangsu Province, China
| | - Xing-Li Fu
- Department of Medicine, Jiangsu University, Zhenjiang City, Jiangsu Province, China
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Chen B, Xia Z, Deng YN, Yang Y, Zhang P, Zhu H, Xu N, Liang S. Emerging microRNA biomarkers for colorectal cancer diagnosis and prognosis. Open Biol 2019; 9:180212. [PMID: 30958116 PMCID: PMC6367136 DOI: 10.1098/rsob.180212] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 01/02/2019] [Indexed: 02/05/2023] Open
Abstract
MicroRNAs (miRNAs) are one abundant class of small, endogenous non-coding RNAs, which regulate various biological processes by inhibiting expression of target genes. miRNAs have important functional roles in carcinogenesis and development of colorectal cancer (CRC), and emerging evidence has indicated the feasibility of miRNAs as robust cancer biomarkers. This review summarizes the progress in miRNA-related research, including study of its oncogene or tumour-suppressor roles and the advantages of miRNA biomarkers for CRC diagnosis, treatment and recurrence prediction. Along with analytical technique improvements in miRNA research, use of the emerging extracellular miRNAs is feasible for CRC diagnosis and prognosis.
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Affiliation(s)
- Bing Chen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, No. 17, 3rd Section of People's South Road, Chengdu 610041, People's Republic of China
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Eastern Road, Zhengzhou 450052, People's Republic of China
| | - Zijing Xia
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, No. 17, 3rd Section of People's South Road, Chengdu 610041, People's Republic of China
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People's Republic of China
| | - Ya-Nan Deng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, No. 17, 3rd Section of People's South Road, Chengdu 610041, People's Republic of China
| | - Yanfang Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, No. 17, 3rd Section of People's South Road, Chengdu 610041, People's Republic of China
| | - Peng Zhang
- Department of Urinary Surgery, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, People's Republic of China
| | - Hongxia Zhu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100034, People's Republic of China
| | - Ningzhi Xu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, No. 17, 3rd Section of People's South Road, Chengdu 610041, People's Republic of China
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100034, People's Republic of China
| | - Shufang Liang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, No. 17, 3rd Section of People's South Road, Chengdu 610041, People's Republic of China
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Pakiet A, Kobiela J, Stepnowski P, Sledzinski T, Mika A. Changes in lipids composition and metabolism in colorectal cancer: a review. Lipids Health Dis 2019; 18:29. [PMID: 30684960 PMCID: PMC6347819 DOI: 10.1186/s12944-019-0977-8] [Citation(s) in RCA: 214] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 01/16/2019] [Indexed: 02/06/2023] Open
Abstract
Altered metabolism of lipids is currently considered a hallmark characteristic of many malignancies, including colorectal cancer (CRC). Lipids are a large group of metabolites that differ in terms of their fatty acid composition. This review summarizes recent evidence, documenting many alterations in the content and composition of fatty acids, polar lipids, oxylipins and triacylglycerols in CRC patients' sera, tumor tissues and adipose tissue. Some of altered lipid molecules may be potential biomarkers of CRC risk, development and progression. Owing to a significant role of many lipids in cancer cell metabolism, some of lipid metabolism pathways may also constitute specific targets for anti-CRC therapy.
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Affiliation(s)
- Alicja Pakiet
- Department of Environmental Analysis, Faculty of Chemistry, University of Gdansk, Gdansk, Poland
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdansk, Dębinki 1, 80-211, Gdansk, Poland
| | - Jarosław Kobiela
- Department of General, Endocrine and Transplant Surgery, Faculty of Medicine, Medical University of Gdansk, Gdansk, Poland
| | - Piotr Stepnowski
- Department of Environmental Analysis, Faculty of Chemistry, University of Gdansk, Gdansk, Poland
| | - Tomasz Sledzinski
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdansk, Dębinki 1, 80-211, Gdansk, Poland.
| | - Adriana Mika
- Department of Environmental Analysis, Faculty of Chemistry, University of Gdansk, Gdansk, Poland
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdansk, Dębinki 1, 80-211, Gdansk, Poland
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Abstract
Purpose of Review Metabolic reprogramming is essential for the rapid proliferation of cancer cells and is thus recognized as a hallmark of cancer. In this review, we will discuss the etiologies and effects of metabolic reprogramming in colorectal cancer. Recent Findings Changes in cellular metabolism may precede the acquisition of driver mutations ultimately leading to colonocyte transformation. Oncogenic mutations and loss of tumor suppressor genes further reprogram CRC cells to upregulate glycolysis, glutaminolysis, one-carbon metabolism, and fatty acid synthesis. These metabolic changes are not uniform throughout tumors, as subpopulations of tumor cells may rely on different pathways to adapt to nutrient availability in the local tumor microenvironment. Finally, metabolic cross-communication between stromal cells, immune cells, and the gut microbiota enable CRC growth, invasion, and metastasis. Summary Altered cellular metabolism occurs in CRC at multiple levels, including in the cells that make up the bulk of CRC tumors, cancer stem cells, the tumor microenvironment, and host-microbiome interactions. This knowledge may inform the development of improved screening and therapeutics for CRC.
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Affiliation(s)
- Rachel E Brown
- Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA.,Vanderbilt University School of Medicine, Vanderbilt University, Nashville, TN, USA
| | - Sarah P Short
- Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA.,Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, B2215 Garland Ave., 1065D MRB-IV, Nashville, TN 37232-0252, USA
| | - Christopher S Williams
- Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA.,Vanderbilt University School of Medicine, Vanderbilt University, Nashville, TN, USA.,Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, B2215 Garland Ave., 1065D MRB-IV, Nashville, TN 37232-0252, USA.,Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.,Veterans Affairs Tennessee Valley HealthCare System, Nashville, TN, USA
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To KKW, Tong CWS, Wu M, Cho WCS. MicroRNAs in the prognosis and therapy of colorectal cancer: From bench to bedside. World J Gastroenterol 2018; 24:2949-2973. [PMID: 30038463 PMCID: PMC6054943 DOI: 10.3748/wjg.v24.i27.2949] [Citation(s) in RCA: 151] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 06/28/2018] [Accepted: 06/30/2018] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are small, single-stranded, noncoding RNAs that can post-transcriptionally regulate the expression of various oncogenes and tumor suppressor genes. Dysregulated expression of many miRNAs have been shown to mediate the signaling pathways critical in the multistep carcinogenesis of colorectal cancer (CRC). MiRNAs are stable and protected from RNase-mediated degradation, thereby enabling its detection in biological fluids and archival tissues for biomarker studies. This review focuses on the role and application of miRNAs in the prognosis and therapy of CRC. While stage II CRC is potentially curable by surgical resection, a significant percentage of stage II CRC patients do develop recurrence. MiRNA biomarkers may be used to stratify such high-risk population for adjuvant chemotherapy to provide better prognoses. Growing evidence also suggests that miRNAs are involved in the metastatic process of CRC. Certain of these miRNAs may thus be used as prognostic biomarkers to identify patients more likely to have micro-metastasis, who could be monitored more closely after surgery and/or given more aggressive adjuvant chemotherapy. Intrinsic and acquired resistance to chemotherapy severely hinders successful chemotherapy in CRC treatment. Predictive miRNA biomarkers for response to chemotherapy may identify patients who will benefit the most from a particular regimen and also spare the patients from unnecessary side effects. Selection of patients to receive the new targeted therapy is becoming possible with the use of predictive miRNA biomarkers. Lastly, forced expression of tumor suppressor miRNA or silencing of oncogenic miRNA in tumors by gene therapy can also be adopted to treat CRC alone or in combination with other chemotherapeutic drugs.
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Affiliation(s)
- Kenneth KW To
- School of Pharmacy, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
| | - Christy WS Tong
- School of Pharmacy, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
| | - Mingxia Wu
- School of Pharmacy, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
| | - William CS Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China
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