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Márquez-Mendoza JM, Baranda-Ávila N, Lizano M, Langley E. Micro-RNAs targeting the estrogen receptor alpha involved in endocrine therapy resistance in breast cancer. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167783. [PMID: 40057206 DOI: 10.1016/j.bbadis.2025.167783] [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: 09/13/2024] [Revised: 03/03/2025] [Accepted: 03/04/2025] [Indexed: 03/29/2025]
Abstract
Endocrine therapy resistance (ETR) in breast cancer (BC) is a multicausal phenomenon with diverse alterations in the tumor cell interactome. Within these alterations, non-coding RNAs (ncRNAs) such as micro-RNAs (miRNAs) modulate the expression of tumor suppressor genes and proto-oncogenes, such as the ESR1 gene encoding estrogen receptor alpha (ERα). This work aims to review the effects of miRNAs targeting ERα mRNA and their mechanisms related to ETR in BC. A thorough review of the literature and an in silico study were carried out to elucidate the involvement of each miRNA, thus contributing to the understanding of ETR in BC.
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Affiliation(s)
- J M Márquez-Mendoza
- Programa de Doctorado en Ciencias Biomédicas, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City 04510, Mexico
| | - N Baranda-Ávila
- Unidad de Investigación Biomédica en Cáncer, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico
| | - M Lizano
- Unidad de Investigación Biomédica en Cáncer, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico; Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City 04510, Mexico
| | - E Langley
- Unidad de Investigación Biomédica en Cáncer, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico.
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2
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Khatami N, Caraus I, Rahaman M, Nepotchatykh E, Elbakry M, Elremaly W, Franco A, Beauséjour M, Laberge AM, Parent S, Labelle H, Aubin CÉ, Lachaine J, Moreau A. Genome-wide profiling of circulating microRNAs in adolescent idiopathic scoliosis and their relation to spinal deformity severity, and disease pathophysiology. Sci Rep 2025; 15:5305. [PMID: 39939711 PMCID: PMC11822005 DOI: 10.1038/s41598-025-88985-3] [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: 11/04/2024] [Accepted: 02/03/2025] [Indexed: 02/14/2025] Open
Abstract
Adolescent Idiopathic Scoliosis (AIS) is the most common orthopedic condition requiring surgery, affecting 4% of adolescents. There is currently no proven method or prognostic test to identify symptomatic patients at risk of developing severe scoliosis who could benefit from growth-guided devices or minimally invasive non-fusion instrumentation surgeries. These innovative treatments must be performed at an early disease stage in younger patients to benefit from their growth potential. In this prospective cross-sectional study, we investigated the clinical utility of circulating microRNAs (miRNAs), an important class of small non-coding RNA, as biomarkers to predict the risk of developing severe scoliosis in AIS. Blood samples and clinical data were collected from 116 AIS patients who were followed until skeletal maturity and stratified according to their clinical outcome. Genome-wide expression profiling of miRNAs was performed with plasma obtained at the time of diagnosis of AIS (mean age of 13.3 ± 1.7 years with a mean Cobb angle of 24.4° ± 12.4°). This approach led to the identification of 15 circulating miRNAs that are upregulated in AIS patients who developed a severe scoliosis (Cobb angle ≥ 45°) at skeletal maturity compared to moderate and mild scoliosis groups (Cobb angle between 25°-44° and < 25° respectively). After optimization and the application of Random Forest Models a panel of six miRNAs (miR-1-3p, miR-19a-3p, miR-19b-3p, miR-133b, miR-143-3p, and miR-148b-3p) out of 15 led us to develop an algorithm predicting the risk of developing a severe scoliosis with great accuracy (100%), sensitivity (100%) and specificity (100%). Having a scoliosis predictive bioassay and decision-making tools to predict curve progression in order to find the best treatment plan will undoubtedly transform the orthopedic care system in the field of pediatric scoliosis by integrating innovative precision medicine approaches. In addition, investigation of genes targeted by these miRNAs could fill our gaps in our understanding of AIS pathogenesis and reveal new actionable targets.
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Affiliation(s)
- Nasrin Khatami
- Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, room 2.17.027, 3175 Cote-Ste-Catherine Road, Montreal, QC, H3T 1C5, Canada
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada
| | - Iurie Caraus
- Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, room 2.17.027, 3175 Cote-Ste-Catherine Road, Montreal, QC, H3T 1C5, Canada
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada
| | - Mahamuda Rahaman
- Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, room 2.17.027, 3175 Cote-Ste-Catherine Road, Montreal, QC, H3T 1C5, Canada
| | - Evguenia Nepotchatykh
- Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, room 2.17.027, 3175 Cote-Ste-Catherine Road, Montreal, QC, H3T 1C5, Canada
- Molecular Biology PhD Program, Faculty of Graduate and Postdoctoral Studies, Université de Montréal, Montreal, QC, Canada
| | - Mohamed Elbakry
- Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, room 2.17.027, 3175 Cote-Ste-Catherine Road, Montreal, QC, H3T 1C5, Canada
- Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta, Egypt
| | - Wesam Elremaly
- Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, room 2.17.027, 3175 Cote-Ste-Catherine Road, Montreal, QC, H3T 1C5, Canada
| | - Anita Franco
- Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, room 2.17.027, 3175 Cote-Ste-Catherine Road, Montreal, QC, H3T 1C5, Canada
| | - Marie Beauséjour
- Azrieli Research Center, CHU Sainte-Justine, Montreal, QC, Canada
- Department of Surgery, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada
- Department of Community Health Sciences, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Longueuil, QC, Canada
| | - Anne-Marie Laberge
- Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montreal, QC, Canada
| | - Stefan Parent
- Azrieli Research Center, CHU Sainte-Justine, Montreal, QC, Canada
- Department of Surgery, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada
- Orthopedic Division, CHU Sainte-Justine, Montreal, QC, Canada
- Institut TransMedTech Montreal, CHU Sainte-Justine, Montreal, QC, Canada
| | - Hubert Labelle
- Azrieli Research Center, CHU Sainte-Justine, Montreal, QC, Canada
- Department of Surgery, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada
- Orthopedic Division, CHU Sainte-Justine, Montreal, QC, Canada
- Institut TransMedTech Montreal, CHU Sainte-Justine, Montreal, QC, Canada
| | - Carl-Éric Aubin
- Azrieli Research Center, CHU Sainte-Justine, Montreal, QC, Canada
- Institut TransMedTech Montreal, CHU Sainte-Justine, Montreal, QC, Canada
- Polytechnique Montréal, Montreal, QC, Canada
| | - Jean Lachaine
- Faculty of Pharmacy, Université de Montréal, Montreal, QC, Canada
| | - Alain Moreau
- Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, room 2.17.027, 3175 Cote-Ste-Catherine Road, Montreal, QC, H3T 1C5, Canada.
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.
- Molecular Biology PhD Program, Faculty of Graduate and Postdoctoral Studies, Université de Montréal, Montreal, QC, Canada.
- Institut TransMedTech Montreal, CHU Sainte-Justine, Montreal, QC, Canada.
- Department of Stomatology, Faculty of Dentistry, Université de Montréal, Montreal, QC, Canada.
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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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Sheng MHC, Stiffel VM, Taipia J, Rundle CH, Lau KHW. Overexpression of miR17 ~ 92 in Myeloid Cells in Mice Increased Bone Mass Through Reduced Bone Resorption and Increased Bone Formation in Sex-Dependent Manner. Calcif Tissue Int 2025; 116:9. [PMID: 39751939 PMCID: PMC11698891 DOI: 10.1007/s00223-024-01325-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 10/10/2024] [Indexed: 01/04/2025]
Abstract
This study assessed the feasibility of miR17 ~ 92-based antiresorptive strategy by determining the effects of conditional transgenic (cTG) overexpression of miR17 ~ 92 in myeloid cells on bone and osteoclasts. Osteoclasts of male and female cTG mutant mice each showed 3- to fivefold overexpression of miR17 ~ 92 cluster genes compared to those of age- and sex-matched wildtype (WT) littermates. Male but not female cTG mutant mice had more trabecular and cortical bones as well as lower bone resorption reflected by reduction in osteoclast number and resorbing surface. Osteoclasts of male but not female cTG mutants showed decreased bone resorption activity. Consistent with suppression of osteoclast maturation, osteoclasts of male cTG mutants were smaller, contained less nuclei, showed reduced levels of mRNA of genes associated with osteoclast differentiation and fusion, and formed more diffused actin ring. Osteoclastic overexpression of miR17 ~ 92 also increased bone formation, but the increase was much larger in males than in females. The increase in male mutants was due to higher mineral apposition rate, and conversely, it was caused by increasing bone-forming surface in female mutants. In summary, osteoclastic overexpression of miR17 ~ 92 increased bone mass through reduction in bone resorption along with coupled increase in bone formation in male-specific manner. Although the osteoclastic overexpression of miR17 ~ 92-induced suppression of bone resorption and increases in bone formation support the feasibility of miR17 ~ 92-based antiresorptive strategies, the male-specific sexual disparity in skeletal responses to osteoclastic overexpression of miR17 ~ 92 could limit its clinical utility as it may not be used in women with postmenopausal osteoporosis.
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Affiliation(s)
- Matilda H-C Sheng
- Jerry L. Pettis Memorial VA Medical Center, VA Loma Linda Healthcare System, Loma Linda, CA, USA
- Departments of Medicine and Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Virginia M Stiffel
- Jerry L. Pettis Memorial VA Medical Center, VA Loma Linda Healthcare System, Loma Linda, CA, USA
| | - Jordan Taipia
- Jerry L. Pettis Memorial VA Medical Center, VA Loma Linda Healthcare System, Loma Linda, CA, USA
| | - Charles H Rundle
- Jerry L. Pettis Memorial VA Medical Center, VA Loma Linda Healthcare System, Loma Linda, CA, USA
- Departments of Medicine and Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Kin-Hing William Lau
- Jerry L. Pettis Memorial VA Medical Center, VA Loma Linda Healthcare System, Loma Linda, CA, USA.
- Departments of Medicine and Biochemistry, Loma Linda University School of Medicine, Loma Linda, CA, USA.
- Musculoskeletal Disease Center (151), Jerry L. Pettis Memorial VA Medical Center, 11201 Benton Street, Loma Linda, CA, 92357, USA.
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Zhao Y, Klionsky DJ, Wang X, Huang Q, Deng Z, Xiang J. The Estrogen-Autophagy Axis: Insights into Cytoprotection and Therapeutic Potential in Cancer and Infection. Int J Mol Sci 2024; 25:12576. [PMID: 39684286 PMCID: PMC11641569 DOI: 10.3390/ijms252312576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/14/2024] [Accepted: 11/16/2024] [Indexed: 12/18/2024] Open
Abstract
Macroautophagy, commonly referred to as autophagy, is an essential cytoprotective mechanism that plays a significant role in cellular homeostasis. It has emerged as a promising target for drug development aimed at treating various cancers and infectious diseases. However, the scientific community has yet to reach a consensus on the most effective approach to manipulating autophagy, with ongoing debates about whether its inhibition or stimulation is preferable for managing these complex conditions. One critical factor contributing to the variability in treatment responses for both cancers and infectious diseases is estrogen, a hormone known for its diverse biological effects. Given the strong correlations observed between estrogen signaling and autophagy, this review seeks to summarize the intricate molecular mechanisms that underlie the dual cytoprotective effects of estrogen signaling in conjunction with autophagy. We highlight recent findings from studies that involve various ligands, disease contexts, and cell types, including immune cells. Furthermore, we discuss several factors that regulate autophagy in the context of estrogen's influence. Ultimately, we propose a hypothetical model to elucidate the regulatory effects of the estrogen-autophagy axis on cell fate. Understanding these interactions is crucial for advancing our knowledge of related diseases and facilitating the development of innovative treatment strategies.
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Affiliation(s)
- Ying Zhao
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; (Y.Z.); (X.W.); (Q.H.); (Z.D.)
| | - Daniel J. Klionsky
- Life Sciences Institute, University of Michigan, Mary Sue Coleman Hall, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA;
| | - Xin Wang
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; (Y.Z.); (X.W.); (Q.H.); (Z.D.)
| | - Qiaoying Huang
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; (Y.Z.); (X.W.); (Q.H.); (Z.D.)
| | - Zixin Deng
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; (Y.Z.); (X.W.); (Q.H.); (Z.D.)
| | - Jin Xiang
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; (Y.Z.); (X.W.); (Q.H.); (Z.D.)
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Choudhury AR, Nagesh AM, Gupta S, Chaturvedi PK, Kumar N, Sandeep K, Pandey D. MicroRNA signature of stromal-epithelial interactions in prostate and breast cancers. Exp Cell Res 2024; 441:114171. [PMID: 39029573 DOI: 10.1016/j.yexcr.2024.114171] [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: 05/15/2024] [Revised: 07/01/2024] [Accepted: 07/17/2024] [Indexed: 07/21/2024]
Abstract
Stromal-epithelial communication is an absolute necessity when it comes to the morphogenesis and pathogenesis of solid tissues, including the prostate and breast. So far, signalling pathways of several growth factors have been investigated. Besides such chemical factors, non-coding RNAs such as miRNAs have recently gained much interest because of their variety and complexity of action. Prostate and breast tissues being highly responsive to steroid hormones such as androgen and estrogen, respectively, it is not surprising that a huge set of available literature critically investigated the interplay between such hormones and miRNAs, especially in carcinogenesis. This review showcases our effort to highlight hormonally-related miRNAs that also somehow perturb the regular stromal-epithelial interactions during carcinogenesis in the prostate and breast. In future, we look forward to exploring how hormonal changes in the tissue microenvironment bring about miRNA-mediated changes in stromal-epithelial interactome in carcinogenesis and cancer progression.
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Affiliation(s)
- Ankit Roy Choudhury
- Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India; Department of Biology, Philipps University, Marburg, Germany
| | - A Muni Nagesh
- Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India
| | - Surabhi Gupta
- Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India
| | | | - Neeraj Kumar
- Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India
| | - Kumar Sandeep
- Department of Preventive Oncology, Dr. Bhim Rao Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Deepak Pandey
- Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India.
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Tsamou M, Roggen EL. Sex-associated microRNAs potentially implicated in sporadic Alzheimer's disease (sAD). Brain Res 2024; 1829:148791. [PMID: 38307153 DOI: 10.1016/j.brainres.2024.148791] [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: 09/22/2023] [Revised: 01/08/2024] [Accepted: 01/23/2024] [Indexed: 02/04/2024]
Abstract
BACKGROUND The onset and pathology of sporadic Alzheimer's disease (sAD) seem to be affected by both sex and genetic mechanisms. Evidence supports that the high prevalence of sAD in women, worldwide, may be attributed to an interplay among aging, sex, and lifestyle, influenced by genetics, metabolic changes, and hormones. Interestingly, epigenetic mechanisms such as microRNAs (miRNAs), known as master regulators of gene expression, may contribute to this observed sexual dimorphism in sAD. OBJECTIVES To investigate the potential impact of sex-associated miRNAs on processes manifesting sAD pathology, as described by the Tau-driven Adverse Outcome Pathway (AOP) leading to memory loss. METHODS Using publicly available human miRNA datasets, sex-biased miRNAs, defined as differentially expressed by sex in tissues possibly affected by sAD pathology, were collected. In addition, sex hormone-related miRNAs were also retrieved from the literature. The compiled sex-biased and sex hormone-related miRNAs were further plugged into the dysregulated processes of the Tau-driven AOP for memory loss. RESULTS Several miRNAs, previously identified as sex-associated, were implicated in dysregulated processes associated with the manifestation of sAD pathology. Importantly, the described pathology processes were not confined to a particular sex. A mechanistic-based approach utilizing miRNAs was adopted in order to elucidate the link between sex and biological processes potentially involved in the development of memory loss. CONCLUSIONS The identification of sex-associated miRNAs involved in the early processes manifesting memory loss may shed light to the complex molecular mechanisms underlying sAD pathogenesis in a sex-specific manner.
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Affiliation(s)
- Maria Tsamou
- ToxGenSolutions (TGS), Oxfordlaan 70, 6229EV Maastricht, The Netherlands.
| | - Erwin L Roggen
- ToxGenSolutions (TGS), Oxfordlaan 70, 6229EV Maastricht, The Netherlands
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Bajpai AK, Gu Q, Jiao Y, Starlard-Davenport A, Gu W, Quarles LD, Xiao Z, Lu L. Systems genetics and bioinformatics analyses using ESR1-correlated genes identify potential candidates underlying female bone development. Genomics 2024; 116:110769. [PMID: 38141931 PMCID: PMC10811775 DOI: 10.1016/j.ygeno.2023.110769] [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: 07/22/2023] [Revised: 11/14/2023] [Accepted: 12/18/2023] [Indexed: 12/25/2023]
Abstract
Estrogen receptor α (ESR1) is involved in E2 signaling and plays a major role in postmenopausal bone loss. However, the molecular network underlying ESR1 has not been explored. We used systems genetics and bioinformatics to identify important genes associated with Esr1 in postmenopausal bone loss. We identified ~2300 Esr1-coexpressed genes in female BXD bone femur, functional analysis of which revealed 'osteoblast signaling' as the most enriched pathway. PPI network led to the identification of 25 'female bone candidates'. The gene-regulatory analysis revealed RUNX2 as a key TF. ANKRD1 and RUNX2 were significantly different between osteoporosis patients and healthy controls. Sp7, Col1a1 and Pth1r correlated with multiple femur bone phenotypes in BXD mice. miR-3121-3p targeted Csf1, Ankrd1, Sp7 and Runx2. β-estradiol treatment markedly increased the expression of these candidates in mouse osteoblast. Our study revealed that Esr1-correlated genes Ankrd1, Runx2, Csf1 and Sp7 may play important roles in female bone development.
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Affiliation(s)
- Akhilesh K Bajpai
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Qingqing Gu
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, USA; Department of Cardiology, Affiliated Hospital of Nantong University, Jiangsu 226001, China
| | - Yan Jiao
- Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Athena Starlard-Davenport
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Weikuan Gu
- Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Leigh Darryl Quarles
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Zhousheng Xiao
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
| | - Lu Lu
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, USA.
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9
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Al-Kabariti AY, Abbas MA. Progress in the Understanding of Estrogen Receptor Alpha Signaling in Triple-Negative Breast Cancer: Reactivation of Silenced ER-α and Signaling through ER-α36. Mol Cancer Res 2023; 21:1123-1138. [PMID: 37462782 DOI: 10.1158/1541-7786.mcr-23-0321] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/21/2023] [Accepted: 07/14/2023] [Indexed: 11/02/2023]
Abstract
Triple-negative breast cancer (TNBC) is an aggressive tumor that accounts for approximately 15% of total breast cancer cases. It is characterized by poor prognosis and high rate of recurrence compared to other types of breast cancer. TNBC has a limited range of treatment options that include chemotherapy, surgery, and radiation due to the absence of estrogen receptor alpha (ER-α) rendering hormonal therapy ineffective. However, possible targets for improving the clinical outcomes in TNBC exist, such as targeting estrogen signaling through membranous ER-α36 and reactivating silenced ER-α. It has been shown that epigenetic drugs such as DNA methyltransferase and histone deacetylase inhibitors can restore the expression of ER-α. This reactivation of ER-α, presents a potential strategy to re-sensitize TNBC to hormonal therapy. Also, this review provides up-to-date information related to the direct involvement of miRNA in regulating the translation of ER-α mRNA. Specific epi-miRNAs can regulate ER-α expression indirectly by post-transcriptional targeting of mRNAs of enzymes that are involved in DNA methylation and histone deacetylation. Furthermore, ER-α36, an alternative splice variant of ER-α66, is highly expressed in ER-negative breast tumors and activates MAPK/ERK pathway, promoting cell proliferation, escaping apoptosis, and enhancing metastasis. In the future, these recent advances may be helpful for researchers working in the field to obtain novel treatment options for TNBC, utilizing epigenetic drugs and epi-miRNAs that regulate ER-α expression. Also, there is some evidence to suggest that drugs that decrease the expression of ER-α36 may be effective in treating TNBC.
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Affiliation(s)
- Aya Y Al-Kabariti
- Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan
- Pharmacological and Diagnostic Research Centre, Al-Ahliyya Amman University, Amman, Jordan
| | - Manal A Abbas
- Pharmacological and Diagnostic Research Centre, Al-Ahliyya Amman University, Amman, Jordan
- Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman, Jordan
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Bembenek BM, Meyers-Manor JE, Forbes-Lorman RM. Decrease in ERɑ within the BNST of sexually naïve male rats following an encounter with a novel female. Behav Brain Res 2023; 454:114626. [PMID: 37595756 DOI: 10.1016/j.bbr.2023.114626] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 07/27/2023] [Accepted: 08/09/2023] [Indexed: 08/20/2023]
Abstract
Testosterone and its metabolites facilitate male-typical social behaviors in sexually experienced animals. The metabolite estradiol acts on estrogen receptors (ERs) within the bed nucleus of the stria terminalis (BNST) to facilitate socio-sexual behaviors. While circulating testosterone does not increase in naïve males, aromatase-expressing neurons within the BNST of naïve males are necessary for sex recognition, suggesting that local estradiol production may be responsible. In the present study, we examined ERɑ-immunoreactive (ir) cell number within the brain of sexually naïve male rats 24 h after an encounter with a novel animal. As expected, males investigated females more than males. Additionally, males that encountered females had fewer ERɑ-ir cells within both anterior and posterior BNST compared to those who encountered a novel male or a non-social control. There were no changes within the AVPV, MPN, or MeA. The decrease in ERɑ-ir cell number within the posterior BNST only occurred in males that encountered estrus females whereas the decrease in the anterior BNST occurred only in males that encountered non-estrus females. Additionally, anogenital investigations were correlated with fewer ERɑ-ir cells in the posterior BNST, while cage sniffing correlated with the number ERɑ-ir cells in the anterior BNST. There were no differences in serum testosterone 45 min or 24 h after the encounter, suggesting changes in ERɑ were due to local changes in estradiol levels. Our results expand upon previous research regarding the role of estradiol within the subregions of the BNST in naïve male rat socio-sexual behavior.
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Affiliation(s)
- Brianna M Bembenek
- Ripon College, Ripon, WI 54971, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN 55905, USA
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11
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Zhu Z, Huang X, Du M, Wu C, Fu J, Tan W, Wu B, Zhang J, Liao ZB. Recent advances in the role of miRNAs in post-traumatic stress disorder and traumatic brain injury. Mol Psychiatry 2023; 28:2630-2644. [PMID: 37340171 PMCID: PMC10615752 DOI: 10.1038/s41380-023-02126-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 05/12/2023] [Accepted: 06/08/2023] [Indexed: 06/22/2023]
Abstract
Post-traumatic stress disorder (PTSD) is usually considered a psychiatric disorder upon emotional trauma. However, with the rising number of conflicts and traffic accidents around the world, the incidence of PTSD has skyrocketed along with traumatic brain injury (TBI), a complex neuropathological disease due to external physical force and is also the most common concurrent disease of PTSD. Recently, the overlap between PTSD and TBI is increasingly attracting attention, as it has the potential to stimulate the emergence of novel treatments for both conditions. Of note, treatments exploiting the microRNAs (miRNAs), a well-known class of small non-coding RNAs (ncRNAs), have rapidly gained momentum in many nervous system disorders, given the miRNAs' multitudinous and key regulatory role in various biological processes, including neural development and normal functioning of the nervous system. Currently, a wealth of studies has elucidated the similarities of PTSD and TBI in pathophysiology and symptoms; however, there is a dearth of discussion with respect to miRNAs in both PTSD and TBI. In this review, we summarize the recent available studies of miRNAs in PTSD and TBI and discuss and highlight promising miRNAs therapeutics for both conditions in the future.
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Affiliation(s)
- Ziyu Zhu
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Xuekang Huang
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Mengran Du
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Chenrui Wu
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Jiayuanyuan Fu
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Weilin Tan
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Biying Wu
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Jie Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Z B Liao
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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12
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Arnesen S, Polaski J, Blanchard Z, Osborne K, Welm A, O’Connell R, Gertz J. Estrogen receptor alpha mutations regulate gene expression and cell growth in breast cancer through microRNAs. NAR Cancer 2023; 5:zcad027. [PMID: 37275275 PMCID: PMC10233889 DOI: 10.1093/narcan/zcad027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 04/18/2023] [Accepted: 05/18/2023] [Indexed: 06/07/2023] Open
Abstract
Estrogen receptor α (ER) mutations occur in up to 30% of metastatic ER-positive breast cancers. Recent data has shown that ER mutations impact the expression of thousands of genes not typically regulated by wildtype ER. While the majority of these altered genes can be explained by constant activity of mutant ER or genomic changes such as altered ER binding and chromatin accessibility, as much as 33% remain unexplained, indicating the potential for post-transcriptional effects. Here, we explored the role of microRNAs in mutant ER-driven gene regulation and identified several microRNAs that are dysregulated in ER mutant cells. These differentially regulated microRNAs target a significant portion of mutant-specific genes involved in key cellular processes. When the activity of microRNAs is altered using mimics or inhibitors, significant changes are observed in gene expression and cellular proliferation related to mutant ER. An in-depth evaluation of miR-301b led us to discover an important role for PRKD3 in the proliferation of ER mutant cells. Our findings show that microRNAs contribute to mutant ER gene regulation and cellular effects in breast cancer cells.
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Affiliation(s)
- Spencer Arnesen
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Jacob T Polaski
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Zannel Blanchard
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Kyle S Osborne
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Alana L Welm
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Ryan M O’Connell
- Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA
| | - Jason Gertz
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
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Treeck O, Haerteis S, Ortmann O. Non-Coding RNAs Modulating Estrogen Signaling and Response to Endocrine Therapy in Breast Cancer. Cancers (Basel) 2023; 15:cancers15061632. [PMID: 36980520 PMCID: PMC10046587 DOI: 10.3390/cancers15061632] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 02/28/2023] [Accepted: 03/02/2023] [Indexed: 03/09/2023] Open
Abstract
The largest part of human DNA is transcribed into RNA that does not code for proteins. These non-coding RNAs (ncRNAs) are key regulators of protein-coding gene expression and have been shown to play important roles in health, disease and therapy response. Today, endocrine therapy of ERα-positive breast cancer (BC) is a successful treatment approach, but resistance to this therapy is a major clinical problem. Therefore, a deeper understanding of resistance mechanisms is important to overcome this resistance. An increasing amount of evidence demonstrate that ncRNAs affect the response to endocrine therapy. Thus, ncRNAs are considered versatile biomarkers to predict or monitor therapy response. In this review article, we intend to give a summary and update on the effects of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) on estrogen signaling in BC cells, this pathway being the target of endocrine therapy, and their role in therapy resistance. For this purpose, we reviewed articles on these topics listed in the PubMed database. Finally, we provide an assessment regarding the clinical use of these ncRNA types, particularly their circulating forms, as predictive BC biomarkers and their potential role as therapy targets to overcome endocrine resistance.
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Affiliation(s)
- Oliver Treeck
- Department of Gynecology and Obstetrics, University Medical Center Regensburg, 93053 Regensburg, Germany
- Correspondence:
| | - Silke Haerteis
- Institute for Molecular and Cellular Anatomy, University of Regensburg, 93053 Regensburg, Germany
| | - Olaf Ortmann
- Department of Gynecology and Obstetrics, University Medical Center Regensburg, 93053 Regensburg, Germany
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Santos SAA, Portela LMF, Camargo ACL, Constantino FB, Colombelli KT, Fioretto MN, Mattos R, de Almeida Fantinatti BE, Denti MA, Piazza S, Felisbino SL, Zambrano E, Justulin LA. miR-18a-5p Is Involved in the Developmental Origin of Prostate Cancer in Maternally Malnourished Offspring Rats: A DOHaD Approach. Int J Mol Sci 2022; 23:14855. [PMID: 36499183 PMCID: PMC9739077 DOI: 10.3390/ijms232314855] [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: 09/09/2022] [Revised: 11/13/2022] [Accepted: 11/15/2022] [Indexed: 12/02/2022] Open
Abstract
The Developmental Origins of Health and Disease (DOHaD) concept correlates early life exposure to stressor conditions with the increased incidence of non-communicable chronic diseases, including prostate cancer (PCa), throughout the life span. However, the molecular mechanisms involved in this process remain poorly understood. In this study, the deregulation of two miRNAs (rno-miR-18a-5p and rno-miR-345-3p) was described in the ventral prostate VP of old rats born to dams fed with a low protein diet (LPD) (6% protein in the diet) during gestational and lactational periods. Integrative analysis of the (VP) transcriptomic and proteomic data revealed changes in the expression profile of 14 identified predicted targets of these two DE miRNAs, which enriched terms related to post-translational protein modification, metabolism of proteins, protein processing in endoplasmic reticulum, phosphonate and phosphinate metabolism, the calnexin/calreticulin cycle, metabolic pathways, N-glycan trimming in the ER and the calnexin/calreticulin cycle, hedgehog ligand biogenesis, the ER-phagosome pathway, detoxification of reactive oxygen species, antigenprocessing-cross presentation, RAB geranylgeranylation, collagen formation, glutathione metabolism, the metabolism of xenobiotics by cytochrome P450, and platinum drug resistance. RT-qPCR validated the deregulation of the miR-18a-5p/P4HB (prolyl 4-hydroxylase subunit beta) network in the VP of older offspring as well as in the PNT-2 cells transfected with mimic miR-18a-5p. Functional in vitro studies revealed a potential modulation of estrogen receptor α (ESR1) by miR-18a-5p in PNT-2 cells, which was also confirmed in the VP of older offspring. An imbalance of the testosterone/estrogen ratio was also observed in the offspring rats born to dams fed with an LPD. In conclusion, deregulation of the miR-18a-5p/P4HB network can contribute to the developmental origins of prostate cancer in maternally malnourished offspring, highlighting the need for improving maternal healthcare during critical windows of vulnerability early in life.
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Affiliation(s)
- Sergio Alexandre Alcantara Santos
- Department of Structural and Functional Biology, Institute of Biosciences, Sao Paulo State University (UNESP), Unesp Botucatu, Botucatu 18618-689, SP, Brazil
- Cancer Signaling and Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Luiz Marcos Frediani Portela
- Department of Structural and Functional Biology, Institute of Biosciences, Sao Paulo State University (UNESP), Unesp Botucatu, Botucatu 18618-689, SP, Brazil
| | - Ana Carolina Lima Camargo
- Department of Structural and Functional Biology, Institute of Biosciences, Sao Paulo State University (UNESP), Unesp Botucatu, Botucatu 18618-689, SP, Brazil
| | - Flavia Bessi Constantino
- Department of Structural and Functional Biology, Institute of Biosciences, Sao Paulo State University (UNESP), Unesp Botucatu, Botucatu 18618-689, SP, Brazil
| | - Ketlin Thassiani Colombelli
- Department of Structural and Functional Biology, Institute of Biosciences, Sao Paulo State University (UNESP), Unesp Botucatu, Botucatu 18618-689, SP, Brazil
| | - Matheus Naia Fioretto
- Department of Structural and Functional Biology, Institute of Biosciences, Sao Paulo State University (UNESP), Unesp Botucatu, Botucatu 18618-689, SP, Brazil
| | - Renato Mattos
- Department of Structural and Functional Biology, Institute of Biosciences, Sao Paulo State University (UNESP), Unesp Botucatu, Botucatu 18618-689, SP, Brazil
| | - Bruno Evaristo de Almeida Fantinatti
- Department of Structural and Functional Biology, Institute of Biosciences, Sao Paulo State University (UNESP), Unesp Botucatu, Botucatu 18618-689, SP, Brazil
| | - Michela Alessandra Denti
- Department of Cellular, Computational and Integrative Biology—CIBIO, University of Trento, 38123 Trento, Italy
| | - Silvano Piazza
- Department of Cellular, Computational and Integrative Biology—CIBIO, University of Trento, 38123 Trento, Italy
| | - Sérgio Luis Felisbino
- Department of Structural and Functional Biology, Institute of Biosciences, Sao Paulo State University (UNESP), Unesp Botucatu, Botucatu 18618-689, SP, Brazil
| | - Elena Zambrano
- Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Mexico City 14080, Mexico
| | - Luis Antonio Justulin
- Department of Structural and Functional Biology, Institute of Biosciences, Sao Paulo State University (UNESP), Unesp Botucatu, Botucatu 18618-689, SP, Brazil
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15
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Zu Y, Guo S, Li G, Gao Q, Wang X, Zhang C, Liu D. Serum microRNAs as non-invasive diagnostic biomarkers for intrahepatic cholestasis of pregnancy. Am J Transl Res 2022; 14:6763-6773. [PMID: 36247288 PMCID: PMC9556493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 08/08/2022] [Indexed: 06/16/2023]
Abstract
OBJECTIVES Intrahepatic cholestasis of pregnancy (IHCP) causes itching, preterm birth, and stillbirth. However, there is no accurate diagnostic method for IHCP. Currently, circulating microRNAs (miRNAs) have become candidate biomarkers for the diagnosis of multiple diseases. Here, we investigated the diagnostic value of miRNAs in IHCP and aimed to predict the molecular mechanism of IHCP pathogenesis. METHODS We analyzed differentially expressed miRNAs in both women with IHCP and normal pregnant women. The selected candidate miRNAs were validated in 46 IHCP cases and 46 normal pregnant subjects, and we constructed receiver operator characteristic curves of miRNAs. Pearson correlations between levels of total bile acid (TBA) and differentially expressed miRNAs were also calculated. In addition, we clustered functionally significant biological pathways using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. RESULTS The expression levels of 13 miRNAs were remarkably upregulated while the other 35 miRNAs were significantly downregulated, in women with IHCP (P≤0.05) when compared with healthy pregnant women. The areas under the curves of miRNA-7706, miRNA-877-3p, and miRNA-128-3p were higher than 0.90, indicating more reliable diagnosis of IHCP. The Pearson analysis showed that the levels of these miRNAs were positively correlated to TBA level. Additionally, the results of bioinformatics analysis revealed that the differentially expressed miRNAs mainly influenced fatty acid biosynthesis, the endoplasmic reticulum ubiquitin ligase complex, and the p53, and mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) signaling pathways. CONCLUSION The panel of three-miRNAs (miRNA-7706, miRNA-877-3p, and miRNA-128-3p) may be a useful noninvasive diagnostic biomarker of IHCP.
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Affiliation(s)
- Yue Zu
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, Hubei, China
| | - Sheng Guo
- The First Affiliated Hospital of Xinxiang Medical UniversityWeihui, Henan, China
| | - Guodong Li
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, Hubei, China
| | - Qianyan Gao
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, Hubei, China
| | - Ximin Wang
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, Hubei, China
| | - Chengliang Zhang
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, Hubei, China
| | - Dong Liu
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430030, Hubei, China
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16
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Teli G, Sharma P, Chawla PA. Exploring the Potential of Substituted 4-Thiazolidinone Derivatives in the Treatment of Breast Cancer: Synthesis, Biological Screening and In Silico Studies. Polycycl Aromat Compd 2022. [DOI: 10.1080/10406638.2022.2112708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Affiliation(s)
- Ghanshyam Teli
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, India
| | | | - Pooja A. Chawla
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, India
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17
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Singh P, Paramanik V. Neuromodulating roles of estrogen and phytoestrogens in cognitive therapeutics through epigenetic modifications during aging. Front Aging Neurosci 2022; 14:945076. [PMID: 35992599 PMCID: PMC9381870 DOI: 10.3389/fnagi.2022.945076] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/12/2022] [Indexed: 11/13/2022] Open
Abstract
Estrogen (E2) plays important role in regulating hippocampal learning and memory. The decline of E2 after menopause affects learning and memory and increases the risk of neurodegenerative diseases like Alzheimer's disease (AD). Additionally, from the estrogen receptor (ER) mediated gene regulation; E2 also regulates gene expression at the transcriptional and posttranscriptional levels through epigenetic modifications. E2 recruits a number of proteins called co-regulators at the promoter region of genes. These co-regulators act as chromatin modifiers, alter DNA and histone modifications and regulate gene expression. Several studies show that E2 regulates learning and memory by altering chromatin at the promoters of memory-linked genes. Due to structural similarities with E2 and low side effects, phytoestrogens are now used as neuroprotective agents to recover learning and memory in animal models as well as human subjects during aging and different neurological disorders. Growing evidence suggests that apart from anti-oxidative and anti-inflammatory properties, phytoestrogens also act as epigenetic modifiers and regulate gene expression through epigenetic modifications. The epigenetic modifying properties of phytoestrogens are mostly studied in cancer cells but very little is known regarding the regulation of synaptic plasticity genes, learning and memory, and neurological disorders. In this article, we discuss the epigenetic modifying properties of E2 and the roles of phytoestrogens as epigenetic modifiers in the brain to recover and maintain cognitive functions.
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18
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Soni M, Saatci O, Gupta G, Patel Y, Keerthi Raja MR, Li J, Liu X, Xu P, Wang H, Fan D, Sahin O, Chen H. miR-489 Confines Uncontrolled Estrogen Signaling through a Negative Feedback Mechanism and Regulates Tamoxifen Resistance in Breast Cancer. Int J Mol Sci 2022; 23:8086. [PMID: 35897675 PMCID: PMC9331933 DOI: 10.3390/ijms23158086] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/19/2022] [Accepted: 07/21/2022] [Indexed: 02/01/2023] Open
Abstract
Approximately 75% of diagnosed breast cancer tumors are estrogen-receptor-positive tumors and are associated with a better prognosis due to response to hormonal therapies. However, around 40% of patients relapse after hormonal therapies. Genomic analysis of gene expression profiles in primary breast cancers and tamoxifen-resistant cell lines suggested the potential role of miR-489 in the regulation of estrogen signaling and development of tamoxifen resistance. Our in vitro analysis showed that loss of miR-489 expression promoted tamoxifen resistance, while overexpression of miR-489 in tamoxifen-resistant cells restored tamoxifen sensitivity. Mechanistically, we found that miR-489 is an estrogen-regulated miRNA that negatively regulates estrogen receptor signaling by using at least the following two mechanisms: (i) modulation of the ER phosphorylation status by inhibiting MAPK and AKT kinase activities; (ii) regulation of nuclear-to-cytosol translocation of estrogen receptor α (ERα) by decreasing p38 expression and consequently ER phosphorylation. In addition, miR-489 can break the positive feed-forward loop between the estrogen-Erα axis and p38 MAPK in breast cancer cells, which is necessary for its function as a transcription factor. Overall, our study unveiled the underlying molecular mechanism by which miR-489 regulates an estrogen signaling pathway through a negative feedback loop and uncovered its role in both the development of and overcoming of tamoxifen resistance in breast cancers.
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Affiliation(s)
- Mithil Soni
- Department of Biological Science, University of South Carolina, Columbia, SC 29208, USA; (M.S.); (G.G.); (Y.P.); (M.R.K.R.)
| | - Ozge Saatci
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA; (O.S.); (P.X.); (O.S.)
| | - Gourab Gupta
- Department of Biological Science, University of South Carolina, Columbia, SC 29208, USA; (M.S.); (G.G.); (Y.P.); (M.R.K.R.)
| | - Yogin Patel
- Department of Biological Science, University of South Carolina, Columbia, SC 29208, USA; (M.S.); (G.G.); (Y.P.); (M.R.K.R.)
| | - Manikanda Raja Keerthi Raja
- Department of Biological Science, University of South Carolina, Columbia, SC 29208, USA; (M.S.); (G.G.); (Y.P.); (M.R.K.R.)
| | - Jie Li
- Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29201, USA;
| | - Xinfeng Liu
- Department of Mathematics, University of South Carolina, Columbia, SC 29201, USA;
| | - Peisheng Xu
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA; (O.S.); (P.X.); (O.S.)
| | - Hongjun Wang
- Department of Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, USA;
| | - Daping Fan
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA;
| | - Ozgur Sahin
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA; (O.S.); (P.X.); (O.S.)
| | - Hexin Chen
- Department of Biological Science, University of South Carolina, Columbia, SC 29208, USA; (M.S.); (G.G.); (Y.P.); (M.R.K.R.)
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Sukocheva OA, Lukina E, Friedemann M, Menschikowski M, Hagelgans A, Aliev G. The crucial role of epigenetic regulation in breast cancer anti-estrogen resistance: Current findings and future perspectives. Semin Cancer Biol 2022; 82:35-59. [PMID: 33301860 DOI: 10.1016/j.semcancer.2020.12.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/22/2020] [Accepted: 12/03/2020] [Indexed: 02/07/2023]
Abstract
Breast cancer (BC) cell de-sensitization to Tamoxifen (TAM) or other selective estrogen receptor (ER) modulators (SERM) is a complex process associated with BC heterogeneity and the transformation of ER signalling. The most influential resistance-related mechanisms include modifications in ER expression and gene regulation patterns. During TAM/SERM treatment, epigenetic mechanisms can effectively silence ER expression and facilitate the development of endocrine resistance. ER status is efficiently regulated by specific epigenetic tools including hypermethylation of CpG islands within ER promoters, increased histone deacetylase activity in the ER promoter, and/or translational repression by miRNAs. Over-methylation of the ER α gene (ESR1) promoter by DNA methyltransferases was associated with poor prognosis and indicated the development of resistance. Moreover, BC progression and spreading were marked by transformed chromatin remodelling, post-translational histone modifications, and expression of specific miRNAs and/or long non-coding RNAs. Therefore, targeted inhibition of histone acetyltransferases (e.g. MYST3), deacetylases (e.g. HDAC1), and/or demethylases (e.g. lysine-specific demethylase LSD1) was shown to recover and increase BC sensitivity to anti-estrogens. Indicated as a powerful molecular instrument, the administration of epigenetic drugs can regain ER expression along with the activation of tumour suppressor genes, which can in turn prevent selection of resistant cells and cancer stem cell survival. This review examines recent advances in the epigenetic regulation of endocrine drug resistance and evaluates novel anti-resistance strategies. Underlying molecular mechanisms of epigenetic regulation will be discussed, emphasising the utilization of epigenetic enzymes and their inhibitors to re-program irresponsive BCs.
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Affiliation(s)
- Olga A Sukocheva
- Discipline of Health Sciences, College of Nursing and Health Sciences, Flinders University, Bedford Park, South Australia, 5042, Australia.
| | - Elena Lukina
- Discipline of Biology, College of Sciences, Flinders University, Bedford Park, South Australia, 5042, Australia
| | - Markus Friedemann
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital `Carl Gustav Carus`, Technical University of Dresden, Dresden 01307, Germany
| | - Mario Menschikowski
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital `Carl Gustav Carus`, Technical University of Dresden, Dresden 01307, Germany
| | - Albert Hagelgans
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital `Carl Gustav Carus`, Technical University of Dresden, Dresden 01307, Germany
| | - Gjumrakch Aliev
- Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Russia; Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, 142432, Russia; Federal State Budgetary Institution «Research Institute of Human Morphology», 3, Tsyurupy Str., Moscow, 117418, Russian Federation; GALLY International Research Institute, San Antonio, TX, 78229, USA.
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20
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Prochownik EV, Wang H. Normal and Neoplastic Growth Suppression by the Extended Myc Network. Cells 2022; 11:747. [PMID: 35203395 PMCID: PMC8870482 DOI: 10.3390/cells11040747] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/09/2022] [Accepted: 02/15/2022] [Indexed: 12/20/2022] Open
Abstract
Among the first discovered and most prominent cellular oncogenes is MYC, which encodes a bHLH-ZIP transcription factor (Myc) that both activates and suppresses numerous genes involved in proliferation, energy production, metabolism and translation. Myc belongs to a small group of bHLH-ZIP transcriptional regulators (the Myc Network) that includes its obligate heterodimerization partner Max and six "Mxd proteins" (Mxd1-4, Mnt and Mga), each of which heterodimerizes with Max and largely opposes Myc's functions. More recently, a second group of bHLH-ZIP proteins (the Mlx Network) has emerged that bears many parallels with the Myc Network. It is comprised of the Myc-like factors ChREBP and MondoA, which, in association with the Max-like member Mlx, regulate smaller and more functionally restricted repertoires of target genes, some of which are shared with Myc. Opposing ChREBP and MondoA are heterodimers comprised of Mlx and Mxd1, Mxd4 and Mnt, which also structurally and operationally link the two Networks. We discuss here the functions of these "Extended Myc Network" members, with particular emphasis on their roles in suppressing normal and neoplastic growth. These roles are complex due to the temporal- and tissue-restricted expression of Extended Myc Network proteins in normal cells, their regulation of both common and unique target genes and, in some cases, their functional redundancy.
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Affiliation(s)
- Edward V. Prochownik
- Division of Hematology/Oncology, The Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA;
- The Department of Microbiology and Molecular Genetics, The University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA
- The Hillman Cancer Center of UPMC, Pittsburgh, PA 15224, USA
- The Pittsburgh Liver Research Center, Pittsburgh, PA 15224, USA
| | - Huabo Wang
- Division of Hematology/Oncology, The Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA;
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21
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The Role of Androgen Receptor and microRNA Interactions in Androgen-Dependent Diseases. Int J Mol Sci 2022; 23:ijms23031553. [PMID: 35163477 PMCID: PMC8835816 DOI: 10.3390/ijms23031553] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/25/2022] [Accepted: 01/25/2022] [Indexed: 12/31/2022] Open
Abstract
The androgen receptor (AR) is a member of the steroid hormone receptor family of nuclear transcription factors. It is present in the primary/secondary sexual organs, kidneys, skeletal muscles, adrenal glands, skin, nervous system, and breast. Abnormal AR functioning has been identified in numerous diseases, specifically in prostate cancer (PCa). Interestingly, recent studies have indicated a relationship between the AR and microRNA (miRNA) crosstalk and cancer progression. MiRNAs are small, endogenous, non-coding molecules that are involved in crucial cellular processes, such as proliferation, apoptosis, or differentiation. On the one hand, AR may be responsible for the downregulation or upregulation of specific miRNA, while on the other hand, AR is often a target of miRNAs due to their regulatory function on AR gene expression. A deeper understanding of the AR–miRNA interactions may contribute to the development of better diagnostic tools as well as to providing new therapeutic approaches. While most studies usually focus on the role of miRNAs and AR in PCa, in this review, we go beyond PCa and provide insight into the most recent discoveries about the interplay between AR and miRNAs, as well as about other AR-associated and AR-independent diseases.
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22
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Kalinina T, Kononchuk V, Klyushova L, Gulyaeva L. Effects of Endocrine Disruptors o, p'-Dichlorodiphenyltrichloroethane, p, p'-Dichlorodiphenyltrichloroethane, and Endosulfan on the Expression of Estradiol-, Progesterone-, and Testosterone-Responsive MicroRNAs and Their Target Genes in MCF-7 Cells. TOXICS 2022; 10:25. [PMID: 35051067 PMCID: PMC8780485 DOI: 10.3390/toxics10010025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/02/2022] [Accepted: 01/04/2022] [Indexed: 12/10/2022]
Abstract
Many studies have shown that dichlorodiphenyltrichloroethane (DDT) exposure raises breast cancer risk. Another insecticide with similar properties is endosulfan, which has been actively used in agriculture after DDT prohibition. Previously, we have identified some estradiol-, progesterone-, and testosterone-sensitive microRNAs (miRNAs, miRs). Because DDT and endosulfan have estrogenic, antiandrogenic, and antiprogesterone properties, we hypothesized that these miRNAs are affected by the insecticides. We quantified relative levels of miRNAs and expression levels of their target genes in breast cancer MCF-7 cells treated with p,p'-DDT, o,p'-DDT, or endosulfan. We also quantified miR-19b expression, which, as previously shown, is regulated by estrogen. Here, we observed that miR-19b expression increased in response not only to estradiol but also to testosterone and progesterone. Treatment of MCF-7 cells with p,p'-DDT or endosulfan decreased the protein levels of apoptosis regulators TP53INP1 and APAF1. In cells treated with o,p'-DDT, the TP53INP1 amount decreased after 24 h of incubation, but increased after 48 h of incubation with insecticide. OXTR expression, which is known to be associated with breast carcinogenesis, significantly diminished under the exposure of all insecticides. In cells treated with p,p'-DDT or o,p'-DDT, the observed changes were accompanied by alterations of the levels of hormone-responsive miRNAs: miR-324, miR-190a, miR-190b, miR-27a, miR-193b, and miR-19b.
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Affiliation(s)
- Tatiana Kalinina
- Federal Research Center of Fundamental and Translational Medicine, Timakova Str. 2/12, 630117 Novosibirsk, Russia; (V.K.); (L.K.); (L.G.)
| | - Vladislav Kononchuk
- Federal Research Center of Fundamental and Translational Medicine, Timakova Str. 2/12, 630117 Novosibirsk, Russia; (V.K.); (L.K.); (L.G.)
- Meshalkin National Medical Research Center, Ministry of Health of the Russian Federation, Rechkunovskaya Str. 15, 630055 Novosibirsk, Russia
| | - Lyubov Klyushova
- Federal Research Center of Fundamental and Translational Medicine, Timakova Str. 2/12, 630117 Novosibirsk, Russia; (V.K.); (L.K.); (L.G.)
| | - Lyudmila Gulyaeva
- Federal Research Center of Fundamental and Translational Medicine, Timakova Str. 2/12, 630117 Novosibirsk, Russia; (V.K.); (L.K.); (L.G.)
- Institute for Medicine and Psychology, Novosibirsk State University, Pirogova Str. 2, 630090 Novosibirsk, Russia
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23
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Rysz J, Franczyk B, Ławiński J, Gluba-Brzózka A. Characteristics of Clear Cell Papillary Renal Cell Carcinoma (ccpRCC). Int J Mol Sci 2021; 23:ijms23010151. [PMID: 35008576 PMCID: PMC8745490 DOI: 10.3390/ijms23010151] [Citation(s) in RCA: 10] [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: 11/04/2021] [Revised: 12/16/2021] [Accepted: 12/20/2021] [Indexed: 02/07/2023] Open
Abstract
Renal cell carcinomas (RCCs) is a group of various malignant tumours of the renal cortex displaying distinct clinical, morphologic, and genetic features. Clear cell papillary renal cell carcinoma (ccpRCC), belonging to this group, shares morphologic features with both clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC) and therefore, more strict diagnostic criteria should be developed to avoid misdiagnosis. Despite overlapping features, ccpRCC has also distinct clinical behaviour, histologic characteristics (morphologic and immunohistochemical), and genomic features. The concepts concerning this tumour are constantly developing since its biological potential and molecular basis remains to be fully unravelled. First reports indicated the presence of ccpRCC in end-stage renal disease, and they underlined the enriched development in this group of patients; however, currently, it is known that such tumours can also occur spontaneously in the normal kidney. Numerous studies have demonstrated that clinical outcomes and prognosis of ccpRCC patients is highly favourable. Till now, no convincing evidence of metastatic ccpRCC or death caused by the disease has been found. Therefore, it is of high importance to correctly differentiate ccpRCC from other subtypes of RCC with a much worse prognosis and to introduce appropriate management.
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Affiliation(s)
- Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 113 Zeromskiego Street, 90-549 Lodz, Poland; (J.R.); (B.F.)
| | - Beata Franczyk
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 113 Zeromskiego Street, 90-549 Lodz, Poland; (J.R.); (B.F.)
| | - Janusz Ławiński
- Department of Urology, Institute of Medical Sciences, Medical College of Rzeszow University, 35-055 Rzeszow, Poland;
| | - Anna Gluba-Brzózka
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 113 Zeromskiego Street, 90-549 Lodz, Poland; (J.R.); (B.F.)
- Correspondence: or ; Tel.: +48-42-639-3750
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24
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Decaesteker B, Durinck K, Van Roy N, De Wilde B, Van Neste C, Van Haver S, Roberts S, De Preter K, Vermeirssen V, Speleman F. From DNA Copy Number Gains and Tumor Dependencies to Novel Therapeutic Targets for High-Risk Neuroblastoma. J Pers Med 2021; 11:1286. [PMID: 34945759 PMCID: PMC8707517 DOI: 10.3390/jpm11121286] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/19/2021] [Accepted: 11/20/2021] [Indexed: 12/15/2022] Open
Abstract
Neuroblastoma is a pediatric tumor arising from the sympatho-adrenal lineage and a worldwide leading cause of childhood cancer-related deaths. About half of high-risk patients die from the disease while survivors suffer from multiple therapy-related side-effects. While neuroblastomas present with a low mutational burden, focal and large segmental DNA copy number aberrations are highly recurrent and associated with poor survival. It can be assumed that the affected chromosomal regions contain critical genes implicated in neuroblastoma biology and behavior. More specifically, evidence has emerged that several of these genes are implicated in tumor dependencies thus potentially providing novel therapeutic entry points. In this review, we briefly review the current status of recurrent DNA copy number aberrations in neuroblastoma and provide an overview of the genes affected by these genomic variants for which a direct role in neuroblastoma has been established. Several of these genes are implicated in networks that positively regulate MYCN expression or stability as well as cell cycle control and apoptosis. Finally, we summarize alternative approaches to identify and prioritize candidate copy-number driven dependency genes for neuroblastoma offering novel therapeutic opportunities.
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Grants
- P30 CA008748 NCI NIH HHS
- G087221N, G.0507.12, G049720N,12U4718N, 11C3921N, 11J8313N, 12B5313N, 1514215N, 1197617N,1238420N, 12Q8322N, 3F018519, 12N6917N Fund for Scientific Research Flanders
- 2018-087, 2018-125, 2020-112 Belgian Foundation against Cancer
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Affiliation(s)
- Bieke Decaesteker
- Department for Biomolecular Medicine, Ghent University, Medical Research Building (MRB1), Corneel Heymanslaan 10, B-9000 Ghent, Belgium; (B.D.); (K.D.); (N.V.R.); (B.D.W.); (C.V.N.); (S.V.H.); (K.D.P.); (V.V.)
| | - Kaat Durinck
- Department for Biomolecular Medicine, Ghent University, Medical Research Building (MRB1), Corneel Heymanslaan 10, B-9000 Ghent, Belgium; (B.D.); (K.D.); (N.V.R.); (B.D.W.); (C.V.N.); (S.V.H.); (K.D.P.); (V.V.)
| | - Nadine Van Roy
- Department for Biomolecular Medicine, Ghent University, Medical Research Building (MRB1), Corneel Heymanslaan 10, B-9000 Ghent, Belgium; (B.D.); (K.D.); (N.V.R.); (B.D.W.); (C.V.N.); (S.V.H.); (K.D.P.); (V.V.)
| | - Bram De Wilde
- Department for Biomolecular Medicine, Ghent University, Medical Research Building (MRB1), Corneel Heymanslaan 10, B-9000 Ghent, Belgium; (B.D.); (K.D.); (N.V.R.); (B.D.W.); (C.V.N.); (S.V.H.); (K.D.P.); (V.V.)
- Department of Internal Medicine and Pediatrics, Ghent University Hospital, Corneel Heymanslaan 10, B-9000 Ghent, Belgium
| | - Christophe Van Neste
- Department for Biomolecular Medicine, Ghent University, Medical Research Building (MRB1), Corneel Heymanslaan 10, B-9000 Ghent, Belgium; (B.D.); (K.D.); (N.V.R.); (B.D.W.); (C.V.N.); (S.V.H.); (K.D.P.); (V.V.)
| | - Stéphane Van Haver
- Department for Biomolecular Medicine, Ghent University, Medical Research Building (MRB1), Corneel Heymanslaan 10, B-9000 Ghent, Belgium; (B.D.); (K.D.); (N.V.R.); (B.D.W.); (C.V.N.); (S.V.H.); (K.D.P.); (V.V.)
| | - Stephen Roberts
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
| | - Katleen De Preter
- Department for Biomolecular Medicine, Ghent University, Medical Research Building (MRB1), Corneel Heymanslaan 10, B-9000 Ghent, Belgium; (B.D.); (K.D.); (N.V.R.); (B.D.W.); (C.V.N.); (S.V.H.); (K.D.P.); (V.V.)
| | - Vanessa Vermeirssen
- Department for Biomolecular Medicine, Ghent University, Medical Research Building (MRB1), Corneel Heymanslaan 10, B-9000 Ghent, Belgium; (B.D.); (K.D.); (N.V.R.); (B.D.W.); (C.V.N.); (S.V.H.); (K.D.P.); (V.V.)
- Department of Biomedical Molecular Biology, Ghent University, Technologiepark 71, B-9052 Zwijnaarde, Belgium
| | - Frank Speleman
- Department for Biomolecular Medicine, Ghent University, Medical Research Building (MRB1), Corneel Heymanslaan 10, B-9000 Ghent, Belgium; (B.D.); (K.D.); (N.V.R.); (B.D.W.); (C.V.N.); (S.V.H.); (K.D.P.); (V.V.)
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25
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Florijn BW, Bijkerk R, Kruyt ND, van Zonneveld AJ, Wermer MJH. Sex-Specific MicroRNAs in Neurovascular Units in Ischemic Stroke. Int J Mol Sci 2021; 22:11888. [PMID: 34769320 PMCID: PMC8585074 DOI: 10.3390/ijms222111888] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 10/25/2021] [Accepted: 10/27/2021] [Indexed: 12/24/2022] Open
Abstract
Accumulating evidence pinpoints sex differences in stroke incidence, etiology and outcome. Therefore, more understanding of the sex-specific mechanisms that lead to ischemic stroke and aggravation of secondary damage after stroke is needed. Our current mechanistic understanding of cerebral ischemia states that endothelial quiescence in neurovascular units (NVUs) is a major physiological parameter affecting the cellular response to neuron, astrocyte and vascular smooth muscle cell (VSMC) injury. Although a hallmark of the response to injury in these cells is transcriptional activation, noncoding RNAs such as microRNAs exhibit cell-type and context dependent regulation of gene expression at the post-transcriptional level. This review assesses whether sex-specific microRNA expression (either derived from X-chromosome loci following incomplete X-chromosome inactivation or regulated by estrogen in their biogenesis) in these cells controls NVU quiescence, and as such, could differentiate stroke pathophysiology in women compared to men. Their adverse expression was found to decrease tight junction affinity in endothelial cells and activate VSMC proliferation, while their regulation of paracrine astrocyte signaling was shown to neutralize sex-specific apoptotic pathways in neurons. As such, these microRNAs have cell type-specific functions in astrocytes and vascular cells which act on one another, thereby affecting the cell viability of neurons. Furthermore, these microRNAs display actual and potential clinical implications as diagnostic and prognostic biomarkers in ischemic stroke and in predicting therapeutic response to antiplatelet therapy. In conclusion, this review improves the current mechanistic understanding of the molecular mechanisms leading to ischemic stroke in women and highlights the clinical promise of sex-specific microRNAs as novel diagnostic biomarkers for (silent) ischemic stroke.
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Affiliation(s)
- Barend W. Florijn
- Department of Neurology, Leiden University Medical Center, 2333 ZR Leiden, The Netherlands; (N.D.K.); (M.J.H.W.)
- Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (R.B.); (A.J.v.Z.)
| | - Roel Bijkerk
- Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (R.B.); (A.J.v.Z.)
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Nyika D. Kruyt
- Department of Neurology, Leiden University Medical Center, 2333 ZR Leiden, The Netherlands; (N.D.K.); (M.J.H.W.)
| | - Anton Jan van Zonneveld
- Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (R.B.); (A.J.v.Z.)
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Marieke J. H. Wermer
- Department of Neurology, Leiden University Medical Center, 2333 ZR Leiden, The Netherlands; (N.D.K.); (M.J.H.W.)
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26
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Hansda AK, Goswami R. 17-β estradiol signalling affects cardiovascular and cancer pathogenesis by regulating the crosstalk between transcription factors and EC-miRNAs. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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27
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Kim CK, Linscott ML, Flury S, Zhang M, Newby ML, Pak TR. 17β-Estradiol Regulates miR-9-5p and miR-9-3p Stability and Function in the Aged Female Rat Brain. Noncoding RNA 2021; 7:53. [PMID: 34564315 PMCID: PMC8482090 DOI: 10.3390/ncrna7030053] [Citation(s) in RCA: 4] [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: 07/27/2021] [Revised: 08/23/2021] [Accepted: 08/25/2021] [Indexed: 12/13/2022] Open
Abstract
Clinical studies demonstrated that the ovarian hormone 17β-estradiol (E2) is neuroprotective within a narrow window of time following menopause, suggesting that there is a biological switch in E2 action that is temporally dependent. However, the molecular mechanisms mediating this temporal switch have not been determined. Our previous studies focused on microRNAs (miRNA) as one potential molecular mediator and showed that E2 differentially regulated a subset of mature miRNAs which was dependent on age and the length of time following E2 deprivation. Notably, E2 significantly increased both strands of the miR-9 duplex (miR-9-5p and miR-9-3p) in the hypothalamus, raising the possibility that E2 could regulate miRNA stability/degradation. We tested this hypothesis using a biochemical approach to measure miRNA decay in a hypothalamic neuronal cell line and in hypothalamic brain tissue from a rat model of surgical menopause. Notably, we found that E2 treatment stabilized both miRNAs in neuronal cells and in the rat hypothalamus. We also used polysome profiling as a proxy for miR-9-5p and miR-9-3p function and found that E2 was able to shift polysome loading of the miRNAs, which repressed the translation of a predicted miR-9-3p target. Moreover, miR-9-5p and miR-9-3p transcripts appeared to occupy different fractions of the polysome profile, indicating differential subcellular. localization. Together, these studies reveal a novel role for E2 in modulating mature miRNA behavior, independent of its effects at regulating the primary and/or precursor form of miRNAs.
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Affiliation(s)
| | | | | | | | | | - Toni R. Pak
- Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University, Maywood, IL 60153, USA; (C.K.K.); (M.L.L.); (S.F.); (M.Z.); (M.L.N.)
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28
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Rodrigues AD. Drug Interactions Involving 17α-Ethinylestradiol: Considerations Beyond Cytochrome P450 3A Induction and Inhibition. Clin Pharmacol Ther 2021; 111:1212-1221. [PMID: 34342002 DOI: 10.1002/cpt.2383] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 07/29/2021] [Indexed: 11/08/2022]
Abstract
It is widely acknowledged that drug-drug interactions (DDIs) involving estrogen (17α-ethinylestradiol (EE))-containing oral contraceptives (OCs) are important. Consequently, sponsors of new molecular entities (NMEs) often conduct clinical studies with priority given to OCs as victims of cytochrome P450 (CYP) 3A (CYP3A) induction and inhibition. Such scenarios are reflected in the US Food and Drug Administration-issued guidance documentation related to OC DDI studies. Although CYP3A is important, OCs such as EE are metabolized by sulfotransferase 1E1 and UDP-glucuronosyltransferase (UGT) 1A1, expressed in the gut and liver, and so both can also serve as loci of victim OC DDI. Therefore, for any NME, one should carefully consider its induction and inhibition profile involving CYP3A4/5, UGT1A1, and SULT1E1. As DDI perpetrators, available clinical DDI data indicate that EE-containing OCs can induce (e.g., UGT1A4 and CYP2A6) and inhibit (CYP1A2 ≥ CYP2C19 > CYP3A4/5 > CYP2C8, CYP2B6, CYP2D6, and CYP2C9) various CYP forms. Although available in vitro CYP inhibition data do not explain such a graded inhibitory effect in vivo, it is hypothesized that EE differentially modulates CYP expression via potent agonism of the estrogen receptor expressed in the gut and liver. From the standpoint of the NME as potential OC DDI victim, therefore, it is important to assess its projected (pre-phase I) or known therapeutic index and pharmacokinetic profile (fraction absorbed, absolute oral bioavailability, clearance/extraction class, fraction metabolized by CYP1A2, CYP2C19, CYP2A6, and UGT1A4). Such information can enable the prioritization, design, and interpretation of NME-OC DDI studies.
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Affiliation(s)
- A David Rodrigues
- ADME Sciences, Medicine Design, Worldwide Research & Development, Pfizer Inc, Groton, Connecticut, USA
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29
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Kesharwani D, Kumar A, Poojary M, Scaria V, Datta M. RNA sequencing reveals potential interacting networks between the altered transcriptome and ncRNome in the skeletal muscle of diabetic mice. Biosci Rep 2021; 41:BSR20210495. [PMID: 34190986 PMCID: PMC8276098 DOI: 10.1042/bsr20210495] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 06/21/2021] [Accepted: 06/29/2021] [Indexed: 12/12/2022] Open
Abstract
For a global epidemic like Type 2 diabetes mellitus (T2DM), while impaired gene regulation is identified as a primary cause of aberrant cellular physiology; in the past few years, non-coding RNAs (ncRNAs) have emerged as important regulators of cellular metabolism. However, there are no reports of comprehensive in-depth cross-talk between these regulatory elements and the potential consequences in the skeletal muscle during diabetes. Here, using RNA sequencing, we identified 465 mRNAs and 12 long non-coding RNAs (lncRNAs), to be differentially regulated in the skeletal muscle of diabetic mice and pathway enrichment analysis of these altered transcripts revealed pathways of insulin, FOXO and AMP-activated protein kinase (AMPK) signaling to be majorly over-represented. Construction of networks showed that these pathways significantly interact with each other that might underlie aberrant skeletal muscle metabolism during diabetes. Gene-gene interaction network depicted strong interactions among several differentially expressed genes (DEGs) namely, Prkab2, Irs1, Pfkfb3, Socs2 etc. Seven altered lncRNAs depicted multiple interactions with the altered transcripts, suggesting possible regulatory roles of these lncRNAs. Inverse patterns of expression were observed between several of the deregulated microRNAs (miRNAs) and the differentially expressed transcripts in the tissues. Towards validation, overexpression of miR-381-3p and miR-539-5p in skeletal muscle C2C12 cells significantly decreased the transcript levels of their targets, Nfkbia, Pik3r1 and Pi3kr1, Cdkn2d, respectively. Collectively, the findings provide a comprehensive understanding of the interactions and cross-talk between the ncRNome and transcriptome in the skeletal muscle during diabetes and put forth potential therapeutic options for improving insulin sensitivity.
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Affiliation(s)
- Devesh Kesharwani
- CSIR-Institute of Genomics and Integrative Biology, Functional and Genomics Unit, Mall Road, Delhi, India
- Academy of Scientific and Innovative Research, CSIR-HRDC, Kamala Nehru Nagar, Ghaziabad 201002, Uttar Pradesh, India
| | - Amit Kumar
- CSIR-Institute of Genomics and Integrative Biology, Functional and Genomics Unit, Mall Road, Delhi, India
- Academy of Scientific and Innovative Research, CSIR-HRDC, Kamala Nehru Nagar, Ghaziabad 201002, Uttar Pradesh, India
| | - Mukta Poojary
- Academy of Scientific and Innovative Research, CSIR-HRDC, Kamala Nehru Nagar, Ghaziabad 201002, Uttar Pradesh, India
- GN Ramachandran Knowledge Centre for Genome Informatics, CSIR-Institute of Genomics and Integrative Biology, Mathura Road, Delhi 110025, India
| | - Vinod Scaria
- Academy of Scientific and Innovative Research, CSIR-HRDC, Kamala Nehru Nagar, Ghaziabad 201002, Uttar Pradesh, India
- GN Ramachandran Knowledge Centre for Genome Informatics, CSIR-Institute of Genomics and Integrative Biology, Mathura Road, Delhi 110025, India
| | - Malabika Datta
- CSIR-Institute of Genomics and Integrative Biology, Functional and Genomics Unit, Mall Road, Delhi, India
- Academy of Scientific and Innovative Research, CSIR-HRDC, Kamala Nehru Nagar, Ghaziabad 201002, Uttar Pradesh, India
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30
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The Sex-Related Interplay between TME and Cancer: On the Critical Role of Estrogen, MicroRNAs and Autophagy. Cancers (Basel) 2021; 13:cancers13133287. [PMID: 34209162 PMCID: PMC8267629 DOI: 10.3390/cancers13133287] [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: 05/16/2021] [Revised: 06/17/2021] [Accepted: 06/25/2021] [Indexed: 01/18/2023] Open
Abstract
The interplay between cancer cells and the tumor microenvironment (TME) has a fundamental role in tumor progression and response to therapy. The plethora of components constituting the TME, such as stroma, fibroblasts, endothelial and immune cells, as well as macromolecules, e.g., hormones and cytokines, and epigenetic factors, such as microRNAs, can modulate the survival or death of cancer cells. Actually, the TME can stimulate the genetically regulated programs that the cell puts in place under stress: apoptosis or, of interest here, autophagy. However, the implication of autophagy in tumor growth appears still undefined. Autophagy mainly represents a cyto-protective mechanism that allows cell survival but, in certain circumstances, also leads to the blocking of cell cycle progression, possibly leading to cell death. Since significant sex/gender differences in the incidence, progression and response to cancer therapy have been widely described in the literature, in this review, we analyzed the roles played by key components of the TME, e.g., estrogen and microRNAs, on autophagy regulation from a sex/gender-based perspective. We focused our attention on four paradigmatic and different forms of cancers-colon cancer, melanoma, lymphoma, and lung cancer-concluding that sex-specific differences may exert a significant impact on TME/cancer interaction and, thus, tumor growth.
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Xie J, Kusnadi EP, Furic L, Selth LA. Regulation of mRNA Translation by Hormone Receptors in Breast and Prostate Cancer. Cancers (Basel) 2021; 13:3254. [PMID: 34209750 PMCID: PMC8268847 DOI: 10.3390/cancers13133254] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 12/12/2022] Open
Abstract
Breast and prostate cancer are the second and third leading causes of death amongst all cancer types, respectively. Pathogenesis of these malignancies is characterised by dysregulation of sex hormone signalling pathways, mediated by the estrogen receptor-α (ER) in breast cancer and androgen receptor (AR) in prostate cancer. ER and AR are transcription factors whose aberrant function drives oncogenic transcriptional programs to promote cancer growth and progression. While ER/AR are known to stimulate cell growth and survival by modulating gene transcription, emerging findings indicate that their effects in neoplasia are also mediated by dysregulation of protein synthesis (i.e., mRNA translation). This suggests that ER/AR can coordinately perturb both transcriptional and translational programs, resulting in the establishment of proteomes that promote malignancy. In this review, we will discuss relatively understudied aspects of ER and AR activity in regulating protein synthesis as well as the potential of targeting mRNA translation in breast and prostate cancer.
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Affiliation(s)
- Jianling Xie
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia
| | - Eric P Kusnadi
- Translational Prostate Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
- Cancer Program, Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia
| | - Luc Furic
- Translational Prostate Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
- Cancer Program, Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia
| | - Luke A Selth
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia
- Freemasons Centre for Male Health and Wellbeing, Flinders University, Bedford Park, SA 5042, Australia
- Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia
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Wang X, Yang D. The regulation of RNA metabolism in hormone signaling and breast cancer. Mol Cell Endocrinol 2021; 529:111221. [PMID: 33711334 PMCID: PMC8262629 DOI: 10.1016/j.mce.2021.111221] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 02/09/2021] [Accepted: 02/22/2021] [Indexed: 02/02/2023]
Abstract
As the most frequent women's cancer, breast cancer causes the second most cancer-related death in women worldwide. Majority of the breast cancers are hormone receptor-positive and commonly treated by hormone therapy. Thus, the expression levels of hormone receptors signaling pathways are pivotal in the development and therapy of breast cancer. The expression of hormone receptors signaling pathways is not only regulated at the transcription level but also at the post-transcription level by both proteins and RNAs. In addition to that, the function of hormone receptors can also be regulated by RNAs. In this review, we summarize the roles of RNAs in hormone receptor-positive breast cancer. We introduce how mRNA stability and protein function of genes in hormone receptors signaling pathways are regulated by RNA-binding proteins, miRNAs, and lncRNAs. We believe these proteins and RNAs can be potential therapeutic targets of breast cancer.
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Affiliation(s)
- Xiaofei Wang
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, PA, 15261, USA
| | - Da Yang
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, PA, 15261, USA; UPMC Hillman Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
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33
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Expression of Estrogen Receptor- and Progesterone Receptor-Regulating MicroRNAs in Breast Cancer. Genes (Basel) 2021; 12:genes12040582. [PMID: 33923732 PMCID: PMC8073827 DOI: 10.3390/genes12040582] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/14/2021] [Accepted: 04/15/2021] [Indexed: 12/17/2022] Open
Abstract
In ~70% of breast cancer (BC) cases, estrogen and progesterone receptors (ER and PR) are overexpressed, which can change during tumor progression. Expression changes of these receptors during cancer initiation and progression can be caused by alterations in microRNA (miR, miRNA) expression. To assess the association of BC progression with aberrant expression of miRNAs that target ER and PR mRNAs, we quantified miR-19b, -222, -22, -378a, and -181a in BC samples (n = 174) by real-time PCR. Underexpression of miR-222 and miR-378a in stage T2–T4 BC was characteristic for HER2-overexpressing tumors. In addition, the expression of miR-181a and miR-378a was higher in these tumors than in tumors with a HER2 IHC score of 0 or 1+. In tumors with a Ki-67 index ≥ 14%, all tested miRNAs were underexpressed in BC with a high Allred PR score (6–8). In ER-and-PR–negative tumors, miR-22, miR-222, miR-181a, and miR-378a underexpression was associated with Ki-67 index > 35% (median value). MiR-19b and miR-22 underexpression could be a marker of lymph node metastasis in ER- and/or PR-positive tumors with HER2 IHC score 0. Thus, the association of miR-19b, miR-22, miR-222, miR-378a, and miR-181a levels with BC characteristics is influenced by the status of tumor ER, PR, HER2, and Ki-67.
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Tian J, Adams MJ, Tay JWT, James I, Powell S, Hughes QW, Gilmore G, Baker RI, Tiao JYH. Estradiol-Responsive miR-365a-3p Interacts with Tissue Factor 3'UTR to Modulate Tissue Factor-Initiated Thrombin Generation. Thromb Haemost 2021; 121:1483-1496. [PMID: 33540457 DOI: 10.1055/a-1382-9983] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND High estradiol (E2) levels are linked to an increased risk of venous thromboembolism; however, the underlying molecular mechanism(s) remain poorly understood. We previously identified an E2-responsive microRNA (miR), miR-494-3p, that downregulates protein S expression, and posited additional coagulation factors, such as tissue factor, may be regulated in a similar manner via miRs. OBJECTIVES To evaluate the coagulation capacity of cohorts with high physiological E2, and to further characterize novel E2-responsive miR and miR regulation on tissue factor in E2-related hypercoagulability. METHODS Ceveron Alpha thrombin generation assay (TGA) was used to assess plasma coagulation profile of three cohorts. The effect of physiological levels of E2, 10 nM, on miR expression in HuH-7 cells was compared using NanoString nCounter and validated with independent assays. The effect of tissue factor-interacting miR was confirmed by dual-luciferase reporter assays, immunoblotting, flow cytometry, biochemistry assays, and TGA. RESULTS Plasma samples from pregnant women and women on the contraceptive pill were confirmed to be hypercoagulable (compared with sex-matched controls). At equivalent and high physiological levels of E2, miR-365a-3p displayed concordant E2 downregulation in two independent miR quantification platforms, and tissue factor protein was upregulated by E2 treatment. Direct interaction between miR-365a-3p and F3-3'UTR was confirmed and overexpression of miR-365a-3p led to a decrease of (1) tissue factor mRNA transcripts, (2) protein levels, (3) activity, and (4) tissue factor-initiated thrombin generation. CONCLUSION miR-365a-3p is a novel tissue factor regulator. High E2 concentrations induce a hypercoagulable state via a miR network specific for coagulation factors.
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Affiliation(s)
- Jiayin Tian
- Western Australian Centre for Thrombosis and Haemostasis, Murdoch University, Murdoch, Perth, Australia.,Perth Blood Institute, West Perth, Perth, Australia.,College of Science, Health, Engineering and Education, Murdoch University, Murdoch, Perth, Australia.,Centre for Molecular Medicine and Innovative Therapeutics, Health Futures Institute, Murdoch University, Murdoch, Perth, Australia
| | - Murray J Adams
- College of Science, Health, Engineering and Education, Murdoch University, Murdoch, Perth, Australia
| | - Jasmine Wee Ting Tay
- Western Australian Centre for Thrombosis and Haemostasis, Murdoch University, Murdoch, Perth, Australia.,Perth Blood Institute, West Perth, Perth, Australia
| | - Ian James
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Perth, Australia
| | - Suzanne Powell
- Western Australian Centre for Thrombosis and Haemostasis, Murdoch University, Murdoch, Perth, Australia
| | - Quintin W Hughes
- Western Australian Centre for Thrombosis and Haemostasis, Murdoch University, Murdoch, Perth, Australia.,Perth Blood Institute, West Perth, Perth, Australia
| | - Grace Gilmore
- Western Australian Centre for Thrombosis and Haemostasis, Murdoch University, Murdoch, Perth, Australia.,Perth Blood Institute, West Perth, Perth, Australia.,Centre for Molecular Medicine and Innovative Therapeutics, Health Futures Institute, Murdoch University, Murdoch, Perth, Australia
| | - Ross I Baker
- Western Australian Centre for Thrombosis and Haemostasis, Murdoch University, Murdoch, Perth, Australia.,Perth Blood Institute, West Perth, Perth, Australia.,Centre for Molecular Medicine and Innovative Therapeutics, Health Futures Institute, Murdoch University, Murdoch, Perth, Australia
| | - Jim Yu-Hsiang Tiao
- Western Australian Centre for Thrombosis and Haemostasis, Murdoch University, Murdoch, Perth, Australia.,Perth Blood Institute, West Perth, Perth, Australia.,Centre for Molecular Medicine and Innovative Therapeutics, Health Futures Institute, Murdoch University, Murdoch, Perth, Australia
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Abstract
Health and lifespan disparities between sexes are dependent on the immune responses. Men and women have different life styles which determine the environment, nutritional requirements and their interactions with the sex hormones. Sexual dimorphism in innate and adaptive immunity determines responses to infections and other environmental factors regulating health and diseases. Sex hormones regulate immune responses through the expression of receptors which differ for female and male hormones. Estrogen receptors are expressed in brain, lymphoid tissue cells and many immune cells while androgen receptors are limited in expression. Genetic, epigenetic factors and X chromosome linked immune function genes are important in enhanced adaptive immunity in females, leading to production of higher levels of antibodies compared to males. Different nutritional requirements and hormonal control of the mucosal microbiome and its function regulate mucosal immunity. Hormonal changes during various aspects of life and during aging control immune senescence. Evolutionarily, females have an advantage during young age when they are protected from infections by heightened immune reactivity though during aging that can lead to pathologies. Considering the sexual dimorphism in immunity, guidelines need to be established for sex-based treatments for optimal response.
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Affiliation(s)
- Veena Taneja
- Department of Immunology and Rheumatology, Mayo Clinic, Rochester, MN, United States.
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37
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Regulatory Interplay between miR-181a-5p and Estrogen Receptor Signaling Cascade in Breast Cancer. Cancers (Basel) 2021; 13:cancers13030543. [PMID: 33535487 PMCID: PMC7867078 DOI: 10.3390/cancers13030543] [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: 12/18/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/18/2022] Open
Abstract
Simple Summary Despite huge efforts in breast cancer care programs, patient’s survival rates greatly vary. Differences in response to therapy still represent the major challenge for clinicians and biologists. Define new anticancer mechanisms and innovative predictors for resistance could be a valid strategy to permanently defeat breast cancer. Here we propose the epigenetic based reprogramming of breast cancer, which leverages on the crosstalk between miR-181a-5p and Estrogen Receptor α. This simultaneously approach allows to induce miR-181a-5p and reduce the receptor expression, blocking the estrogen-dependent proliferative pathway underlying breast cancer progression. Since the epigenetic approach insists on transcriptional regulation, it is mostly independent of the acquired resistance mechanisms typically induced by prolonged endocrine therapy and therefore can be used as a sensitizer, neoadjuvant, or in combination with the standard in care treatments against breast cancer. Abstract The efficacy and side effects of endocrine therapy in breast cancer (BC) depend largely on estrogen receptor alpha (ERα) expression, the specific drug administered, and treatment scheduling. Although the benefits of endocrine therapy outweigh any adverse effects in the initial stages of BC, later- or advanced-stage tumors acquire resistance to treatments. The mechanisms underlying tumor resistance to therapy are still not well understood, posing a major challenge for BC patient care. Epigenetic regulation and miRNA expression may be involved in the switch from a treatment-sensitive to a treatment-resistant state and could provide a valid therapeutic strategy for ERα negative BC. Here, a hybrid lysine-specific histone demethylase inhibitor, MC3324, displaying selective estrogen receptor down-regulator-like activities in BC, was used to highlight the interplay between epigenetic and ERα signaling. MC3324 anticancer action is mediated by microRNA (miRNA) expression regulation, indicating an innovative function for this molecule. Integrated analysis suggests a crosstalk between estrogen signaling, ERα interactors, miRNAs, and their putative targets. Specifically, miR-181a-5p expression is regulated by MC3324 and has an impact on cellular levels of ERα. A comparison of breast tumor versus healthy mammary tissues confirmed the important role of miR-181a-5p in ERα regulation and points to its putative predictive function in BC therapy.
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Abstract
Despite the decline in death rate from breast cancer and recent advances in targeted therapies and combinations for the treatment of metastatic disease, metastatic breast cancer remains the second leading cause of cancer-associated death in U.S. women. The invasion-metastasis cascade involves a number of steps and multitudes of proteins and signaling molecules. The pathways include invasion, intravasation, circulation, extravasation, infiltration into a distant site to form a metastatic niche, and micrometastasis formation in a new environment. Each of these processes is regulated by changes in gene expression. Noncoding RNAs including microRNAs (miRNAs) are involved in breast cancer tumorigenesis, progression, and metastasis by post-transcriptional regulation of target gene expression. miRNAs can stimulate oncogenesis (oncomiRs), inhibit tumor growth (tumor suppressors or miRsupps), and regulate gene targets in metastasis (metastamiRs). The goal of this review is to summarize some of the key miRNAs that regulate genes and pathways involved in metastatic breast cancer with an emphasis on estrogen receptor α (ERα+) breast cancer. We reviewed the identity, regulation, human breast tumor expression, and reported prognostic significance of miRNAs that have been documented to directly target key genes in pathways, including epithelial-to-mesenchymal transition (EMT) contributing to the metastatic cascade. We critically evaluated the evidence for metastamiRs and their targets and miRNA regulation of metastasis suppressor genes in breast cancer progression and metastasis. It is clear that our understanding of miRNA regulation of targets in metastasis is incomplete.
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Affiliation(s)
- Belinda J Petri
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Carolyn M Klinge
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
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Şoica C, Voicu M, Ghiulai R, Dehelean C, Racoviceanu R, Trandafirescu C, Roșca OJ, Nistor G, Mioc M, Mioc A. Natural Compounds in Sex Hormone-Dependent Cancers: The Role of Triterpenes as Therapeutic Agents. Front Endocrinol (Lausanne) 2021; 11:612396. [PMID: 33552000 PMCID: PMC7859451 DOI: 10.3389/fendo.2020.612396] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 11/30/2020] [Indexed: 12/12/2022] Open
Abstract
Sex hormone-dependent cancers currently contribute to the high number of cancer-related deaths worldwide. The study and elucidation of the molecular mechanisms underlying the progression of these tumors was a double-edged sword, leading to the expansion and development of new treatment options, with the cost of triggering more aggressive, therapy resistant relapses. The interaction of androgen, estrogen and progesterone hormones with specific receptors (AR, ER, PR) has emerged as a key player in the development and progression of breast, ovarian, prostate and endometrium cancers. Sex hormone-dependent cancers share a common and rather unique carcinogenesis mechanism involving the active role of endogenous and exogenous sex hormones to maintain high mitotic rates and increased cell proliferation thus increasing the probability of aberrant gene occurrence and accumulation highly correlated with abnormal cell division and the occurrence of malignant phenotypes. Cancer related hormone therapy has evolved, currently being associated with the blockade of other signaling pathways often associated with carcinogenesis and tumor progression in cancers, with promising results. However, despite the established developments, there are still several shortcomings to be addressed. Triterpenes are natural occurring secondary metabolites biosynthesized by various pathways starting from squalene cyclization. Due to their versatile therapeutic potential, including the extensively researched antiproliferative effect, these compounds are most definitely a cornerstone in the research and development of new natural/semisynthetic anticancer therapies. The present work thoroughly describes the ongoing research related to the antitumor activity of triterpenes in sex hormone-dependent cancers. Also, the current review highlights both the biological activity of various triterpenoid compounds and their featured mechanisms of action correlated with important chemical structural features.
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Affiliation(s)
- Codruţa Şoica
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
| | - Mirela Voicu
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
| | - Roxana Ghiulai
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
| | - Cristina Dehelean
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
| | - Roxana Racoviceanu
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
| | - Cristina Trandafirescu
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
| | - Oana-Janina Roșca
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
- Department of Vascular Surgery, Pius Brinzeu Timisoara City Emergency Clinical Hospital, Timisoara, Romania
| | - Gabriela Nistor
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
| | - Marius Mioc
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
| | - Alexandra Mioc
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
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Gonella-Diaza AM, Lopes E, Ribeiro da Silva K, Perecin Nociti R, Mamede Andrade G, Atuesta-Bustos JE, Coelho da Silveira J, Vieira Meirelles F, Binelli M. Steroidal Regulation of Oviductal microRNAs Is Associated with microRNA-Processing in Beef Cows. Int J Mol Sci 2021; 22:953. [PMID: 33477993 PMCID: PMC7835783 DOI: 10.3390/ijms22020953] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/12/2021] [Accepted: 01/13/2021] [Indexed: 12/21/2022] Open
Abstract
Information on molecular mechanisms through which sex-steroids regulate oviductal function to support early embryo development is lacking. Here, we hypothesized that the periovulatory endocrine milieu affects the miRNA processing machinery and miRNA expression in bovine oviductal tissues. Growth of the preovulatory follicle was controlled to obtain cows that ovulated a small follicle (SF) and subsequently bore a small corpus luteum (CL; SF-SCL) or a large follicle (LF) and large CL (LF-LCL). These groups differed in the periovulatory plasmatic sex-steroid's concentrations. Ampulla and isthmus samples were collected on day four of the estrous cycle. Abundance of DROSHA, DICER1, and AGO4 transcripts was greater in the ampulla than the isthmus. In the ampulla, transcription of these genes was greater for the SF-SCL group, while the opposite was observed in the isthmus. The expression of the 88 most abundant miRNAs and 14 miRNAs in the ampulla and 34 miRNAs in isthmus were differentially expressed between LF-LCL and SF-SCL groups. Integration of transcriptomic and miRNA data and molecular pathways enrichment showed that important pathways were inhibited in the SF-SCL group due to miRNA control. In conclusion, the endocrine milieu affects the miRNA expression in the bovine oviduct in a region-specific manner.
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Affiliation(s)
- Angela Maria Gonella-Diaza
- North Florida Research and Education Center, Institute of Food and Agricultural Sciences, University of Florida, Marianna, FL 32446, USA;
- Department of Animal Reproduction, School of Veterinary Medicine and Animal Science, University of São Paulo, 225, Avenida Duque de Caxias, Norte, Jardim, Elite, Pirassununga, SP 13635-900, Brazil; (E.L.); (K.R.d.S.)
| | - Everton Lopes
- Department of Animal Reproduction, School of Veterinary Medicine and Animal Science, University of São Paulo, 225, Avenida Duque de Caxias, Norte, Jardim, Elite, Pirassununga, SP 13635-900, Brazil; (E.L.); (K.R.d.S.)
- Unianchieta, Av. Doutor Adoniro Ladeira, 94, (Km 55, 5 Rodovia Anhanguera), Jundiaí, SP 13210-795, Brazil
| | - Kauê Ribeiro da Silva
- Department of Animal Reproduction, School of Veterinary Medicine and Animal Science, University of São Paulo, 225, Avenida Duque de Caxias, Norte, Jardim, Elite, Pirassununga, SP 13635-900, Brazil; (E.L.); (K.R.d.S.)
| | - Ricardo Perecin Nociti
- Department of Veterinary Medicine, College of Animal Sciences and Food Engineering, University of São Paulo, Av. Duque de Caxias Norte, 225, Pirassununga, SP 13635-900, Brazil; (R.P.N.); (G.M.A.); (J.C.d.S.); (F.V.M.)
| | - Gabriella Mamede Andrade
- Department of Veterinary Medicine, College of Animal Sciences and Food Engineering, University of São Paulo, Av. Duque de Caxias Norte, 225, Pirassununga, SP 13635-900, Brazil; (R.P.N.); (G.M.A.); (J.C.d.S.); (F.V.M.)
| | - Jorge Eduardo Atuesta-Bustos
- College of Agricultural Science—Agrarian University Foundation of Colombia-UNIAGRARIA, Calle 170 No 54a-10, Bogotá 111166, Colombia;
| | - Juliano Coelho da Silveira
- Department of Veterinary Medicine, College of Animal Sciences and Food Engineering, University of São Paulo, Av. Duque de Caxias Norte, 225, Pirassununga, SP 13635-900, Brazil; (R.P.N.); (G.M.A.); (J.C.d.S.); (F.V.M.)
| | - Flávio Vieira Meirelles
- Department of Veterinary Medicine, College of Animal Sciences and Food Engineering, University of São Paulo, Av. Duque de Caxias Norte, 225, Pirassununga, SP 13635-900, Brazil; (R.P.N.); (G.M.A.); (J.C.d.S.); (F.V.M.)
| | - Mario Binelli
- Department of Animal Reproduction, School of Veterinary Medicine and Animal Science, University of São Paulo, 225, Avenida Duque de Caxias, Norte, Jardim, Elite, Pirassununga, SP 13635-900, Brazil; (E.L.); (K.R.d.S.)
- Department of Animal Sciences, University of Florida, PO Box 110910, Gainesville, FL 32611, USA
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MicroRNA-19b predicts widespread pain and posttraumatic stress symptom risk in a sex-dependent manner following trauma exposure. Pain 2021; 161:47-60. [PMID: 31569141 DOI: 10.1097/j.pain.0000000000001709] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Posttraumatic widespread pain (PTWP) and posttraumatic stress symptoms (PTSS) are frequent comorbid sequelae of trauma that occur at different rates in women and men. We sought to identify microRNA (miRNA) that may contribute to sex-dependent differences in vulnerability to these outcomes. Monte Carlo simulations (x10,000) identified miRNA in which predicted targeting of PTWP or PTSS genes was most enriched. Expression of the leading candidate miRNA to target PTWP/PTSS-related genes, miR-19b, has been shown to be influenced by estrogen and stress exposure. We evaluated whether peritraumatic miR-19b blood expression levels predicted PTWP and PTSS development in women and men experiencing trauma of motor vehicle collision (n = 179) and in women experiencing sexual assault trauma (n = 74). A sex-dependent relationship was observed between miR-19b expression levels and both PTWP (β = -2.41, P = 0.034) and PTSS (β = -3.01, P = 0.008) development 6 months after motor vehicle collision. The relationship between miR-19b and PTSS (but not PTWP) was validated in sexual assault survivors (β = -0.91, P = 0.013). Sex-dependent expression of miR-19b was also observed in blood and nervous tissue from 2 relevant animal models. Furthermore, in support of increasing evidence indicating a role for the circadian rhythm (CR) in PTWP and PTSS pathogenesis, miR-19b targets were enriched in CR gene transcripts. Human cohort and in vitro analyses assessing miR-19b regulation of key CR transcripts, CLOCK and RORA, supported the potential importance of miR-19b to regulating the CR pathway. Together, these results highlight the potential role that sex-dependent expression of miR-19b might play in PTWP and PTSS development after trauma/stress exposure.
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Wang L, Yi J, Lu LY, Zhang YY, Wang L, Hu GS, Liu YC, Ding JC, Shen HF, Zhao FQ, Huang HH, Liu W. Estrogen-induced circRNA, circPGR, functions as a ceRNA to promote estrogen receptor-positive breast cancer cell growth by regulating cell cycle-related genes. Theranostics 2021; 11:1732-1752. [PMID: 33408778 PMCID: PMC7778588 DOI: 10.7150/thno.45302] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 09/22/2020] [Indexed: 02/05/2023] Open
Abstract
Estrogen and estrogen receptor (ER)-regulated gene transcriptional events have been well known to be involved in ER-positive breast carcinogenesis. Meanwhile, circular RNAs (circRNAs) are emerging as a new family of functional non-coding RNAs (ncRNAs) with implications in a variety of pathological processes, such as cancer. However, the estrogen-regulated circRNA program and the function of such program remain uncharacterized. Methods: CircRNA sequencing (circRNA-seq) was performed to identify circRNAs induced by estrogen, and cell proliferation, colony formation, wound healing, transwell and tumor xenograft experiments were applied to examine the function of estrogen-induced circRNA, circPGR. RNA sequencing (RNA-seq) and ceRNA network analysis wereperformed to identify circPGR's target genes and the microRNA (miRNA) bound to circPGR. Anti-sense oligonucleotide (ASO) was used to assess circPGR's effects on ER-positive breast cancer cell growth. Results: Genome-wide circRNA profiling by circRNA sequencing (circRNA-seq) revealed that a large number of circRNAs were induced by estrogen, and further functional screening for the several circRNAs originated from PGR revealed that one of them, which we named as circPGR, was required for ER-positive breast cancer cell growth and tumorigenesis. CircPGR was found to be localized in the cytosol of cells and functioned as a competing endogenous RNA (ceRNA) to sponge miR-301a-5p to regulate the expression of multiple cell cycle genes. The clinical relevance of circPGR was underscored by its high and specific expression in ER-positive breast cancer cell lines and clinical breast cancer tissue samples. Accordingly, anti-sense oligonucleotide (ASO) targeting circPGR was proven to be effective in suppressing ER-positive breast cancer cell growth. Conclusions: These findings reveled that, besides the well-known messenger RNA (mRNA), microRNA (miRNA), long non-coding RNA (lncRNA) and enhancer RNA (eRNA) programs, estrogen also induced a circRNA program, and exemplified by circPGR, these estrogen-induced circRNAs were required for ER-positive breast cancer cell growth, providing a new class of therapeutic targets for ER-positive breast cancer.
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MESH Headings
- Animals
- Apoptosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Breast Neoplasms/drug therapy
- Breast Neoplasms/genetics
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Cell Cycle
- Cell Cycle Proteins/genetics
- Cell Cycle Proteins/metabolism
- Cell Proliferation
- Estrogens/pharmacology
- Female
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic/drug effects
- Humans
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- MicroRNAs/genetics
- Prognosis
- RNA, Circular/genetics
- Receptors, Estrogen/genetics
- Receptors, Estrogen/metabolism
- Receptors, Progesterone/genetics
- Survival Rate
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Lei Wang
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China
| | - Jia Yi
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China
| | - Ling-yun Lu
- Department of Orthopedics, The Fifth Hospital of Xiamen, Xiamen, Fujian 361101, China
| | - Yue-ying Zhang
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China
| | - Lan Wang
- Department of Pathology, The Second Affiliated Hospital, Shantou University Medical College, Dongxia North Road, Shantou, Guangdong 515041, China
| | - Guo-sheng Hu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China
| | - Yi-chen Liu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China
| | - Jian-cheng Ding
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China
| | - Hai-feng Shen
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China
| | - Fang-qing Zhao
- Computational Genomics Lab, Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China
| | - Hai-hua Huang
- Department of Pathology, The Second Affiliated Hospital, Shantou University Medical College, Dongxia North Road, Shantou, Guangdong 515041, China
| | - Wen Liu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China
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43
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Xu P, Li Z, Wang Y, Yu X, Shao X, Li YX, Peng C, Zhao Y, Wang YL. miR-18a Contributes to Preeclampsia by Downregulating Smad2 (Full Length) and Reducing TGF-β Signaling. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 22:542-556. [PMID: 33230456 PMCID: PMC7566009 DOI: 10.1016/j.omtn.2020.09.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 09/17/2020] [Indexed: 01/07/2023]
Abstract
The study investigated the regulation of Smad2 by miR-18a and its role in preeclampsia (PE). Bioinformatics analysis showed that both Smad2 and Smad3 were the predicted targets for miR-18a. Mass spectrum analysis showed that two mature Smad2 isoforms existed in human placenta: full length, Smad2(FL), and that lacking exon3, Smad2(Δexon3). The protein level of Smad2(FL), but not Smad2(Δexon3) or Smad3, was significantly increased in severe PE (sPE) placenta, which was inversely correlated with the level of miR-18a. Elevated Smad2(FL) phosphorylation level appeared in sPE placenta, and Smad2 was colocalized with miR-18a in various subtypes of trophoblasts in human placenta. Smad2(FL) was validated as the direct target of miR-18a in HTR8/SVneo cells. miR-18a enhanced trophoblast cell invasion, which was blocked by the overexpression of Smad2(FL). Furthermore, overexpression of miR-18a repressed Smad2 activation and the inhibition of trophoblast cell invasion by transforming growth factor-β (TGF-β). In conclusion, our results suggest that miR-18a inhibits the expression of Smad2(FL), but not Smad2(Δexon3) or Smad3, which can reduce TGF-β signaling, leading to the enhancement of trophoblast cell invasion. A lack of miR-18a, which results in the upregulation of Smad2(FL), contributes to the development of PE.
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Affiliation(s)
- Peng Xu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- School of Life Science, Shanxi University, Taiyuan, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Zhilang Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yongqing Wang
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China
| | - Xin Yu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xuan Shao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yu-xia Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Chun Peng
- Department of Biology, York University, Toronto, Ontario, Canada
| | - Yangyu Zhao
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China
| | - Yan-Ling Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing, China
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44
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Kandettu A, Radhakrishnan R, Chakrabarty S, Sriharikrishnaa S, Kabekkodu SP. The emerging role of miRNA clusters in breast cancer progression. Biochim Biophys Acta Rev Cancer 2020; 1874:188413. [PMID: 32827583 DOI: 10.1016/j.bbcan.2020.188413] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 08/01/2020] [Accepted: 08/11/2020] [Indexed: 02/07/2023]
Abstract
Micro RNAs (miRNAs) are small non-coding RNAs that are essential for regulation of gene expression of the target genes. Large number of miRNAs are organized into defined units known as miRNA clusters (MCs). The MCs consist of two or more than two miRNA encoding genes driven by a single promoter, transcribed together in the same orientation, that are not separated from each other by a transcription unit. Aberrant miRNA clusters expression is reported in breast cancer (BC), exhibiting both pro-tumorogenic and anti-tumorigenic role. Altered MCs expression facilitates to breast carcinogenesis by promoting the breast cells to acquire the various hallmarks of the cancer. Since miRNA clusters contain multiple miRNA encoding genes, targeting cluster may be more attractive than targeting individual miRNAs. Besides targeting dysregulated miRNA clusters in BC, studies have focused on the mechanism of action, and its contribution to the progression of the BC. The present review provides a comprehensive overview of dysregulated miRNA clusters and its role in the acquisition of cancer hallmarks in BC. More specifically, we have presented the regulation, differential expression, classification, targets, mechanism of action, and signaling pathways of miRNA clusters in BC. Additionally, we have also discussed the potential utility of the miRNA cluster as a diagnostic and prognostic indicator in BC.
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Affiliation(s)
- Amoolya Kandettu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576106, India
| | - Raghu Radhakrishnan
- Department of Oral Pathology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576106, India; Center for DNA Repair and Genome Stability (CDRGS), Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - S Sriharikrishnaa
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576106, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576106, India; Center for DNA Repair and Genome Stability (CDRGS), Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
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45
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Xu P, Li Z, Wang Y, Yu X, Shao X, Li YX, Peng C, Zhao Y, Wang YL. miR-18a Contributes to Preeclampsia by Downregulating Smad2 (Full Length) and Reducing TGF-β Signaling. MOLECULAR THERAPY - NUCLEIC ACIDS 2020; 22:542-556. [DOI: pmid: 33230456 doi: 10.1016/j.omtn.2020.09.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/17/2025]
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46
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Gil-Zamorano J, Tomé-Carneiro J, Lopez de Las Hazas MC, Del Pozo-Acebo L, Crespo MC, Gómez-Coronado D, Chapado LA, Herrera E, Latasa MJ, Ruiz-Roso MB, Castro-Camarero M, Briand O, Dávalos A. Intestinal miRNAs regulated in response to dietary lipids. Sci Rep 2020; 10:18921. [PMID: 33144601 PMCID: PMC7642330 DOI: 10.1038/s41598-020-75751-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Accepted: 10/08/2020] [Indexed: 02/07/2023] Open
Abstract
The role of miRNAs in intestinal lipid metabolism is poorly described. The small intestine is constantly exposed to high amounts of dietary lipids, and it is under conditions of stress that the functions of miRNAs become especially pronounced. Approaches consisting in either a chronic exposure to cholesterol and triglyceride rich diets (for several days or weeks) or an acute lipid challenge were employed in the search for intestinal miRNAs with a potential role in lipid metabolism regulation. According to our results, changes in miRNA expression in response to fat ingestion are dependent on factors such as time upon exposure, gender and small intestine section. Classic and recent intestinal in vitro models (i.e. differentiated Caco-2 cells and murine organoids) partially mirror miRNA modulation in response to lipid challenges in vivo. Moreover, intestinal miRNAs might play a role in triglyceride absorption and produce changes in lipid accumulation in intestinal tissues as seen in a generated intestinal Dicer1-deletion murine model. Overall, despite some variability between the different experimental cohorts and in vitro models, results show that some miRNAs analysed here are modulated in response to dietary lipids, hence likely to participate in the regulation of lipid metabolism, and call for further research.
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Affiliation(s)
- Judit Gil-Zamorano
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies Food (IMDEA Food), CEI UAM + CSIC, Carretera de Canto Blanco, 8, 28049, Madrid, Spain
| | - João Tomé-Carneiro
- Laboratory of Functional Foods, Madrid Institute for Advanced Studies Food (IMDEA Food), CEI UAM CSIC, 28049, Madrid, Spain
| | - María-Carmen Lopez de Las Hazas
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies Food (IMDEA Food), CEI UAM + CSIC, Carretera de Canto Blanco, 8, 28049, Madrid, Spain
| | - Lorena Del Pozo-Acebo
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies Food (IMDEA Food), CEI UAM + CSIC, Carretera de Canto Blanco, 8, 28049, Madrid, Spain
| | - M Carmen Crespo
- Laboratory of Functional Foods, Madrid Institute for Advanced Studies Food (IMDEA Food), CEI UAM CSIC, 28049, Madrid, Spain
| | - Diego Gómez-Coronado
- Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRYCIS, 28034, Madrid, Spain.,Centre of Biomedical Research in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Luis A Chapado
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies Food (IMDEA Food), CEI UAM + CSIC, Carretera de Canto Blanco, 8, 28049, Madrid, Spain
| | - Emilio Herrera
- Department of Biochemistry and Chemistry, Faculties of Pharmacy and Medicine, Universidad San Pablo CEU, 28668, Madrid, Spain
| | - María-Jesús Latasa
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies Food (IMDEA Food), CEI UAM + CSIC, Carretera de Canto Blanco, 8, 28049, Madrid, Spain
| | - María Belén Ruiz-Roso
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies Food (IMDEA Food), CEI UAM + CSIC, Carretera de Canto Blanco, 8, 28049, Madrid, Spain
| | - Mónica Castro-Camarero
- Servicio de Cirugía Experimental, Hospital Universitario Ramón y Cajal, IRYCIS, 28034, Madrid, Spain
| | - Olivier Briand
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, 59000, France
| | - Alberto Dávalos
- Laboratory of Epigenetics of Lipid Metabolism, Madrid Institute for Advanced Studies Food (IMDEA Food), CEI UAM + CSIC, Carretera de Canto Blanco, 8, 28049, Madrid, Spain.
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47
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Aljaibeji H, Elemam NM, Mohammed AK, Hasswan H, Thahyabat MA, Alkhayyal N, Sulaiman N, Taneera J. Let7b-5p is Upregulated in the Serum of Emirati Patients with Type 2 Diabetes and Regulates Insulin Secretion in INS-1 Cells. Exp Clin Endocrinol Diabetes 2020; 130:22-29. [PMID: 33036033 DOI: 10.1055/a-1261-5282] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Let7b-5p is a member of the Let-7 miRNA family and one of the top expressed miRNAs in human islets that implicated in glucose homeostasis. The levels of Let7b-5p in type 2 diabetes (T2DM) patients or its role in β-cell function is still unclear. In the current study, we measured the serum levels of let7b-5p in Emirati patients with T2DM (with/without complications) and control subjects. Overexpression or silencing of let7b-5p in INS-1 (832/13) cells was performed to investigate the impact on insulin secretion, content, cell viability, apoptosis, and key functional genes. We found that serum levels of let7b-5p are significantly (p<0.05) higher in T2DM-patients or T2DM with complications compared to control subjects. Overexpression of let7b-5p increased insulin content and decreased glucose-stimulated insulin secretion, whereas silencing of let7b-5p reduced insulin content and secretion. Modulation of the expression levels of let7b-5p did not influence cell viability nor apoptosis. Analysis of mRNA and protein expression of hallmark genes in let7b-5p transfected cells revealed a marked dysregulation of Insulin, Pancreatic And Duodenal Homeobox 1 (PDX1), glucokinase (GCK), glucose transporter 2 (GLUT2), and INSR. In conclusion, an appropriate level of let7b-5p is essential to maintain β-cell function and may be regarded as a biomarker for T2DM.
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Affiliation(s)
- Hayat Aljaibeji
- Sharjah Institute for Medical Research, University of Sharjah
| | | | | | - Hind Hasswan
- Sharjah Institute for Medical Research, University of Sharjah
| | | | - Noura Alkhayyal
- Sharjah Institute for Medical Research, University of Sharjah
| | - Nabil Sulaiman
- Department of Family Medicine, College of Medicine, University of Sharjah.,Baker/IDI Heart and Diabetes Institute, Melbourne, Victoria
| | - Jalal Taneera
- Sharjah Institute for Medical Research, University of Sharjah.,Department of Basic Medical Sciences, College of Medicine, University of Sharjah
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48
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Malami I, Bunza AM, Alhassan AM, Muhammad A, Abubakar IB, Yunusa A, Waziri PM, Etti IC. Dihydroartemisinin as a potential drug candidate for cancer therapy: a structural-based virtual screening for multitarget profiling. J Biomol Struct Dyn 2020; 40:1347-1362. [PMID: 32964804 DOI: 10.1080/07391102.2020.1824811] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Cancer is a rapidly growing non-communicable disease worldwide that is responsible for high mortality rates, which account for 9.6 million death in 2018. Dihydroartemisinin (DHA) is an active metabolite of artemisinin, an active principle present in the Chinese medicinal plant Artemisia annua used for malaria treatment. Dihydroartemisinin possesses remarkable and selective anticancer properties however the underlying mechanism of the antitumor effects of DHA from the structural point of view is still not yet elucidated. In the present study, we employed molecular docking simulation techniques using Autodock suits to access the binding properties of dihydroartemisinin to multiple protein targets implicated in cancer pathogenesis. Its potential targets with comprehensive pharmacophore were predicted using a PharmMapper database. The co-crystallised structures of the protein were obtained from a Protein Data Bank and prepared for molecular docking simulation. Out of the 24 selected protein targets, DHA has shown about 29% excellent binding to the targets compared to their co-crystallised ligand. Additionally, 75% of the targets identified for dihydroartemisinin binding are protein kinases, and 25% are non-protein kinases. Hydroxyl functional group of dihydroartemisinin contributed to 58.5% of the total hydrogen interactions, while pyran (12.2%), endoperoxide (9.8%), and oxepane (19.5%) contributed to the remaining hydrogen bonding. The present findings have elucidated the possible antitumor properties of dihydroartemisinin through the structural-based virtual studies, which provides a lead to a safe and effective anticancer agent useful for cancer therapy.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Ibrahim Malami
- Department of Pharmacognosy and Ethnopharmacy, Faculty of Pharmaceutical Sciences, Usmanu Danfodiyo University, Sokoto, Nigeria.,Centre for Advanced Medical Research and Training (CAMRET), Usmanu Danfodiyo University, Sokoto, Nigeria
| | - Aisha Muktar Bunza
- Department of Pharmacognosy and Ethnopharmacy, Faculty of Pharmaceutical Sciences, Usmanu Danfodiyo University, Sokoto, Nigeria
| | - Alhassan Muhammad Alhassan
- Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Usmanu Danfodiyo University, Sokoto, Nigeria
| | - Aliyu Muhammad
- Department of Biochemistry, Faculty of life Sciences, Ahmadu Bello University, Zaria, Nigeria
| | | | - Abdulmajeed Yunusa
- Department of Pharmacology and Therapeutics, College of Health Sciences, Usmanu Danfodiyo University, Sokoto, Nigeria
| | - Peter M Waziri
- Department of Biochemistry, Kaduna State University, Kaduna, Nigeria
| | - Imaobong C Etti
- Department of Pharmacology and Toxicology, University of Uyo, Uyo, Nigeria
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49
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Pontecorvi G, Bellenghi M, Ortona E, Carè A. microRNAs as new possible actors in gender disparities of Covid-19 pandemic. Acta Physiol (Oxf) 2020; 230:e13538. [PMID: 32672403 PMCID: PMC7404333 DOI: 10.1111/apha.13538] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Giada Pontecorvi
- Center for Gender‐Specific Medicine Istituto Superiore di Sanità Rome Italy
| | - Maria Bellenghi
- Center for Gender‐Specific Medicine Istituto Superiore di Sanità Rome Italy
| | - Elena Ortona
- Center for Gender‐Specific Medicine Istituto Superiore di Sanità Rome Italy
| | - Alessandra Carè
- Center for Gender‐Specific Medicine Istituto Superiore di Sanità Rome Italy
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50
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Kolenda T, Guglas K, Kopczyńska M, Sobocińska J, Teresiak A, Bliźniak R, Lamperska K. Good or not good: Role of miR-18a in cancer biology. Rep Pract Oncol Radiother 2020; 25:808-819. [PMID: 32884453 DOI: 10.1016/j.rpor.2020.07.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 04/24/2020] [Accepted: 07/31/2020] [Indexed: 02/06/2023] Open
Abstract
miR-18a is a member of primary transcript called miR-17-92a (C13orf25 or MIR17HG) which also contains five other miRNAs: miR-17, miR-19a, miR-20a, miR-19b and miR-92a. This cluster as a whole shows specific characteristics, where miR-18a seems to be unique. In contrast to the other members, the expression of miR-18a is additionally controlled and probably functions as its own internal controller of the cluster. miR-18a regulates many genes involved in proliferation, cell cycle, apoptosis, response to different kinds of stress, autophagy and differentiation. The disturbances of miR-18a expression are observed in cancer as well as in different diseases or pathological states. The miR-17-92a cluster is commonly described as oncogenic and it is known as 'oncomiR-1', but this statement is a simplification because miR-18a can act both as an oncogene and a suppressor. In this review we summarize the current knowledge about miR-18a focusing on its regulation, role in cancer biology and utility as a potential biomarker.
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Key Words
- 5-FU, 5-fluorouracyl
- ACVR2A, activin A receptor type 2A
- AKT, AKT serine/threonine kinase
- AR, androgen receptor
- ATG7, autophagy related 7
- ATM, ATM serine/threonine kinase
- BAX, BCL2 associated Xapoptosis regulator
- BCL2, BCL2 apoptosis regulator
- BCL2L10, BCL2 like 10
- BDNF, brain derived neurotrophic factor
- BLCA, bladder urothelial carcinoma
- BRCA, breast cancer
- Biomarker
- Bp, base pair
- C-myc (MYCBP), MYC binding protein
- CASC2, cancer susceptibility 2
- CD133 (PROM1), prominin 1
- CDC42, cell division cycle 42
- CDKN1, Bcyclin dependent kinase inhibitor 1B
- COAD, colon adenocarcinoma
- Cancer
- Circulating miRNA
- DDR, DNA damage repair
- E2F family (E2F1, E2F2, E2F3), E2F transcription factors
- EBV, Epstein-Barr virus
- EMT, epithelial-to-mesenchymal transition
- ER, estrogen receptor
- ERBB (EGFR), epidermal growth factor receptor
- ESCA, esophageal carcinoma
- FENDRR, FOXF1 adjacent non-coding developmental regulatory RNA
- FER1L4, fer-1 like family member 4 (pseudogene)
- GAS5, growth arrest–specific 5
- HIF-1α (HIF1A), hypoxia inducible factor 1 subunit alpha
- HNRNPA1, heterogeneous nuclear ribonucleoprotein A1
- HNSC, head and neck squamous cell carcinoma
- HRR, homologous recombination-based DNA repair
- IFN-γ (IFNG), interferon gamma
- IGF1, insulin like growth factor 1
- IL6, interleukin 6
- IPMK, inositol phosphate multikinase
- KIRC, clear cell kidney carcinoma
- KIRP, kidney renal papillary cell carcinoma
- KRAS, KRAS proto-oncogene, GTPase
- LIHC, liver hepatocellular carcinoma
- LMP1, latent membrane protein 1
- LUAD, lung adenocarcinoma
- LUSC, lung squamous cell carcinoma
- Liquid biopsy
- MAPK, mitogen-activated protein kinase
- MCM7, minichromosome maintenance complex component 7
- MET, mesenchymal-to-epithelial transition
- MTOR, mechanistic target of rapamycin kinase
- N-myc (MYCN), MYCN proto-oncogene, bHLH transcription factor
- NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells
- NOTCH2, notch receptor 2
- Oncogene
- PAAD, pancreatic adenocarcinoma
- PERK (EIF2AK3), eukaryotic translation initiation factor 2 alpha kinase 3
- PI3K (PIK3CA), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
- PIAS3, protein inhibitor of activated STAT 3
- PRAD, prostate adenocarcinoma
- RISC, RNA-induced silencing complex
- SMAD2, SMAD family member 2
- SMG1, SMG1 nonsense mediated mRNA decay associated PI3K related kinase
- SNHG1, small nucleolar RNA host gene 1
- SOCS5, suppressor of cytokine signaling 5
- STAD, stomach adenocarcinoma
- STAT3, signal transducer and activator of transcription 3
- STK4, serine/threonine kinase 4
- Suppressor
- TCGA
- TCGA, The Cancer Genome Atlas
- TGF-β (TGFB1), transforming growth factor beta 1
- TGFBR2, transforming growth factor beta receptor 2
- THCA, papillary thyroid carcinoma
- TNM, Classification of Malignant Tumors: T - tumor / N - lymph nodes / M – metastasis
- TP53, tumor protein p53
- TP53TG1, TP53 target 1
- TRIAP1, p53-regulating inhibitor of apoptosis gene
- TSC1, TSC complex subunit 1
- UCA1, urothelial cancer associated 1
- UCEC, uterine corpus endometrial carcinoma
- UTR, untranslated region
- WDFY3-AS2, WDFY3 antisense RNA 2
- WEE1, WEE1 G2 checkpoint kinase
- WNT family, Wingless-type MMTV integration site family/Wnt family ligands
- ZEB1/ZEB2, zinc finger E-box binding homeobox 1 and 2
- ceRNA, competitive endogenous RNA
- cncRNA, protein coding and non-coding RNA
- lncRNA, long-non coding RNA
- miR-17-92a
- miR-18a
- miRNA
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Affiliation(s)
- Tomasz Kolenda
- Laboratory of Cancer Genetics, Greater Poland Cancer Centre, Poznan, Poland.,Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland.,Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warszawa, Poland
| | - Kacper Guglas
- Laboratory of Cancer Genetics, Greater Poland Cancer Centre, Poznan, Poland.,Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warszawa, Poland
| | - Magda Kopczyńska
- Laboratory of Cancer Genetics, Greater Poland Cancer Centre, Poznan, Poland.,Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland
| | - Joanna Sobocińska
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland
| | - Anna Teresiak
- Laboratory of Cancer Genetics, Greater Poland Cancer Centre, Poznan, Poland
| | - Renata Bliźniak
- Laboratory of Cancer Genetics, Greater Poland Cancer Centre, Poznan, Poland
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