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Liu S, Wu H, Zhang P, Zhou H, Wu D, Jin Y, Yang H, Xing R, Wu Y, Wu G. NELL2 suppresses epithelial-mesenchymal transition and induces ferroptosis via notch signaling pathway in HCC. Sci Rep 2025; 15:10193. [PMID: 40133552 PMCID: PMC11937300 DOI: 10.1038/s41598-025-94669-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 03/17/2025] [Indexed: 03/27/2025] Open
Abstract
Although various malignant tumors have been associated with the aberrant expression of Neural Epidermal Growth Factor-Like 2 (NELL2), its involvement in hepatocellular carcinoma (HCC) has not been previously documented. In this study, NELL2, recognized as a crucial tumor-suppressor gene, was found to be infrequently expressed in HCC. In vitro experiments demonstrated that the overexpression of NELL2 significantly inhibited the proliferation, migration, and invasion of liver cancer cells, whereas the suppression of NELL2 markedly enhanced these oncogenic properties. Further investigation revealed that NELL2 impedes epithelial-mesenchymal transition (EMT) via the Notch signaling pathway. Inhibition of the Notch pathway reversed the increased tumor proliferation, migration, and invasion observed following the downregulation of NELL2 expression. Notably, gene enrichment analysis and in vitro studies indicated that NELL2 effectively induced ferroptosis in HCC cells, as evidenced by increased levels of cellular malondialdehyde (MDA), iron, and Reactive Oxygen Species (ROS), alongside decreased glutathione (GSH) levels. The blockade of the Notch signaling pathway substantially diminished NELL2's capacity to induce ferroptosis. In summary, our findings suggest that NELL2 modulates the Notch signaling pathway to inhibit EMT and promote ferroptosis. Consequently, NELL2 may serve as a novel therapeutic target, potentially functioning as a tumor suppressor gene in HCC.
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Affiliation(s)
- Shiqi Liu
- Hepatobiliary Surgery Department, First Hospital of China Medical University, No.155, Nanjingbei Street, Shenyang, 110001, Liaoning, People's Republic of China
- Key Laboratory of General Surgery of Liaoning Province, First Hospital of China Medical University, No.155, Nanjingbei Street, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Haomin Wu
- Hepatobiliary Surgery Department, First Hospital of China Medical University, No.155, Nanjingbei Street, Shenyang, 110001, Liaoning, People's Republic of China
- Key Laboratory of General Surgery of Liaoning Province, First Hospital of China Medical University, No.155, Nanjingbei Street, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Pengjie Zhang
- Hepatobiliary Surgery Department, First Hospital of China Medical University, No.155, Nanjingbei Street, Shenyang, 110001, Liaoning, People's Republic of China
| | - Haonan Zhou
- Hepatobiliary Surgery Department, First Hospital of China Medical University, No.155, Nanjingbei Street, Shenyang, 110001, Liaoning, People's Republic of China
| | - Di Wu
- Hepatobiliary Surgery Department, First Hospital of China Medical University, No.155, Nanjingbei Street, Shenyang, 110001, Liaoning, People's Republic of China
| | - Yifan Jin
- Hepatobiliary Surgery Department, First Hospital of China Medical University, No.155, Nanjingbei Street, Shenyang, 110001, Liaoning, People's Republic of China
- Key Laboratory of General Surgery of Liaoning Province, First Hospital of China Medical University, No.155, Nanjingbei Street, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Hongwei Yang
- Hepatobiliary Surgery Department, First Hospital of China Medical University, No.155, Nanjingbei Street, Shenyang, 110001, Liaoning, People's Republic of China
- Key Laboratory of General Surgery of Liaoning Province, First Hospital of China Medical University, No.155, Nanjingbei Street, Shenyang, 110001, Liaoning Province, People's Republic of China
| | - Ruilin Xing
- Hepatobiliary Surgery Department, First Hospital of China Medical University, No.155, Nanjingbei Street, Shenyang, 110001, Liaoning, People's Republic of China
| | - Yubo Wu
- Hepatobiliary Surgery Department, First Hospital of China Medical University, No.155, Nanjingbei Street, Shenyang, 110001, Liaoning, People's Republic of China
| | - Gang Wu
- Hepatobiliary Surgery Department, First Hospital of China Medical University, No.155, Nanjingbei Street, Shenyang, 110001, Liaoning, People's Republic of China.
- Key Laboratory of General Surgery of Liaoning Province, First Hospital of China Medical University, No.155, Nanjingbei Street, Shenyang, 110001, Liaoning Province, People's Republic of China.
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Hu Y, Setayesh T, Wei D, Testerman T, Ji Y, Wan YJY. Multi-pathway targeted therapy of MASH-HCC using miR-22. Cell Biosci 2025; 15:20. [PMID: 39953622 PMCID: PMC11829531 DOI: 10.1186/s13578-025-01352-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 01/13/2025] [Indexed: 02/17/2025] Open
Abstract
BACKGROUND The treatment options for hepatocellular carcinoma (HCC) are limited, and there is no effective drug that can improve long-term survival rates. Complicated cocktails consisting of multiple medications with toxicities are frequently used to treat cancer. The current study addresses these challenges. METHODS The study uses metabolic dysfunction-associated steatohepatitis (MASH)-HCC and HCC mouse models established by transfecting the livers using myr-AKT1, NRasV12, and Sleeping Beauty transposase. AAV8-miR-22 was delivered to MASH-HCC and HCC to study its preventive and therapeutic effects. Spatial transcriptomic profiling revealed the signaling pathways affected by miR-22 according to histological locations. RESULTS miR-22 treatment effectively treated MASH-HCC and HCC. Treating mice with miR-22 before tumor initiation prevented oncogenesis. The promising anti-cancer effects were revealed by reduced tumor load, fibrosis, and splenomegaly, extending the survival time. miR-22 treatment generated anti-tumor immunity. The favorable treatment outcomes were accompanied by a reduction in dendritic cells, T and B cells, and plasma cells, which were expanded inside the tumors of MASH-HCC. In all animal trials, miR-22 improved metabolism and reduced glycolysis inside the tumors. Moreover, miR-22 profoundly inhibited extracellular matrix (ECM) and targeted MET, PDGF, tyrosine kinase signaling, and IGF pathways inside the tumors. Furthermore, the roles of miR-22 in blocking collagen formation and cross-assembly of collagen fibrils could be due to miR-22's effects in inhibiting Rho GTPase pathways, revealed at the tumor margin. CONCLUSION miR-22 generates anti-HCC effects by targeting many critical pathways in liver carcinogenesis in cancer and tumorigenic niches, potentially revolutionizing HCC treatment.
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Affiliation(s)
- Ying Hu
- Department of Pathology and Laboratory Medicine, Research Building III, University of California Davis Health, Room 3400B, 4645 2nd Ave, Sacramento, CA, 95817, USA
| | - Tahereh Setayesh
- Department of Pathology and Laboratory Medicine, Research Building III, University of California Davis Health, Room 3400B, 4645 2nd Ave, Sacramento, CA, 95817, USA
| | - Dongguang Wei
- Department of Pathology and Laboratory Medicine, Research Building III, University of California Davis Health, Room 3400B, 4645 2nd Ave, Sacramento, CA, 95817, USA
| | - Trenton Testerman
- Department of Pathology and Laboratory Medicine, Research Building III, University of California Davis Health, Room 3400B, 4645 2nd Ave, Sacramento, CA, 95817, USA
| | - Yutong Ji
- Department of Pathology and Laboratory Medicine, Research Building III, University of California Davis Health, Room 3400B, 4645 2nd Ave, Sacramento, CA, 95817, USA
| | - Yu-Jui Yvonne Wan
- Department of Pathology and Laboratory Medicine, Research Building III, University of California Davis Health, Room 3400B, 4645 2nd Ave, Sacramento, CA, 95817, USA.
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Dallavalasa S, Tulimilli SV, Bettada VG, Karnik M, Uthaiah CA, Anantharaju PG, Nataraj SM, Ramashetty R, Sukocheva OA, Tse E, Salimath PV, Madhunapantula SV. Vitamin D in Cancer Prevention and Treatment: A Review of Epidemiological, Preclinical, and Cellular Studies. Cancers (Basel) 2024; 16:3211. [PMID: 39335182 PMCID: PMC11430526 DOI: 10.3390/cancers16183211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 09/12/2024] [Accepted: 09/17/2024] [Indexed: 09/30/2024] Open
Abstract
Inhibition of human carcinomas has previously been linked to vitamin D due to its effects on cancer cell proliferation, migration, angiogenesis, and apoptosis induction. The anticancer activity of vitamin D has been confirmed by several studies, which have shown that increased cancer incidence is associated with decreased vitamin D and that dietary supplementation of vitamin D slows down the growth of xenografted tumors in mice. Vitamin D inhibits the growth of cancer cells by the induction of apoptosis as well as by arresting the cells at the G0/G1 (or) G2/M phase of the cell cycle. Aim and Key Scientific Concepts of the Review: The purpose of this article is to thoroughly review the existing information and discuss and debate to conclude whether vitamin D could be used as an agent to prevent/treat cancers. The existing empirical data have demonstrated that vitamin D can also work in the absence of vitamin D receptors (VDRs), indicating the presence of multiple mechanisms of action for this sunshine vitamin. Polymorphism in the VDR is known to play a key role in tumor cell metastasis and drug resistance. Although there is evidence that vitamin D has both therapeutic and cancer-preventive properties, numerous uncertainties and concerns regarding its use in cancer treatment still exist. These include (a) increased calcium levels in individuals receiving therapeutic doses of vitamin D to suppress the growth of cancer cells; (b) hyperglycemia induction in certain vitamin D-treated study participants; (c) a dearth of evidence showing preventive or therapeutic benefits of cancer in clinical trials; (d) very weak support from proof-of-principle studies; and (e) the inability of vitamin D alone to treat advanced cancers. Addressing these concerns, more potent and less toxic vitamin D analogs have been created, and these are presently undergoing clinical trial evaluation. To provide key information regarding the functions of vitamin D and VDRs, this review provided details of significant advancements in the functional analysis of vitamin D and its analogs and VDR polymorphisms associated with cancers.
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Affiliation(s)
- Siva Dallavalasa
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST Supported Center and ICMR Collaborating Center of Excellence—ICMR-CCoE), Department of Biochemistry (DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru 570015, Karnataka, India; (S.D.); (S.V.T.); (V.G.B.); (M.K.); (C.A.U.); (P.G.A.); (S.M.N.)
| | - SubbaRao V. Tulimilli
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST Supported Center and ICMR Collaborating Center of Excellence—ICMR-CCoE), Department of Biochemistry (DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru 570015, Karnataka, India; (S.D.); (S.V.T.); (V.G.B.); (M.K.); (C.A.U.); (P.G.A.); (S.M.N.)
| | - Vidya G. Bettada
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST Supported Center and ICMR Collaborating Center of Excellence—ICMR-CCoE), Department of Biochemistry (DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru 570015, Karnataka, India; (S.D.); (S.V.T.); (V.G.B.); (M.K.); (C.A.U.); (P.G.A.); (S.M.N.)
| | - Medha Karnik
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST Supported Center and ICMR Collaborating Center of Excellence—ICMR-CCoE), Department of Biochemistry (DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru 570015, Karnataka, India; (S.D.); (S.V.T.); (V.G.B.); (M.K.); (C.A.U.); (P.G.A.); (S.M.N.)
| | - Chinnappa A. Uthaiah
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST Supported Center and ICMR Collaborating Center of Excellence—ICMR-CCoE), Department of Biochemistry (DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru 570015, Karnataka, India; (S.D.); (S.V.T.); (V.G.B.); (M.K.); (C.A.U.); (P.G.A.); (S.M.N.)
| | - Preethi G. Anantharaju
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST Supported Center and ICMR Collaborating Center of Excellence—ICMR-CCoE), Department of Biochemistry (DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru 570015, Karnataka, India; (S.D.); (S.V.T.); (V.G.B.); (M.K.); (C.A.U.); (P.G.A.); (S.M.N.)
| | - Suma M. Nataraj
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST Supported Center and ICMR Collaborating Center of Excellence—ICMR-CCoE), Department of Biochemistry (DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru 570015, Karnataka, India; (S.D.); (S.V.T.); (V.G.B.); (M.K.); (C.A.U.); (P.G.A.); (S.M.N.)
| | - Rajalakshmi Ramashetty
- Department of Physiology, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru 570015, Karnataka, India;
| | - Olga A. Sukocheva
- Department of Hepatology, Royal Adelaide Hospital, Port Rd., Adelaide, SA 5000, Australia;
| | - Edmund Tse
- Department of Hepatology, Royal Adelaide Hospital, Port Rd., Adelaide, SA 5000, Australia;
| | | | - SubbaRao V. Madhunapantula
- Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory (DST-FIST Supported Center and ICMR Collaborating Center of Excellence—ICMR-CCoE), Department of Biochemistry (DST-FIST Supported Department), JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru 570015, Karnataka, India; (S.D.); (S.V.T.); (V.G.B.); (M.K.); (C.A.U.); (P.G.A.); (S.M.N.)
- Special Interest Group in Cancer Biology and Cancer Stem Cells (SIG-CBCSC), JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru 570015, Karnataka, India
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Pereira F, Fernández-Barral A, Larriba MJ, Barbáchano A, González-Sancho JM. From molecular basis to clinical insights: a challenging future for the vitamin D endocrine system in colorectal cancer. FEBS J 2024; 291:2485-2518. [PMID: 37699548 DOI: 10.1111/febs.16955] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 08/03/2023] [Accepted: 09/11/2023] [Indexed: 09/14/2023]
Abstract
Colorectal cancer (CRC) is one of the most life-threatening neoplasias in terms of incidence and mortality worldwide. Vitamin D deficiency has been associated with an increased risk of CRC. 1α,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the most active vitamin D metabolite, is a pleiotropic hormone that, through its binding to a transcription factor of the nuclear receptor superfamily, is a major regulator of the human genome. 1,25(OH)2D3 acts on colon carcinoma and stromal cells and displays tumor protective actions. Here, we review the variety of molecular mechanisms underlying the effects of 1,25(OH)2D3 in CRC, which affect multiple processes that are dysregulated during tumor initiation and progression. Additionally, we discuss the epidemiological data that associate vitamin D deficiency and CRC, and the most relevant randomized controlled trials of vitamin D3 supplementation conducted in both healthy individuals and CRC patients.
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Affiliation(s)
- Fábio Pereira
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Servicio de Oncología Radioterápica, Complejo Hospitalario Universitario de Ourense, Spain
| | - Asunción Fernández-Barral
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-IdiPAZ (Hospital Universitario La Paz-Universidad Autónoma de Madrid), Spain
| | - María Jesús Larriba
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-IdiPAZ (Hospital Universitario La Paz-Universidad Autónoma de Madrid), Spain
| | - Antonio Barbáchano
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-IdiPAZ (Hospital Universitario La Paz-Universidad Autónoma de Madrid), Spain
| | - José Manuel González-Sancho
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-IdiPAZ (Hospital Universitario La Paz-Universidad Autónoma de Madrid), Spain
- Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain
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Nobutoki T. Vitamin D in tuberous sclerosis complex-associated tumors. Front Pediatr 2024; 12:1392380. [PMID: 38846332 PMCID: PMC11153746 DOI: 10.3389/fped.2024.1392380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 05/10/2024] [Indexed: 06/09/2024] Open
Abstract
Mammalian target of rapamycin inhibitors (mTORi) have been used to treat pediatric tuberous sclerosis complex (TSC)-associated tumors, particularly in cases with contraindications to surgery or difficulties in complete tumor resection. However, some patients experience side effects and tumor regression after discontinuation of the treatment. Therefore, there is an urgent need to develop drugs that can be used in combination with mTORi to increase their efficacy and minimize their side effects. 1,25-Dihydroxyvitamin D3 (1,25-D), which has anticancer properties, may be a promising candidate for adjuvant or alternative therapy because TSC and cancer cells share common mechanisms, including angiogenesis, cell growth, and proliferation. Vitamin D receptor-mediated signaling can be epigenetically modified and plays an important role in susceptibility to 1,25-D. Therefore, vitamin D signaling may be a promising drug target, and in vitro studies are required to evaluate the efficacy of 1,25-D in TSC-associated tumors, brain development, and core symptoms of psychiatric disorders.
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Affiliation(s)
- Tatsuro Nobutoki
- Department of Pediatrics, Social Welfare Aiseikai, Suihoen, Japan
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6
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Hong X, Jiang M, Kho AT, Tiwari A, Guo H, Wang AL, McGeachie MJ, Weiss ST, Tantisira KG, Li J. Circulating miRNAs associate with historical childhood asthma hospitalization in different serum vitamin D groups. Respir Res 2024; 25:118. [PMID: 38459594 PMCID: PMC10921757 DOI: 10.1186/s12931-024-02737-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] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 02/17/2024] [Indexed: 03/10/2024] Open
Abstract
BACKGROUND Vitamin D may help to alleviate asthma exacerbation because of its anti-inflammation effect, but the evidence is inconsistent in childhood asthma. MiRNAs are important mediators in asthma pathogenesis and also excellent non-invasive biomarkers. We hypothesized that circulating miRNAs are associated with asthma exacerbation and modified by vitamin D levels. METHODS We sequenced baseline serum miRNAs from 461 participants in the Childhood Asthma Management Program (CAMP). Logistic regression was used to associate miRNA expression with asthma exacerbation through interaction analysis first and then stratified by vitamin D insufficient and sufficient groups. Microarray from lymphoblastoid B-cells (LCLs) treated by vitamin D or sham of 43 subjects in CAMP were used for validation in vitro. The function of miRNAs was associated with gene modules by weighted gene co-expression network analysis (WGCNA). RESULTS We identified eleven miRNAs associated with asthma exacerbation with vitamin D effect modification. Of which, five were significant in vitamin D insufficient group and nine were significant in vitamin D sufficient group. Six miRNAs, including hsa-miR-143-3p, hsa-miR-192-5p, hsa-miR-151a-5p, hsa-miR-24-3p, hsa-miR-22-3p and hsa-miR-451a were significantly associated with gene modules of immune-related functions, implying miRNAs may mediate vitamin D effect on asthma exacerbation through immune pathways. In addition, hsa-miR-143-3p and hsa-miR-451a are potential predictors of childhood asthma exacerbation at different vitamin D levels. CONCLUSIONS miRNAs are potential mediators of asthma exacerbation and their effects are directly impacted by vitamin D levels.
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Affiliation(s)
- Xiaoning Hong
- Clinical Big Data Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Mingye Jiang
- Clinical Big Data Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Alvin T Kho
- Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA
| | - Anshul Tiwari
- Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Haiyan Guo
- Department of Respiratory and Critical Care Medicine, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Disease, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, China
| | - Alberta L Wang
- Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Michael J McGeachie
- Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Scott T Weiss
- Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Partners Personalized Medicine, Partners Healthcare, Boston, MA, USA
| | - Kelan G Tantisira
- Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
- Department of Pediatrics, Division of Respiratory Medicine, University of California San Diego, La Jolla, CA, USA.
| | - Jiang Li
- Clinical Big Data Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China.
- Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
- Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research, Shenzhen, Guangdong, China.
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Bird RP. Vitamin D and cancer. ADVANCES IN FOOD AND NUTRITION RESEARCH 2024; 109:92-159. [PMID: 38777419 DOI: 10.1016/bs.afnr.2023.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
The role of vitamin D in the prevention of chronic diseases including cancer, has received a great deal of attention during the past few decades. The term "Cancer" represents multiple disease states with varying biological complexities. The strongest link between vitamin D and cancer is provided by ecological and studies like observational, in preclinical models. It is apparent that vitamin D exerts diverse biological responses in a tissue specific manner. Moreover, several human factors could affect bioactivity of vitamin D. The mechanism(s) underlying vitamin D initiated anti-carcinogenic effects are diverse and includes changes at the muti-system levels. The oncogenic environment could easily corrupt the traditional role of vitamin D or could ensure resistance to vitamin D mediated responses. Several researchers have identified gaps in our knowledge pertaining to the role of vitamin D in cancer. Further areas are identified to solidify the role of vitamin D in cancer control strategies.
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Affiliation(s)
- Ranjana P Bird
- School of Health Sciences, University of Northern British Columbia, Prince George, BC, Canada.
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8
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Ferrer-Mayorga G, Muñoz A, González-Sancho JM. Vitamin D and colorectal cancer. FELDMAN AND PIKE'S VITAMIN D 2024:859-899. [DOI: 10.1016/b978-0-323-91338-6.00039-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Prendecka-Wróbel M, Pigoń-Zając D, Sondej D, Grzywna K, Kamińska K, Szuta M, Małecka-Massalska T. Can Dietary Actives Affect miRNAs and Alter the Course or Prevent Colorectal Cancer? Int J Mol Sci 2023; 24:10142. [PMID: 37373289 DOI: 10.3390/ijms241210142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 06/12/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Colorectal cancer is a diet-related cancer. There is much research into the effects of nutrients on the prevention, modulation, and treatment of colorectal cancer. Researchers are trying to find a correlation between epidemiological observations indicating certain dietary components as the originator in the process of developing colorectal cancer, such as a diet rich in saturated animal fats, and dietary components that could eliminate the impact of harmful elements of the daily nutritional routine, i.e., substances such as polyunsaturated fatty acids, curcumin, or resveratrol. Nevertheless, it is very important to understand the mechanisms underlying how food works on cancer cells. In this case, microRNA (miRNA) seems to be a very significant research target. MiRNAs participate in many biological processes connected to carcinogenesis, progression, and metastasis. However, this is a field with development prospects ahead. In this paper, we review the most significant and well-studied food ingredients and their effects on various miRNAs involved in colorectal cancer.
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Affiliation(s)
- Monika Prendecka-Wróbel
- Department of Human Physiology of the Chair of Preclinical Sciences, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland
| | - Dominika Pigoń-Zając
- Department of Human Physiology of the Chair of Preclinical Sciences, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland
| | - Daria Sondej
- Department of Human Physiology of the Chair of Preclinical Sciences, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland
| | - Karolina Grzywna
- Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland
| | - Katarzyna Kamińska
- Department of Human Physiology of the Chair of Preclinical Sciences, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland
| | - Mariusz Szuta
- Chair of Oral Surgery, Jagiellonian University Medical College, 31-155 Kraków, Poland
| | - Teresa Małecka-Massalska
- Department of Human Physiology of the Chair of Preclinical Sciences, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland
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Hu Y, Setayesh T, Vaziri F, Wu X, Hwang ST, Chen X, Yvonne Wan YJ. miR-22 gene therapy treats HCC by promoting anti-tumor immunity and enhancing metabolism. Mol Ther 2023; 31:1829-1845. [PMID: 37143325 PMCID: PMC10277895 DOI: 10.1016/j.ymthe.2023.04.019] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 03/29/2023] [Accepted: 04/28/2023] [Indexed: 05/06/2023] Open
Abstract
MicroRNA-22 (miR-22) can be induced by beneficial metabolites that have metabolic and immune effects, including retinoic acids, bile acids, vitamin D3, and short-chain fatty acids. The tumor suppressor effects of miR-22 have been suggested, but whether miR-22 treats orthotopic hepatocellular carcinoma (HCC) is not established. The role of miR-22 in regulating tumor immunity is also poorly understood. Our data showed that miR-22 delivered by adeno-associated virus serotype 8 effectively treated HCC. Compared with FDA-approved lenvatinib, miR-22 produced better survival outcomes without noticeable toxicity. miR-22 silenced hypoxia-inducible factor 1 (HIF1α) and enhanced retinoic acid signaling in both hepatocytes and T cells. Moreover, miR-22 treatment improved metabolism and reduced inflammation. In the liver, miR-22 reduced the abundance of IL17-producing T cells and inhibited IL17 signaling by reducing the occupancy of HIF1α in the Rorc and Il17a genes. Conversely, increasing IL17 signaling ameliorated the anti-HCC effect of miR-22. Additionally, miR-22 expanded cytotoxic T cells and reduced regulatory T cells (Treg). Moreover, depleting cytotoxic T cells also abolished the anti-HCC effects of miR-22. In patients, miR-22 high HCC had upregulated metabolic pathways and reduced IL17 pro-inflammatory signaling compared with miR-22 low HCC. Together, miR-22 gene therapy can be a novel option for HCC treatment.
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Affiliation(s)
- Ying Hu
- Department of Pathology and Laboratory Medicine, University of California Davis Health, Sacramento, CA 95817, USA
| | - Tahereh Setayesh
- Department of Pathology and Laboratory Medicine, University of California Davis Health, Sacramento, CA 95817, USA
| | - Farzam Vaziri
- Department of Pathology and Laboratory Medicine, University of California Davis Health, Sacramento, CA 95817, USA
| | - Xuesong Wu
- Department of Dermatology, University of California Davis Health, Sacramento, CA 95817, USA
| | - Samuel T Hwang
- Department of Dermatology, University of California Davis Health, Sacramento, CA 95817, USA
| | - Xin Chen
- Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
| | - Yu-Jui Yvonne Wan
- Department of Pathology and Laboratory Medicine, University of California Davis Health, Sacramento, CA 95817, USA.
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11
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Boughanem H, Kompella P, Tinahones FJ, Macias-Gonzalez M. An overview of vitamins as epidrugs for colorectal cancer prevention. Nutr Rev 2023; 81:455-479. [PMID: 36018754 DOI: 10.1093/nutrit/nuac065] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Gene expression altering epigenomic modifications such as DNA methylation, histone modification, and chromosome remodeling is crucial to regulating many biological processes. Several lifestyle factors, such as diet and natural, bioactive food compounds, such as vitamins, modify epigenetic patterns. However, epigenetic dysregulation can increase the risk of many diseases, including cancer. Various studies have provided supporting and contrasting evidence on the relationship between vitamins and cancer risk. Though there is a gap in knowledge about whether dietary vitamins can induce epigenetic modifications in the context of colorectal cancer (CRC), the possibility of using them as epidrugs for CRC treatment is being explored. This is promising because such studies might be informative about the most effective way to use vitamins in combination with DNA methyltransferase inhibitors and other approved therapies to prevent and treat CRC. This review summarizes the available epidemiological and observational studies involving dietary, circulating levels, and supplementation of vitamins and their relationship with CRC risk. Additionally, using available in vitro, in vivo, and human observational studies, the role of vitamins as potential epigenetic modifiers in CRC is discussed. This review is focused on the action of vitamins as modifiers of DNA methylation because aberrant DNA methylation, together with genetic alterations, can induce the initiation and progression of CRC. Although this review presents some studies with promising results, studies with better study designs are necessary. A thorough understanding of the underlying molecular mechanisms of vitamin-mediated epigenetic regulation of CRC genes can help identify effective therapeutic targets for CRC prevention and treatment.
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Affiliation(s)
- Hatim Boughanem
- are with the Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), University of Malaga, Malaga, Spain.,are with the Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Pallavi Kompella
- are with the Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), University of Malaga, Malaga, Spain.,is with the Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA
| | - Francisco J Tinahones
- are with the Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), University of Malaga, Malaga, Spain.,are with the Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Manuel Macias-Gonzalez
- are with the Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), University of Malaga, Malaga, Spain.,are with the Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
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12
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Lawler T, Su T, Cai Q, Steinwandel MD, Zheng W, Blot WJ, Warren Andersen S. Associations between serum vitamin D biomarkers and tumor expression of Ki67, p53, and COX-2 in colorectal cancer cases from the Southern Community Cohort Study. J Steroid Biochem Mol Biol 2023; 225:106201. [PMID: 36210028 PMCID: PMC9993486 DOI: 10.1016/j.jsbmb.2022.106201] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 09/20/2022] [Accepted: 10/04/2022] [Indexed: 11/15/2022]
Abstract
Higher 25-hydroxyvitamin D is associated with lower colorectal cancer (CRC) risk, with limited data from African Americans (AAs), who have greater risk for CRC and 25-hydroxyvitamin D deficiency. In a predominantly AA sample of CRC cases from the Southern Community Cohort Study (SCCS), we report associations between vitamin D biomarkers and tumor expression of proteins implicated in vitamin D's anti-tumorigenic pathways (e.g. proliferation and inflammation) and CRC prognosis. SCCS participants with incident CRC were identified via state cancer registries. Serum 25-hydroxyvitamin D and vitamin D binding protein (VDBP) were measured at enrollment. 'Free' 25-hydroxyvitamin D was calculated via standard equation. Cellular Ki67, p53, and COX-2 were measured from tumor samples and categorized using literature-defined cut-points related to survival. Generalized linear models were used to measure associations between vitamin D exposures, tumor biomarkers, and stage. In total, 104 cases (40-79 years) were analyzed. 25-hydroxyvitamin D was not associated with high Ki67 (odds ratio (OR) per 1-standard deviation (SD) increase [95% confidence interval] 1.35[0.86-2.11]), p53 (0.75[0.47-1.20]), or COX-2 expression (1.25[0.78-2.01]), or metastatic disease (1.04[0.59-1.81]). Mean biomarker expression was unrelated to 25-hydroxyvitamin D (p-trend ≥.09). Null associations were observed for VDBP and free 25-hydroxyvitamin D. In AAs (n = 70), higher VDBP was associated with lower odds of high Ki67 expression (0.53[0.28-0.98], p-trend =.04). In conclusion, we observed no associations between 25-hydroxyvitamin D and prognostic marker expression in CRC. An inverse association between VDBP and tumor Ki67 in AAs is consistent with reports showing relationships with reduced CRC mortality.
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Affiliation(s)
- Thomas Lawler
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Timothy Su
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Qiuyin Cai
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Mark D Steinwandel
- International Epidemiology Field Station, Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - William J Blot
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA; International Epidemiology Field Station, Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Shaneda Warren Andersen
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA; Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA; School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA.
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13
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Vitamin-D ameliorates sepsis-induced acute lung injury via augmenting miR-149-5p and downregulating ER stress. J Nutr Biochem 2022; 110:109130. [PMID: 35988833 DOI: 10.1016/j.jnutbio.2022.109130] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 06/10/2022] [Accepted: 07/25/2022] [Indexed: 01/13/2023]
Abstract
Acute lung injury is a life-threatening medical problem induced by sepsis or endotoxins and may be associated with enhanced Endoplasmic reticulum stress (ER stress). Vitamin-D (Vit-D) possesses an anti-inflammatory effect; however, this specific mechanism on acute lung injury is still unknown. Here we scrutinize the mechanism of Vit-D on Acute lung injury (ALI) models and explored the Vit-D augmented miRNA's role in regulating the ER stress pathway in ALI. Sepsis was induced by CLP, and Endotoxemia was caused by lipopolysaccharide (LPS). We found that Vit-D alleviates pulmonary edema, improves lung histoarchitecture, infiltration of neutrophils, endothelial barrier in mice, and improves ER stress markers Activating Transcription Factor 6 (ATF6) and CHOP (C/EBP Homologous Protein) expression elevated by CLP/LPS induce ALI. Vit-D decreases the nitric oxide production and ATF6 in macrophages induced by LPS. Vit-D augments miR (miR-149-5p) in LPS-induce macrophages, CLP, and LPS-induced ALI models. Vit-D enhanced miRNA-149-5p when overexpressed, inhibited ER-specific ATF6 inflammatory pathway in LPS-stimulated macrophages, and improved histoarchitecture of the lung in LPS/CLP-induced mice models. This vitro and vivo studies demonstrate that Vit-D could improve ALI induced by CLP/LPS. In this regard, miR-149-5p may play a crucial role in vitamin-D inhibiting LPS/CLP induce ALI. The mechanism might be an association of increased miR-149-5p and its regulated gene target ATF6, and downstream CHOP proteins were suppressed. Thus, these findings demonstrate that the anti-inflammatory effect of Vit-D is achieved by augmentation of miRNA-149-5p expression, which may be a key physiologic mediator in the prevention and treatment of ALI.
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14
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Khayami R, Goltzman D, Rabbani SA, Kerachian MA. Epigenomic effects of vitamin D in colorectal cancer. Epigenomics 2022; 14:1213-1228. [PMID: 36325830 DOI: 10.2217/epi-2022-0288] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Vitamin D regulates a plethora of physiological processes in the human body and has been proposed to exert several anticancer effects. Epigenetics plays an important role in regulating vitamin D actions. In this review, we highlight the recent advances in the understanding of different epigenetic factors such as lncRNAs, miRNAs, methylation and acetylation influenced by vitamin D and its downstream targets in colorectal cancer to find more potential therapeutic targets. We discuss how vitamin D exerts anticancer properties through interactions between the vitamin D receptor and genes (e.g., SLC30A10), the microenvironment, microbiota and other factors in colorectal cancer. Developing therapeutic approaches targeting the vitamin D signaling system will be aided by a better knowledge of the epigenetic impact of vitamin D.
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Affiliation(s)
- Reza Khayami
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - David Goltzman
- Department of Medicine, McGill University Health Center, Montreal, QC, H3G 1A4, Canada
| | - Shafaat A Rabbani
- Department of Medicine, McGill University Health Center, Montreal, QC, H3G 1A4, Canada
| | - Mohammad Amin Kerachian
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, On, H3A 1A4, Canada
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15
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A long non-coding RNA as a direct vitamin D target transcribed from the anti-sense strand of the human HSD17B2 locus. Biosci Rep 2022; 42:231267. [PMID: 35510872 PMCID: PMC9142830 DOI: 10.1042/bsr20220321] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/20/2022] [Accepted: 05/03/2022] [Indexed: 11/29/2022] Open
Abstract
Vitamin D (VD) exerts a wide variety of actions via gene regulation mediated by the nuclear vitamin D receptor (VDR) under physiological and pathological settings. However, the known target genes of VDR appear unlikely to account for all VD actions. We used in silico and transcriptomic approaches in human cell lines to search for non-coding RNAs transcriptionally regulated by VD directly. Four long non-coding RNAs (lncRNAs), but no microRNAs (miRNAs), were found, supported by the presence of consensus VDR-binding motifs in the coding regions. One of these lncRNAs (AS-HSD17β2) is transcribed from the antisense strand of the HSD17β2 locus, which is also a direct VD target. AS-HSD17β2 attenuated HSD17β2 expression. Thus, AS-HSD17β2 represents a direct lncRNA target of VD.
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16
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Matusiewicz M, Marczak K, Kwiecińska B, Kupis J, Zglińska K, Niemiec T, Kosieradzka I. Effect of extracts from eggs of Helix aspersa maxima and Helix aspersa aspersa snails on Caco-2 colon cancer cells. PeerJ 2022; 10:e13217. [PMID: 35433131 PMCID: PMC9012176 DOI: 10.7717/peerj.13217] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 03/14/2022] [Indexed: 01/12/2023] Open
Abstract
Background Colorectal cancer is the third most commonly diagnosed cancer. Natural compounds, administered together with conventional chemotherapeutic agent(s) and/or radiotherapy, may be a novel element in the combination therapy of this cancer. Considering the anticancer properties of compounds derived from different tissues of various snail species confirmed earlier, the purpose of the present research was to evaluate the effect of extracts from eggs of Helix aspera maxima and Helix aspersa aspersa snails, and fractions of extracts containing particles of different molecular weights on Caco-2 human epithelial colorectal adenocarcinoma cells. Methods The extracts and fractions were analyzed for antioxidant activity, phenols and total carbohydrates using colorimetric methods. Lipid peroxidation products and glutathione in eggs were also examined using these methods. Crude protein and fat in eggs were determined. Molecular weights of egg proteins and glycoproteins were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Astaxanthin, selected vitamins and amino acids in eggs were measured using liquid chromatography methods, and minerals by emission spectroscopy, mass spectrometry or X-ray fluorescence. The action of extracts on the cell viability was determined by the MTT (methylthiazolyldiphenyl-tetrazolium bromide) test, based on the mitochondrial oxidative activity, after 24 and 72 h of treatment. The influence of fractions on the cell viability was assayed after 24 h. The effect of extracts on the percentage of live and dead cells was evaluated by the trypan blue assay, in which live cells exclude trypan blue, while dead cells take up this dye, after 12, 24, 48 and 72 h of treatment. Their influence on the integrity of cell membranes was determined based on the activity of LDH (lactate dehydrogenase), released from damaged cells, after 24 and 72 h of treatment. Then, the effect of extracts on the content of lipid peroxidation products in cells was examined using colorimetric method, after 24 h of treatment. Their influence on types of cell death was determined by flow cytometry, after this time. Results The extracts and their fractions containing molecules <3 kDa decreased the cell viability, after 24 h of treatment. The extracts reduced the percentage of live cells (also after 48 h), increased the degree of cell membrane damage and the amount of lipid peroxidation products, induced apoptosis and reduced necrosis. Conclusions Antioxidants, phenols, lipid peroxidation products, anticancer peptides, restriction of methionine, appropriate ratio of essential amino acids to non-essential amino acids, vitamin D3, Ca, Mg, S, Cu, Mn, Zn, Se and other bioactive compounds comprised in the extracts and their additive and synergistic effects may have influenced Caco-2 cells. Natural extracts or the chemical compounds contained in them might be used in the combination therapy of colorectal cancer, which requires further research.
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Affiliation(s)
- Magdalena Matusiewicz
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences, Warsaw, Poland
| | - Karolina Marczak
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences, Warsaw, Poland
| | - Barbara Kwiecińska
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences, Warsaw, Poland
| | - Julia Kupis
- Department of Nanobiotechnology, Institute of Biology, Warsaw University of Life Sciences, Warsaw, Poland
| | - Klara Zglińska
- Department of Animal Nutrition, Institute of Animal Sciences, Warsaw University of Life Sciences, Warsaw, Poland
| | - Tomasz Niemiec
- Department of Animal Nutrition, Institute of Animal Sciences, Warsaw University of Life Sciences, Warsaw, Poland
| | - Iwona Kosieradzka
- Department of Animal Nutrition, Institute of Animal Sciences, Warsaw University of Life Sciences, Warsaw, Poland
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17
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Muñoz A, Grant WB. Vitamin D and Cancer: An Historical Overview of the Epidemiology and Mechanisms. Nutrients 2022; 14:1448. [PMID: 35406059 PMCID: PMC9003337 DOI: 10.3390/nu14071448] [Citation(s) in RCA: 138] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 03/28/2022] [Accepted: 03/28/2022] [Indexed: 02/07/2023] Open
Abstract
This is a narrative review of the evidence supporting vitamin D's anticancer actions. The first section reviews the findings from ecological studies of cancer with respect to indices of solar radiation, which found a reduced risk of incidence and mortality for approximately 23 types of cancer. Meta-analyses of observational studies reported the inverse correlations of serum 25-hydroxyvitamin D [25(OH)D] with the incidence of 12 types of cancer. Case-control studies with a 25(OH)D concentration measured near the time of cancer diagnosis are stronger than nested case-control and cohort studies as long follow-up times reduce the correlations due to changes in 25(OH)D with time. There is no evidence that undiagnosed cancer reduces 25(OH)D concentrations unless the cancer is at a very advanced stage. Meta-analyses of cancer incidence with respect to dietary intake have had limited success due to the low amount of vitamin D in most diets. An analysis of 25(OH)D-cancer incidence rates suggests that achieving 80 ng/mL vs. 10 ng/mL would reduce cancer incidence rates by 70 ± 10%. Clinical trials have provided limited support for the UVB-vitamin D-cancer hypothesis due to poor design and execution. In recent decades, many experimental studies in cultured cells and animal models have described a wide range of anticancer effects of vitamin D compounds. This paper will review studies showing the inhibition of tumor cell proliferation, dedifferentiation, and invasion together with the sensitization to proapoptotic agents. Moreover, 1,25-(OH)2D3 and other vitamin D receptor agonists modulate the biology of several types of stromal cells such as fibroblasts, endothelial and immune cells in a way that interferes the apparition of metastases. In sum, the available mechanistic data support the global protective action of vitamin D against several important types of cancer.
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Affiliation(s)
- Alberto Muñoz
- Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, CIBERONC and IdiPAZ, 28029 Madrid, Spain;
| | - William B. Grant
- Sunlight, Nutrition and Health Research Center, P.O. Box 641603, San Francisco, CA 94164-1603, USA
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18
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Dogra P, Ramírez JR, Butner JD, Peláez MJ, Chung C, Hooda-Nehra A, Pasqualini R, Arap W, Cristini V, Calin GA, Ozpolat B, Wang Z. Translational Modeling Identifies Synergy between Nanoparticle-Delivered miRNA-22 and Standard-of-Care Drugs in Triple-Negative Breast Cancer. Pharm Res 2022; 39:511-528. [PMID: 35294699 PMCID: PMC8986735 DOI: 10.1007/s11095-022-03176-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 01/21/2022] [Indexed: 12/29/2022]
Abstract
PURPOSE Downregulation of miRNA-22 in triple-negative breast cancer (TNBC) is associated with upregulation of eukaryotic elongation 2 factor kinase (eEF2K) protein, which regulates tumor growth, chemoresistance, and tumor immunosurveillance. Moreover, exogenous administration of miRNA-22, loaded in nanoparticles to prevent degradation and improve tumor delivery (termed miRNA-22 nanotherapy), to suppress eEF2K production has shown potential as an investigational therapeutic agent in vivo. METHODS To evaluate the translational potential of miRNA-22 nanotherapy, we developed a multiscale mechanistic model, calibrated to published in vivo data and extrapolated to the human scale, to describe and quantify the pharmacokinetics and pharmacodynamics of miRNA-22 in virtual patient populations. RESULTS Our analysis revealed the dose-response relationship, suggested optimal treatment frequency for miRNA-22 nanotherapy, and highlighted key determinants of therapy response, from which combination with immune checkpoint inhibitors was identified as a candidate strategy for improving treatment outcomes. More importantly, drug synergy was identified between miRNA-22 and standard-of-care drugs against TNBC, providing a basis for rational therapeutic combinations for improved response CONCLUSIONS: The present study highlights the translational potential of miRNA-22 nanotherapy for TNBC in combination with standard-of-care drugs.
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Affiliation(s)
- Prashant Dogra
- Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, Texas, 77030, USA
- Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, 10065, USA
| | - Javier Ruiz Ramírez
- Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, Texas, 77030, USA
| | - Joseph D Butner
- Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, Texas, 77030, USA
| | - Maria J Peláez
- Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, Texas, 77030, USA
| | - Caroline Chung
- Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, 77030, USA
| | - Anupama Hooda-Nehra
- Rutgers Cancer Institute of New Jersey, Newark, New Jersey, 07101, USA
- Department of Medicine, Division of Hematology/Oncology, Rutgers New Jersey Medical School, Newark, New Jersey, 07103, USA
| | - Renata Pasqualini
- Rutgers Cancer Institute of New Jersey, Newark, New Jersey, 07101, USA
- Department of Radiation Oncology, Division of Cancer Biology, Rutgers New Jersey Medical School, Newark, New Jersey, 07103, USA
| | - Wadih Arap
- Rutgers Cancer Institute of New Jersey, Newark, New Jersey, 07101, USA
- Department of Medicine, Division of Hematology/Oncology, Rutgers New Jersey Medical School, Newark, New Jersey, 07103, USA
| | - Vittorio Cristini
- Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, Texas, 77030, USA
- Department of Imaging Physics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, 77230, USA
- Physiology, Biophysics, and Systems Biology Program, Graduate School of Medical Sciences, Weill Cornell Medicine, New York, New York, 10065, USA
| | - George A Calin
- Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, 77030, USA
| | - Bulent Ozpolat
- Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, 77030, USA
| | - Zhihui Wang
- Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, Texas, 77030, USA.
- Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, 10065, USA.
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19
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Rinninella E, Mele MC, Raoul P, Cintoni M, Gasbarrini A. Vitamin D and colorectal cancer: Chemopreventive perspectives through the gut microbiota and the immune system. Biofactors 2022; 48:285-293. [PMID: 34559412 PMCID: PMC9293134 DOI: 10.1002/biof.1786] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 09/13/2021] [Indexed: 12/14/2022]
Abstract
Vitamin D and its receptor are involved in health and diseases through multiple mechanisms including the immune system and gut microbiota modulations. Gut microbiota variations have huge implications in intestinal and extra-intestinal disorders such as colorectal cancer (CRC). This review highlights the preventive role of vitamin D in colorectal tumorigenesis through the effects on the immune system and gut microbiota modulation. The different associations between vitamin D, gut microbial homeostasis, immune system, and CRC, are dissected. Vitamin D is supposed to exert several chemopreventive effects on CRC including direct antineoplastic mechanisms, the effects on the immune system, and gut microbiota modulation. Large clinical studies with a randomized design, are required to confirm the role of vitamin D in CRC, confirming its key role in the complex interplay between the gut immune system and microbiota.
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Affiliation(s)
- Emanuele Rinninella
- UOC di Nutrizione Clinica, Dipartimento di Scienze Mediche e ChirurgicheFondazione Policlinico Universitario A. Gemelli IRCCSRomeItaly
| | - Maria Cristina Mele
- Dipartimento di Medicina e Chirurgia TraslazionaleUniversità Cattolica Del Sacro CuoreRomeItaly
- UOSD di Nutrizione Avanzata in Oncologia, Dipartimento di Scienze Mediche e ChirurgicheFondazione Policlinico Universitario A. Gemelli IRCCSRomeItaly
| | - Pauline Raoul
- Dipartimento di Medicina e Chirurgia TraslazionaleUniversità Cattolica Del Sacro CuoreRomeItaly
- UOSD di Nutrizione Avanzata in Oncologia, Dipartimento di Scienze Mediche e ChirurgicheFondazione Policlinico Universitario A. Gemelli IRCCSRomeItaly
| | - Marco Cintoni
- Scuola di Specializzazione in Scienza dell'AlimentazioneUniversità di Roma Tor VergataRomeItaly
| | - Antonio Gasbarrini
- Dipartimento di Medicina e Chirurgia TraslazionaleUniversità Cattolica Del Sacro CuoreRomeItaly
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e ChirurgicheFondazione Policlinico Universitario A. Gemelli IRCCSRomeItaly
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20
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Whole Blood Transcriptional Fingerprints of High-Grade Glioma and Longitudinal Tumor Evolution under Carbon Ion Radiotherapy. Cancers (Basel) 2022; 14:cancers14030684. [PMID: 35158950 PMCID: PMC8833402 DOI: 10.3390/cancers14030684] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 01/19/2022] [Accepted: 01/27/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary Particle therapy with carbon ions is a promising novel option for the treatment of recurrent high-grade glioma (rHGG). Lack of initial and sequential biopsies limits the investigation of rHGG evolution under therapy. We hypothesized that peripheral blood transcriptome derived from liquid biopsies (lbx) as a minimal invasive method may provide a useful decision support for identification of glioma grade and provide novel means for longitudinal molecular monitoring of tumor evolution under carbon ion irradiation (CIR). We demonstrate feasibility and report patient, tumor and treatment fingerprints in whole blood transcriptomes of rHGG patients with pre-CIR and three post-CIR time points. Abstract Purpose: To assess the value of whole blood transcriptome data from liquid biopsy (lbx) in recurrent high-grade glioma (rHGG) patients for longitudinal molecular monitoring of tumor evolution under carbon ion irradiation (CIR). Methods: Whole blood transcriptome (WBT) analysis (Illumina HumanHT-12 Expression BeadChips) was performed in 14 patients with rHGG pre re-irradiation (reRT) with CIR and 3, 6 and 9 weeks post-CIR (reRT grade III:5, 36%, IV:9, 64%). Patients were irradiated with 30, 33, 36 GyRBE (n = 5, 6, 3) in 3GyRBE per fraction. Results: WTB analysis showed stable correlation with treatment characteristics and patients tumor grade, indicating a preserved tumor origin specific as well as dynamic transcriptional fingerprints of peripheral blood cells. Initial histopathologic tumor grade was indirectly associated with TMEM173 (STING), DNA-repair (ATM, POLD4) and hypoxia related genes. DNA-repair, chromatin remodeling (LIG1, SMARCD1) and immune response (FLT3LG) pathways were affected post-CIR. Longitudinal WTB fingerprints identified two distinct trajectories of rHGG evolution, characterized by differential and prognostic CRISPLD2 expression pre-CIR. Conclusions: Lbx based WTB analysis holds the potential for molecular stratification of rHGG patients and therapy monitoring. We demonstrate the feasibility of the peripheral blood transcriptome as a sentinel organ for identification of patient, tumor characteristics and CIR specific fingerprints in rHGG.
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Shah S, Iqbal Z, Alharbi MG, Kalra HS, Suri M, Soni N, Okpaleke N, Yadav S, Hamid P. Vitamin D and Gastric Cancer: A Ray of Sunshine? Cureus 2021; 13:e18275. [PMID: 34722053 PMCID: PMC8545571 DOI: 10.7759/cureus.18275] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 09/25/2021] [Indexed: 12/31/2022] Open
Abstract
Gastric cancer (GC) is one of the most aggressive malignancies, currently ranking third among cancers leading to death worldwide. Despite the recent advancements in GC research, it is most often diagnosed during the terminal stages and with limited treatment modalities contributing to its poor prognosis and a lower survival rate. Much research has provided conflicting results between a vitamin D deficient status and the development of GC. Vitamin D is a well-known and essential hormone classically known to regulate calcium and phosphate absorption, enabling adequate mineralization of the skeletal system. However, the function of vitamin D is multidimensional. It possesses unique roles, including acting as antioxidants or immunomodulators while crossing the cell membrane, performing several intracellular functions, participating in gene regulation, and controlling the proliferation and invasion of cancer cells, including those of GC. In light of this, it is imperative to analyze the causes of GC, review the factors that can be used to enhance the effectiveness of treatments, and discover the tools to determine prognosis, reduce mortality, and prevent GC development. In this review, we have summarized recent investigations on multiple associations between vitamin D and GC, emphasizing genetic associations, vitamin D receptors, and the prevalence of hormone deficiency in those developing this aggressive malignancy.
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Affiliation(s)
- Suchitra Shah
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Zafar Iqbal
- Emergency Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Mohammed G Alharbi
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Harjeevan S Kalra
- Internal Medicine/Emergency Medicine/Oncology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Megha Suri
- Pediatrics/Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Nitin Soni
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Nkiruka Okpaleke
- Psychiatry and Behavioral Sciences, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Shikha Yadav
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Pousette Hamid
- Neurology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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22
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Li Z, Zhu Z, Wang Y, Wang Y, Li W, Wang Z, Zhou X, Bao Y. hsa‑miR‑15a‑5p inhibits colon cell carcinoma via targeting CCND1. Mol Med Rep 2021; 24:735. [PMID: 34414457 PMCID: PMC8404101 DOI: 10.3892/mmr.2021.12375] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 02/09/2021] [Indexed: 12/24/2022] Open
Abstract
Colon carcinoma is one of the most common cancers worldwide. Epidemiological studies have revealed that colon cancer is the third leading cause of cancer-related deaths, which is due to the increased incidence and mortality rates. However, the treatment strategies for colon cancer remain unsatisfactory for patients, especially for those with advanced or recurrent colon cancer. Dysregulated microRNAs (miRNAs) are considered to influence tumor development and metastasis. However, the molecular mechanism through which miRNAs affect cancer progression is not yet completely understood. The aim of the present study was to investigate the expression levels of has-miR-15a-5p and its molecular mechanism in colon cell carcinoma. In the present study, the expression levels of hsa-miR-15a-5p were found to be decreased in colon tumor tissues and cancer cell lines. Hsa-miR-15a-5p overexpression inhibited colon cell proliferation and migration. Mechanistically, the G1/S-specific cyclin-D1 (CCND1) gene was predicted as a target of hsa-miR-15a-5p, as evidenced by bioinformatics and dual-luciferase reporter assay analyses. CCND1 overexpression significantly increased the progression of colon cancer. Furthermore, CCND1 was demonstrated to mediate the effects of hsa-miR-15a-5p on colon cancer cells. The present study demonstrated that hsa-miR-15a-5p alleviated the proliferation, migration and invasion of colon cancer by targeting the CCND1 gene, which represents a potential molecular target for the diagnosis and treatment of colon cancer.
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Affiliation(s)
- Zhipeng Li
- Department of Integrated Traditional Chinese and Western Medicine, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Zeyu Zhu
- Department of Orthopedics, Huaian Hospital, Huaian, Jiangsu 223200, P.R. China
| | - Yanjun Wang
- Department of Women's Preventive Health, Huishan No. 2 People's Hospital, Wuxi, Jiangsu 214400, P.R. China
| | - Ying Wang
- Department of Radiotherapy, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Weibing Li
- Department of Integrated Traditional Chinese and Western Medicine, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Zhigang Wang
- Department of Hospital Quality Management, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Xinyuan Zhou
- Department of Gastroenterology, Wuxi Hospital of TCM, Affiliated to Nanjing University of Chinese Medicine, Wuxi, Jiangsu 214000, P.R. China
| | - Yuhua Bao
- Department of Integrated Traditional Chinese and Western Medicine, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
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23
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Vitamin D and the risk for cancer: A molecular analysis. Biochem Pharmacol 2021; 196:114735. [PMID: 34411566 DOI: 10.1016/j.bcp.2021.114735] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/12/2021] [Accepted: 08/12/2021] [Indexed: 02/08/2023]
Abstract
Uncontrolled overgrowth of cells, such as in cancer, is an unavoidable risk in life that affects nearly every second individual in industrialized countries. However, in part this risk can be controlled through lifestyle adjustments, such as the avoidance of smoking, unhealthy diet, obesity, physical inactivity and other cancer risk factors. A low vitaminD status is a risk in particular for cancers of colon, prostate, breast and leukocytes. VitaminD3 is produced non-enzymatically, when the cholesterol precursor 7-dehydrocholesterol is exposed to UV-B from sunlight, i.e., all cholesterol synthesizing species, including humans, can make vitaminD3. VitaminD endocrinology started some 550million years ago, when the metabolite 1α,25-dihydroxyvitaminD3 and the transcription factor vitaminD receptor teamed up for regulating the expression of hundreds of target genes in a multitude of different tissues and cell types. Initially, these genes were focused on the control of energy homeostasis, which later also involved energy-demanding innate and adaptive immunity. Rapidly growing cells of the immune system as well as those of malignant tumors rely on comparable genes and pathways, some of which are modulated by vitaminD. Accordingly, vitaminD has anti-cancer effects both directly via controling the differentiation, proliferation and apoptosis of neoplastic cells as well as indirectly through regulating immune cells that belong to the microenvironment of malignant tumors. This review discusses effects of vitaminD on the epigenome and transcriptome of stromal and tumor cells, inter-individual variations in vitaminD responsiveness and their relation to the prevention and possible therapy of cancer.
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24
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Gallardo Martin E, Cousillas Castiñeiras A. Vitamin D modulation and microRNAs in gastric cancer: prognostic and therapeutic role. Transl Cancer Res 2021; 10:3111-3127. [PMID: 35116620 PMCID: PMC8797897 DOI: 10.21037/tcr-20-2813] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 10/10/2020] [Indexed: 12/11/2022]
Abstract
Gastric adenocarcinoma arises after a complex interaction between the host and environmental factors. Tumor location and TNM are the tools that currently guide treatment decisions. Surgery is the only curative treatment, but relapse is common. After relapse or advanced staged disease survival is poor and systemic treatment has modestly improved survival. An association between sun exposure, vitamin D status and gastric cancer (GC) incidence and mortality has been reported. The molecular differences of the histological subtypes and the new molecular classifications account for the great heterogeneity of this disease and are the basis for the discovery of new therapeutic targets. New prognostic and predictive factors are essential and microRNAs (miRNAs) are endogenous small non-coding RNA molecules with a great potential for diagnosis, prognosis and treatment of cancer. There are hundreds of miRNAs with altered expression in tumor gastric tissue when compared to normal gastric tissue. Many of these miRNAs are associated with clinicopathological variables and survival in patients with GC. Furthermore, the expression of some of these miRNAs with prognostic importance in CG is influenced by vitamin D and others are mediators of some of the actions of this vitamin. This review aims to update the evidence on several miRNAs with prognostic value and therapeutic potential in GC, whose expression may be influenced by vitamin D or may regulate vitamin D signaling.
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Affiliation(s)
- Elena Gallardo Martin
- Medical Oncology Department in Complejo Hospitalario Universitario de Pontevedra, University Hospital of Pontevedra, CP 36001 Pontevedra, Spain
| | - Antia Cousillas Castiñeiras
- Medical Oncology Department in Complejo Hospitalario Universitario de Pontevedra, University Hospital of Pontevedra, CP 36001 Pontevedra, Spain
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25
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Luna-Velez MV, Dijkstra JJ, Heuschkel MA, Smit FP, van de Zande G, Smeets D, Sedelaar JPM, Vermeulen M, Verhaegh GW, Schalken JA. Androgen receptor signalling confers clonogenic and migratory advantages in urothelial cell carcinoma of the bladder. Mol Oncol 2021; 15:1882-1900. [PMID: 33797847 PMCID: PMC8253097 DOI: 10.1002/1878-0261.12957] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 03/31/2021] [Indexed: 12/24/2022] Open
Abstract
Bladder urothelial cell carcinoma (UCC) incidence is about three times higher in men compared with women. There are several indications for the involvement of hormonal factors in the aetiology of UCC. Here, we provide evidence of androgen signalling in UCC progression. Microarray and qPCR analysis revealed that the androgen receptor (AR) mRNA level is upregulated in a subset of UCC cases. In an AR‐positive UCC‐derived cell line model, UM‐UC‐3‐AR, androgen treatment increased clonogenic capacity inducing the formation of big stem cell‐like holoclones, while AR knockdown or treatment with the AR antagonist enzalutamide abrogated this clonogenic advantage. Additionally, blockage of AR signalling reduced the cell migration potential of androgen‐stimulated UM‐UC‐3‐AR cells. These phenotypic changes were accompanied by a rewiring of the transcriptome with almost 300 genes being differentially regulated by androgens, some of which correlated with AR expression in UCC patients in two independent data sets. Our results demonstrate that AR signals in UCC favouring the development of an aggressive phenotype and highlights its potential as a therapeutic target for bladder cancer.
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Affiliation(s)
- Maria V Luna-Velez
- Department of Urology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.,Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University, Nijmegen, the Netherlands
| | - Jelmer J Dijkstra
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University, Nijmegen, the Netherlands
| | - Marina A Heuschkel
- Department of Urology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | | | - Guillaume van de Zande
- Department of Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Dominique Smeets
- Department of Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - J P Michiel Sedelaar
- Department of Urology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Michiel Vermeulen
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University, Nijmegen, the Netherlands
| | - Gerald W Verhaegh
- Department of Urology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Jack A Schalken
- Department of Urology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
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26
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Shahrzad MK, Gharehgozlou R, Fadaei S, Hajian P, Mirzaei HR. Vitamin D and Non-coding RNAs: New Insights into the Regulation of Breast Cancer. Curr Mol Med 2021; 21:194-210. [PMID: 32652908 DOI: 10.2174/1566524020666200712182137] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 06/09/2020] [Accepted: 06/11/2020] [Indexed: 11/22/2022]
Abstract
Breast cancer, a life-threatening serious disease with a high incident rate among women, is responsible for thousands of cancer-associated death worldwide. Numerous investigations have evaluated the possible mechanisms related to this malignancy. Among them, non-coding RNAs (ncRNAs), i.e., microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs have recently attracted attention of researchers. In addition to recent studies for evaluating the role of ncRNAs in breast cancer etiology, some investigations have revealed that vitamin D has regulatory and therapeutic roles in breast cancer. Moreover, an important link between vitamin D and ncRNAs in cancer therapy has been highlighted. Herein, the aim of this study was to discuss the available data on the mentioned link in breast cancer.
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Affiliation(s)
- Mohammad Karim Shahrzad
- Department of Internal Medicine and endocrinology, Shohadae Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reyhaneh Gharehgozlou
- Cancer Research Center, Shohada Tajrish Hospital, Department of Radiation Oncology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sara Fadaei
- Department of Internal Medicine and endocrinology, Beheshti University of Medical Sciences, Tehran, Iran
| | - Parastoo Hajian
- Cancer Research Center, Shohada Tajrish Hospital, Department of Radiation Oncology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Reza Mirzaei
- Cancer Research Center, Shohada Tajrish Hospital, Department of Radiation Oncology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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27
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Lin W, Zou H, Mo J, Jin C, Jiang H, Yu C, Jiang Z, Yang Y, He B, Wang K. Micro1278 Leads to Tumor Growth Arrest, Enhanced Sensitivity to Oxaliplatin and Vitamin D and Inhibits Metastasis via KIF5B, CYP24A1, and BTG2, Respectively. Front Oncol 2021; 11:637878. [PMID: 33791222 PMCID: PMC8006274 DOI: 10.3389/fonc.2021.637878] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 02/18/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the most common cancer type in the digestive tract. Chemotherapy drugs, such as oxaliplatin, are frequently administered to CRC patients diagnosed with advanced or metastatic disease. A better understanding of the molecular mechanism underlying CRC tumorigenesis and the identification of optimal biomarkers for assessing chemotherapy sensitivity are essential for the treatment of CRC. Various microRNAs, constituting class of non-coding RNAs with 20-22 nucleotides, have served as oncogenes or tumor suppressors in CRC. We analyzed miR-1278 expression in clinical samples by qRT-PCR. We then explored the role of miR-1278 in CRC growth in vitro and in vivo as well as sensitivity to oxaliplatin via RNA-seq and gain- and loss-of-function assays. We found that miR-1278 was downregulated in CRC samples, correlating with advanced clinical stage, and overexpression of miR-1278 led to tumor growth arrest and increased sensitivity to oxaliplatin via enhanced apoptosis and DNA damage. Suppression of KIF5B by miR-1278 through direct binding to its 3′UTR was the mechanism for the miR-1278-mediated effects in CRC, miR-1278 inhibits metastasis of CRC through upregulation of BTG2. Additionally, we also found that the expression of CYP24A1, the main enzyme determining the biological half-life of calcitriol, was significantly inhibited by miR-1278, according to data from clinical, RNA-seq and functional assays, which allowed miR-1278 to sensitize CRC cells to vitamin D. In summary, our data demonstrated that miR-1278 may serve as a potential tumor suppressor gene and biomarker for determining sensitivity to oxaliplatin and vitamin D in CRC.
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Affiliation(s)
- Weidong Lin
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China.,Taizhou Key Laboratory of General Surgery, Taizhou, China
| | - Heng Zou
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, China
| | - Jinggang Mo
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China.,Taizhou Key Laboratory of General Surgery, Taizhou, China
| | - Chong Jin
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China.,Taizhou Key Laboratory of General Surgery, Taizhou, China
| | - Hao Jiang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China.,Taizhou Key Laboratory of General Surgery, Taizhou, China
| | - Chengyang Yu
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China.,Taizhou Key Laboratory of General Surgery, Taizhou, China
| | - Zufu Jiang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China.,Taizhou Key Laboratory of General Surgery, Taizhou, China
| | - Yusha Yang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China.,Taizhou Key Laboratory of General Surgery, Taizhou, China
| | - Bin He
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China.,Taizhou Key Laboratory of General Surgery, Taizhou, China
| | - Kunpeng Wang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China.,Taizhou Key Laboratory of General Surgery, Taizhou, China
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28
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Vitamin D Effects on Cell Differentiation and Stemness in Cancer. Cancers (Basel) 2020; 12:cancers12092413. [PMID: 32854355 PMCID: PMC7563562 DOI: 10.3390/cancers12092413] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/21/2020] [Accepted: 08/22/2020] [Indexed: 12/14/2022] Open
Abstract
Vitamin D3 is the precursor of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), a pleiotropic hormone that is a major regulator of the human genome. 1,25(OH)2D3 modulates the phenotype and physiology of many cell types by controlling the expression of hundreds of genes in a tissue- and cell-specific fashion. Vitamin D deficiency is common among cancer patients and numerous studies have reported that 1,25(OH)2D3 promotes the differentiation of a wide panel of cultured carcinoma cells, frequently associated with a reduction in cell proliferation and survival. A major mechanism of this action is inhibition of the epithelial–mesenchymal transition, which in turn is largely based on antagonism of the Wnt/β-catenin, TGF-β and EGF signaling pathways. In addition, 1,25(OH)2D3 controls the gene expression profile and phenotype of cancer-associated fibroblasts (CAFs), which are important players in the tumorigenic process. Moreover, recent data suggest a regulatory role of 1,25(OH)2D3 in the biology of normal and cancer stem cells (CSCs). Here, we revise the current knowledge of the molecular and genetic basis of the regulation by 1,25(OH)2D3 of the differentiation and stemness of human carcinoma cells, CAFs and CSCs. These effects support a homeostatic non-cytotoxic anticancer action of 1,25(OH)2D3 based on reprogramming of the phenotype of several cell types.
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29
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Role of vitamin D 3 in selected malignant neoplasms. Nutrition 2020; 79-80:110964. [PMID: 32877827 DOI: 10.1016/j.nut.2020.110964] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 07/14/2020] [Accepted: 07/15/2020] [Indexed: 02/07/2023]
Abstract
Vitamin D3 is a fat-soluble essential nutrient that affects multiple biologic functions in the organism through calcitriol and the vitamin D3 receptor. This review article focuses on the results of studies on the relationship between the level of vitamin D3 and cancer incidence or mortality, but also on the anticancer properties of vitamin D3 that support its significant role in the prevention, clinical course, and overall survival rates of selected cancers (colorectal, prostate, breast, ovarian, endometrial, bladder, and malignant melanoma). The mechanisms of vitamin D3 action involve, among others, polymorphism of vitamin D3 receptor, cell cycle, caspases, and cancer stem cells. The level of vitamin D3 has been also demonstrated to serve as a biomarker in some cancers, and high levels of vitamin D3 can be conducive to successful cancer therapy.
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30
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Carlberg C, Muñoz A. An update on vitamin D signaling and cancer. Semin Cancer Biol 2020; 79:217-230. [DOI: 10.1016/j.semcancer.2020.05.018] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/21/2020] [Accepted: 05/27/2020] [Indexed: 12/15/2022]
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Eldecalcitol (ED-71)-induced exosomal miR-6887-5p suppresses squamous cell carcinoma cell growth by targeting heparin-binding protein 17/fibroblast growth factor-binding protein-1 (HBp17/FGFBP-1). In Vitro Cell Dev Biol Anim 2020; 56:222-233. [PMID: 32185608 DOI: 10.1007/s11626-020-00440-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 02/25/2020] [Indexed: 12/14/2022]
Abstract
Heparin-binding protein 17/fibroblast growth factor-binding protein-1 (HBp17/FGFBP-1) was purified from A431 cell-conditioned media based on its capacity to bind to fibroblast growth factor 1 and 2 (FGF-1 and FGF-2). HBp17/FGFBP-1 has been observed to induce the tumorigenic potential of epithelial cells and is highly expressed in oral cancer cell lines and tissues. HBp17/FGFBP-1 is also recognized as a pro-angiogenic molecule as a consequence of its interaction with FGF-2. We have previously reported that Eldecalcitol (ED-71), an analog of 1α,25(OH)2D3, downregulated the expression of HBp17/FGFBP-1 and inhibited the proliferation of squamous cell carcinoma (SCC) cells in vitro and in vivo through NF-κb inhibition. To explore the possibility of microRNA (miRNA) control of HBp17/FGFBP-1, we analyzed exosomal miRNAs from medium conditioned by A431 cells treated with ED-71. Microarray analysis revealed that 12 exosomal miRNAs were upregulated in ED-71-treated A431 cells. Among them, miR-6887-5p was identified to have a predicted mRNA target matching the 3' untranslated region (3'-UTR) of HBp17/FGFBP-1. The 3'-UTR of HBp17/FGFBP-1 was confirmed to be a direct target of miR-6887-5p in SCC/OSCC cells, as assessed with a luciferase reporter assay. Functional assessment revealed that overexpression of miR-6887-5p in SCC/OSCC cells inhibited cell proliferation and colony formation in vitro, and inhibited tumor growth in vivo compared with control. In conclusion, our present study supports a novel anti-cancer mechanism involving the regulation of HBp17/FGFBP-1 function by exosomal miR-6887-5p in SCC/OSCC cells, which has potential utility as a miRNA-based cancer therapy.
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32
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Zhang Y, Yang M, Zhou P, Yan H, Zhang Z, Zhang H, Qi R, Liu J. β-Hydroxy-β-methylbutyrate-Induced Upregulation of miR-199a-3p Contributes to Slow-To-Fast Muscle Fiber Type Conversion in Mice and C2C12 Cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:530-540. [PMID: 31891490 DOI: 10.1021/acs.jafc.9b05104] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The influence of β-hydroxy-β-methylbutyrate (HMB) on proliferation and differentiation of myogenic cells has been well-studied. However, the role of HMB in myofiber specification and potential mechanisms is largely unknown. Thus, the objective of this research was to explore the role of HMB supplementation in myofiber specification. Results showed that HMB treatment significantly increased the fast MyHC protein level (mice: 1.59 ± 0.08, P < 0.01; C2C12: 2.26 ± 0.11, P < 0.001), decreased the slow MyHC protein level (mice: 0.76 ± 0.05, P < 0.05; C2C12: 0.52 ± 0.02, P < 0.001), and increased the miR-199a-3p level (mice: 4.93 ± 0.37, P < 0.001; C2C12: 11.25 ± 0.57, P < 0.001). Besides, we also observed that HMB promoted the activity of glycolysis-related enzymes and reduced the activities of oxidation-related enzymes in mice and C2C12 cells. Overexpression of miR-199a-3p downregulated the slow MyHC protein level (0.71 ± 0.02, P < 0.01) and upregulated the fast MyHC protein level (2.13 ± 0.09, P < 0.001), while repression of miR-199a-3p exhibited the opposite effect. Target identification results verified that miR-199a-3p targets the 3'UTR of the TEA domain family member 1 (TEAD1) to cause its post-transcriptional inhibition (0.41 ± 0.07, P < 0.01). Knockdown of TEAD1 exhibited a similar effect with miR-199a-3p on myofiber specification. Moreover, suppression of miR-199a-3p blocked slow-to-fast myofiber type transition induced by HMB. Together, our finding revealed that miR-199-3p is induced by HMB and contributes to the action of HMB on slow-to-fast myofiber type conversion via targeting TEAD1.
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Affiliation(s)
- Yong Zhang
- School of Life Science and Engineering , Southwest University of Science and Technology , Mianyang 621010 , China
| | - Min Yang
- Chengdu Agricultural College , Chengdu 611130 , China
| | - Pan Zhou
- School of Life Science and Engineering , Southwest University of Science and Technology , Mianyang 621010 , China
| | - Honglin Yan
- School of Life Science and Engineering , Southwest University of Science and Technology , Mianyang 621010 , China
| | - Zhenzhen Zhang
- School of Life Science and Engineering , Southwest University of Science and Technology , Mianyang 621010 , China
| | - Hongfu Zhang
- School of Life Science and Engineering , Southwest University of Science and Technology , Mianyang 621010 , China
- Institute of Animal Sciences , Chinese Academy of Agricultural Sciences , Beijing 100000 , China
| | - Renli Qi
- Chongqing Academy of Animal Science , Rongchang 402460 , China
| | - Jingbo Liu
- School of Life Science and Engineering , Southwest University of Science and Technology , Mianyang 621010 , China
- Institute of Animal Sciences , Chinese Academy of Agricultural Sciences , Beijing 100000 , China
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Bogusławska J, Popławski P, Alseekh S, Koblowska M, Iwanicka-Nowicka R, Rybicka B, Kędzierska H, Głuchowska K, Hanusek K, Tański Z, Fernie AR, Piekiełko-Witkowska A. MicroRNA-Mediated Metabolic Reprograming in Renal Cancer. Cancers (Basel) 2019; 11:cancers11121825. [PMID: 31756931 PMCID: PMC6966432 DOI: 10.3390/cancers11121825] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 11/15/2019] [Indexed: 02/07/2023] Open
Abstract
Metabolic reprogramming is one of the hallmarks of renal cell cancer (RCC). We hypothesized that altered metabolism of RCC cells results from dysregulation of microRNAs targeting metabolically relevant genes. Combined large-scale transcriptomic and metabolic analysis of RCC patients tissue samples revealed a group of microRNAs that contribute to metabolic reprogramming in RCC. miRNAs expressions correlated with their predicted target genes and with gas chromatography-mass spectrometry (GC-MS) metabolome profiles of RCC tumors. Assays performed in RCC-derived cell lines showed that miR-146a-5p and miR-155-5p targeted genes of PPP (the pentose phosphate pathway) (G6PD and TKT), the TCA (tricarboxylic acid cycle) cycle (SUCLG2), and arginine metabolism (GATM), respectively. miR-106b-5p and miR-122-5p regulated the NFAT5 osmoregulatory transcription factor. Altered expressions of G6PD, TKT, SUCLG2, GATM, miR-106b-5p, miR-155-5p, and miR-342-3p correlated with poor survival of RCC patients. miR-106b-5p, miR-146a-5p, and miR-342-3p stimulated proliferation of RCC cells. The analysis involving >6000 patients revealed that miR-34a-5p, miR-106b-5p, miR-146a-5p, and miR-155-5p are PanCancer metabomiRs possibly involved in global regulation of cancer metabolism. In conclusion, we found that microRNAs upregulated in renal cancer contribute to disturbed expression of key genes involved in the regulation of RCC metabolome. miR-146a-5p and miR-155-5p emerge as a key “metabomiRs” that target genes of crucial metabolic pathways (PPP (the pentose phosphate pathway), TCA cycle, and arginine metabolism).
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Affiliation(s)
- Joanna Bogusławska
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, ul. Marymoncka 99/103, 01-813 Warsaw, Poland; (J.B.); (P.P.); (B.R.); (H.K.); (K.G.); (K.H.)
| | - Piotr Popławski
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, ul. Marymoncka 99/103, 01-813 Warsaw, Poland; (J.B.); (P.P.); (B.R.); (H.K.); (K.G.); (K.H.)
| | - Saleh Alseekh
- Max-Planck Institute of Molecular Plant Physiology, 14476 Potsdam-Golm, Germany; (S.A.); (A.R.F.)
- Center for Plant Systems Biology and Biotechnology, 4000 Plovdiv, Bulgaria
| | - Marta Koblowska
- Laboratory of Systems Biology, Faculty of Biology, University of Warsaw, 02-106 Warsaw, Poland; (M.K.); (R.I.-N.)
- Laboratory for Microarray Analysis, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland
| | - Roksana Iwanicka-Nowicka
- Laboratory of Systems Biology, Faculty of Biology, University of Warsaw, 02-106 Warsaw, Poland; (M.K.); (R.I.-N.)
- Laboratory for Microarray Analysis, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland
| | - Beata Rybicka
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, ul. Marymoncka 99/103, 01-813 Warsaw, Poland; (J.B.); (P.P.); (B.R.); (H.K.); (K.G.); (K.H.)
| | - Hanna Kędzierska
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, ul. Marymoncka 99/103, 01-813 Warsaw, Poland; (J.B.); (P.P.); (B.R.); (H.K.); (K.G.); (K.H.)
| | - Katarzyna Głuchowska
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, ul. Marymoncka 99/103, 01-813 Warsaw, Poland; (J.B.); (P.P.); (B.R.); (H.K.); (K.G.); (K.H.)
| | - Karolina Hanusek
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, ul. Marymoncka 99/103, 01-813 Warsaw, Poland; (J.B.); (P.P.); (B.R.); (H.K.); (K.G.); (K.H.)
| | - Zbigniew Tański
- Masovian Specialist Hospital in Ostroleka, 07-410 Ostroleka, Poland;
| | - Alisdair R. Fernie
- Max-Planck Institute of Molecular Plant Physiology, 14476 Potsdam-Golm, Germany; (S.A.); (A.R.F.)
- Center for Plant Systems Biology and Biotechnology, 4000 Plovdiv, Bulgaria
| | - Agnieszka Piekiełko-Witkowska
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, ul. Marymoncka 99/103, 01-813 Warsaw, Poland; (J.B.); (P.P.); (B.R.); (H.K.); (K.G.); (K.H.)
- Correspondence: ; Tel.: +48-22-5693810
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Montgomery M, Srinivasan A. Epigenetic Gene Regulation by Dietary Compounds in Cancer Prevention. Adv Nutr 2019; 10:1012-1028. [PMID: 31100104 PMCID: PMC6855955 DOI: 10.1093/advances/nmz046] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 03/07/2019] [Accepted: 04/03/2019] [Indexed: 02/06/2023] Open
Abstract
Traditionally, cancer has been viewed as a set of diseases that are driven by the accumulation of genetic mutations, but we now understand that disruptions in epigenetic regulatory mechanisms are prevalent in cancer as well. Unlike genetic mutations, however, epigenetic alterations are reversible, making them desirable therapeutic targets. The potential for diet, and bioactive dietary components, to target epigenetic pathways in cancer is now widely appreciated, but our understanding of how to utilize these compounds for effective chemopreventive strategies in humans is in its infancy. This review provides a brief overview of epigenetic regulation and the clinical applications of epigenetics in cancer. It then describes the capacity for dietary components to contribute to epigenetic regulation, with a focus on the efficacy of dietary epigenetic regulators as secondary cancer prevention strategies in humans. Lastly, it discusses the necessary precautions and challenges that will need to be overcome before the chemopreventive power of dietary-based intervention strategies can be fully harnessed.
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Affiliation(s)
- McKale Montgomery
- Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK,Address correspondence to MM (E-mail: )
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35
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Zhou Z, Li X, Jiang G, Wang J, Qian Y. [Vitamin D down-regulates microRNA-21 expression to promote human placental trophoblast cell migration and invasion in vitro]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2019; 39:437-442. [PMID: 31068287 DOI: 10.12122/j.issn.1673-4254.2019.04.09] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
OBJECTIVE To investigate the effect of vitamin D on microRNA-21(miR-21) expression and migration and invasion of human placental trophoblast cells. METHODS The changes in the expression of miR-21 were detected using RT-qPCR in HTR-8/SVneo cells following stimulation by vitamin D at different doses for 24, 48 and 72 h.HTR-8/SVneo cells transfected with miR-21 mimic or inhibitor with or without vitamin D treatment were examined for changes in cell migration and invasion abilities using Transwell assay, and Western blotting was used to detect protein expressions of E-cadherin, fibronectin, and MMP9. RESULTS Vitamin D obviously inhibited the expression of micoRNA-21 in HTR-8/SVneo cells in a concentration-and time-dependent manner.Transfection with the miR-21 mimic significantly inhibited the migration and invasion of HTR-8/SVneo cells, and this inhibitory effect was abolished by treatment with vitamin D; transfection with miR-21 inhibitor obviously promoted the migration and invasion of HTR-8/SVneo cells, and these effects were not significantly affected by vitamin D treatment. CONCLUSIONS Vitamin D may promote trophoblast cell migration and invasion to accelerate the development of preeclampsia by down-regulating the expression of miR-21.
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Affiliation(s)
- Zhiyi Zhou
- Department of Obstetrics First Affiliated Hospital of Kunming Medical University,, Kunming 650032, China
| | - Xiaojuan Li
- Department of Obstetrics First Affiliated Hospital of Kunming Medical University,, Kunming 650032, China
| | - Guoqing Jiang
- Department of Obstetrics First Affiliated Hospital of Kunming Medical University,, Kunming 650032, China
| | - Jue Wang
- Clinical Laboratory, First Affiliated Hospital of Kunming Medical University, Kunming 650032, China.,Yunnan Provincial Key Laboratory of Laboratory Medicine, Kunming 650032, China.,Yunnan Provincial Institute of Laboratory Diagnosis, Kunming 650032, China
| | - Yuan Qian
- Clinical Laboratory, First Affiliated Hospital of Kunming Medical University, Kunming 650032, China.,Yunnan Provincial Key Laboratory of Laboratory Medicine, Kunming 650032, China.,Yunnan Provincial Institute of Laboratory Diagnosis, Kunming 650032, China
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36
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Xu J, Gu Y, Lewis DF, Cooper DB, McCathran CE, Wang Y. Downregulation of vitamin D receptor and miR-126-3p expression contributes to increased endothelial inflammatory response in preeclampsia. Am J Reprod Immunol 2019; 82:e13172. [PMID: 31323164 DOI: 10.1111/aji.13172] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 06/30/2019] [Accepted: 07/14/2019] [Indexed: 12/12/2022] Open
Abstract
PROBLEM To investigate whether downregulation of miR-126-3p and vitamin D receptor (VDR) expression contributes to increased endothelial inflammatory response in preeclampsia. METHODS OF STUDY Maternal vessel miR-126-3p expression was assessed by in situ hybridization. VDR expression and VCAM-1 expression were determined by immunostaining. Subcutaneous adipose tissue sections from normotensive and preeclamptic pregnant women were used. HUVECs from normotensive deliveries were used to test anti-inflammatory effects of vitamin D and miR-126-3p in endothelial cells (ECs) treated with TNFα in vitro. 1,25(OH)2 D3 was used as bioactive vitamin D. Transient overexpression of miR-126-3p in ECs was induced by transfection of pre-mir-126 precursor. Endothelial VCAM-1 and SOCS-3 expression or production was determined by Western blotting or by ELISA, respectively. RESULTS Reduced VDR and miR-126-3p expression, but increased VCAM-1 expression, was observed in maternal vessel endothelium in tissue sections from women with preeclampsia compared to normotensive pregnant controls. Transient overexpression of miR-126-3p not only attenuated upregulation of VCAM-1 expression and production, but also preserved downregulation of SOCS-3 expression, induced by TNFα in ECs. VDR expression and miR-126-3p expression were significantly upregulated in cells treated with 1,25(OH)2 D3 , but not in cells transfected with VDR siRNA. CONCLUSION Downregulation of VDR and miR-126-3p expression was associated with upregulation of VCAM-1 expression in systemic vessel endothelium in preeclampsia. The finding of increased anti-inflammatory property by 1,25(OH)2 D3 through promotion of VDR and miR-126-3p expression in ECs provide plausible evidence that vitamin D deficiency and downregulation of VDR expression could contribute to increased inflammatory phenotypic changes in maternal vasculature in preeclampsia.
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Affiliation(s)
- Jie Xu
- Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center - Shreveport, Shreveport, LA, USA.,Department of Physiology, Harbin Medical University, Harbin, China
| | - Yang Gu
- Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center - Shreveport, Shreveport, LA, USA
| | - David F Lewis
- Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center - Shreveport, Shreveport, LA, USA
| | - Danielle B Cooper
- Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center - Shreveport, Shreveport, LA, USA
| | - Charles E McCathran
- Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center - Shreveport, Shreveport, LA, USA
| | - Yuping Wang
- Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center - Shreveport, Shreveport, LA, USA
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Provvisiero DP, Negri M, de Angelis C, Di Gennaro G, Patalano R, Simeoli C, Papa F, Ferrigno R, Auriemma RS, De Martino MC, Colao A, Pivonello R, Pivonello C. Vitamin D reverts resistance to the mTOR inhibitor everolimus in hepatocellular carcinoma through the activation of a miR-375/oncogenes circuit. Sci Rep 2019; 9:11695. [PMID: 31406139 PMCID: PMC6690984 DOI: 10.1038/s41598-019-48081-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 07/30/2019] [Indexed: 12/15/2022] Open
Abstract
Primary or acquired resistant mechanisms prevent the employment of individualized therapy with target drugs like the mTOR inhibitor everolimus (EVE) in hepatocellular carcinoma (HCC). The current study evaluated the effect of 1,25(OH)2Vitamin D (VitD) treatment on EVE sensitivity in established models of HCC cell lines resistant to everolimus (EveR). DNA content and colony formation assays, which measure the proliferative index, revealed that VitD pre-treatment re-sensitizes EveR cells to EVE treatment. The evaluation of epithelial and mesenchymal markers by western blot and immunofluorescence showed that VitD restored an epithelial phenotype in EveR cells, in which prolonged EVE treatment induced transition to mesenchymal phenotype. Moreover, VitD treatment prompted hepatic miRNAs regulation, evaluated by liver miRNA finder qPCR array. In particular, miR-375 expression was up-regulated by VitD in EveR cells, in which miR-375 was down-regulated compared to parental cells, with consequent inhibition of oncogenes involved in drug resistance and epithelial-mesenchymal transition (EMT) such as MTDH, YAP-1 and c-MYC. In conclusion, the results of the current study demonstrated that VitD can re-sensitize HCC cells resistant to EVE treatment triggering miR-375 up-regulation and consequently down-regulating several oncogenes responsible of EMT and drug resistance.
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Affiliation(s)
- Donatella Paola Provvisiero
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | - Mariarosaria Negri
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | - Cristina de Angelis
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy.,Dipartimento di Sanità Pubblica, Università Federico II di Napoli, Naples, Italy
| | - Gilda Di Gennaro
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | - Roberta Patalano
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy.,Dipartimento di Sanità Pubblica, Università Federico II di Napoli, Naples, Italy
| | - Chiara Simeoli
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | - Fortuna Papa
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | - Rosario Ferrigno
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | - Renata Simona Auriemma
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | - Maria Cristina De Martino
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | - Annamaria Colao
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | - Rosario Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | - Claudia Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy.
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Zhao Y, Ran Z, Jiang Q, Hu N, Yu B, Zhu L, Shen L, Zhang S, Chen L, Chen H, Jiang J, Chen D. Vitamin D Alleviates Rotavirus Infection through a Microrna-155-5p Mediated Regulation of the TBK1/IRF3 Signaling Pathway In Vivo and In Vitro. Int J Mol Sci 2019; 20:ijms20143562. [PMID: 31330869 PMCID: PMC6678911 DOI: 10.3390/ijms20143562] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 07/09/2019] [Accepted: 07/16/2019] [Indexed: 12/13/2022] Open
Abstract
(1) Background: Vitamin D (VD) plays a vital role in anti-viral innate immunity. However, the role of VD in anti-rotavirus and its mechanism is still unclear. The present study was performed to investigate whether VD alleviates rotavirus (RV) infection through a microRNA-155-5p (miR-155-5p)-mediated regulation of TANK-binding kinase 1 (TBK1)/interferon regulatory factors 3 (IRF3) signaling pathway in vivo and in vitro. (2) Methods: The efficacy of VD treatment was evaluated in DLY pig and IPEC-J2. Dual-luciferase reporter activity assay was performed to verify the role of miR-155-5p in 1α,25-dihydroxy-VD3 (1,25D3) mediating the regulation of the TBK1/IRF3 signaling pathway. (3) Results: A 5000 IU·kg–1 dietary VD3 supplementation attenuated RV-induced the decrease of the villus height and crypt depth (p < 0.05), and up-regulated TBK1, IRF3, and IFN-β mRNA expressions in the jejunum (p < 0.05). Incubation with 1,25D3 significantly decreased the RV mRNA expression and the RV antigen concentration, and increased the TBK1 mRNA and protein levels, and the phosphoprotein IRF3 (p-IRF3) level (p < 0.05). The expression of miR-155-5p was up-regulated in response to an RV infection in vivo and in vitro (p < 0.05). 1,25D3 significantly repressed the up-regulation of miR-155-5p in vivo and in vitro (p < 0.05). Overexpression of miR-155-5p remarkably suppressed the mRNA and protein levels of TBK1 and p-IRF3 (p < 0.01), while the inhibition of miR-155-5p had an opposite effect. Luciferase activity assays confirmed that miR-155-5p regulated RV replication by directly targeting TBK1, and miR-155-5p suppressed the TBK1 protein level (p < 0.01). (4) Conclusions: These results indicate that miR-155-5p is involved in 1,25D3 mediating the regulation of the TBK1/IRF3 signaling pathway by directly targeting TBK1.
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Affiliation(s)
- Ye Zhao
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China.
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Ya'an 625014, China.
| | - Zhiming Ran
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Ya'an 625014, China
- Institute of Animal Nutrition, Sichuan Agricultural University, Ya'an 625014, China
| | - Qin Jiang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Ningming Hu
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Ya'an 625014, China
- Institute of Animal Nutrition, Sichuan Agricultural University, Ya'an 625014, China
| | - Bing Yu
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Ya'an 625014, China
- Institute of Animal Nutrition, Sichuan Agricultural University, Ya'an 625014, China
| | - Li Zhu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Linyuan Shen
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Shunhua Zhang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Lei Chen
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
| | - Hong Chen
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Ya'an 625014, China
- Institute of Animal Nutrition, Sichuan Agricultural University, Ya'an 625014, China
| | - Jun Jiang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China
- Institute of Animal Nutrition, Sichuan Agricultural University, Ya'an 625014, China
| | - Daiwen Chen
- Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Sichuan Agricultural University, Ya'an 625014, China.
- Institute of Animal Nutrition, Sichuan Agricultural University, Ya'an 625014, China.
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MiR-144 inhibits growth and metastasis in colon cancer by down-regulating SMAD4. Biosci Rep 2019; 39:BSR20181895. [PMID: 30745456 PMCID: PMC6395301 DOI: 10.1042/bsr20181895] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 01/10/2019] [Accepted: 01/30/2019] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (MiRs) are thought to display regulator action in tumor suppression and oncogenesis. miR-144 plays an important role in the development of various cancers, such as colorectal cancer, breast cancer, and lung cancer, by targetting different molecules potentially involved in many signaling pathways. SMAD4 is a common signaling during tumor progression, and it can inhibit cell proliferation and promote cell motility in most epithelial cells. The present study focused on the effect of miR-144 and SMAD4 on colon cancer in order to find the novel gene therapy target for the treatment of colon cancer. Quantitative real-time polymerase chain reaction was used to assess the expression level of miR-144 in colon cancer tissues and SW620 cells. MTT assay, scratch test, and transwell assay were used to evaluate cell proliferation, migration, and invasion, respectively. Moreover, luciferase assays were utilized to identify the predictive effect of miR-144 on SMAD4. Western blotting was performed to determine the relative expression of protein related to SMAD4. We found miR-144 level was significantly lower in colon cancer tissues and SW620 cells. Moreover, SMAD4 level, both in mRNA and protein, was obviously elevated in colon cancer tissues. Further, miR-144 mimics treatment inhibited cells proliferation, invasion, and migration. Fluorescence intensity of miR-144 mimics group in wild type cells was decreased. MiR-144 mimics repressed the SMAD4 expression both in mRNA and protein. These findings about miR-144/SMAD4 pair provide a novel therapeutic method for colon cancer patients.
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Sun R, Liu Z, Han L, Yang Y, Wu F, Jiang Q, Zhang H, Ma R, Miao J, He K, Wang X, Zhou D, Huang C. miR‐22 and miR‐214 targeting BCL9L inhibit proliferation, metastasis, and epithelial‐mesenchymal transition by down‐regulating Wnt signaling in colon cancer. FASEB J 2019; 33:5411-5424. [DOI: 10.1096/fj.201801798rr] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Ruifang Sun
- Department of PathologyXi'an Jiaotong University Xi'an China
- Key Laboratory of Environment and Genes Related to DiseasesMinistry of Education of ChinaXi'an Jiaotong University Xi'an China
| | - Zhigang Liu
- Department of Thoracic SurgeryShaanxi Provincial Tumor Hospital Xi'an China
| | - Lin Han
- Department of Cell Biology and GeneticsSchool of Basic Medical SciencesXi'an Jiaotong University Xi'an China
- Key Laboratory of Environment and Genes Related to DiseasesMinistry of Education of ChinaXi'an Jiaotong University Xi'an China
| | - Yang Yang
- Key Laboratory of Environment and Genes Related to DiseasesMinistry of Education of ChinaXi'an Jiaotong University Xi'an China
- School of Public HealthXi'an Jiaotong University Xi'an China
| | - Fei Wu
- Department of Cell Biology and GeneticsSchool of Basic Medical SciencesXi'an Jiaotong University Xi'an China
- Key Laboratory of Environment and Genes Related to DiseasesMinistry of Education of ChinaXi'an Jiaotong University Xi'an China
| | - Qiuyu Jiang
- Department of Cell Biology and GeneticsSchool of Basic Medical SciencesXi'an Jiaotong University Xi'an China
- Key Laboratory of Environment and Genes Related to DiseasesMinistry of Education of ChinaXi'an Jiaotong University Xi'an China
| | | | - Ruili Ma
- School of Basic Medical ScienceXi'an Medical University Xi'an China
| | - Jiyu Miao
- Department of Cell Biology and GeneticsSchool of Basic Medical SciencesXi'an Jiaotong University Xi'an China
- Key Laboratory of Environment and Genes Related to DiseasesMinistry of Education of ChinaXi'an Jiaotong University Xi'an China
| | - Kang He
- Key Laboratory of Environment and Genes Related to DiseasesMinistry of Education of ChinaXi'an Jiaotong University Xi'an China
- Department of PeriodontologyStomatology HospitalXi'an Jiaotong University Xi'an China
| | - Xiaofei Wang
- Department of Cell Biology and GeneticsSchool of Basic Medical SciencesXi'an Jiaotong University Xi'an China
- Key Laboratory of Environment and Genes Related to DiseasesMinistry of Education of ChinaXi'an Jiaotong University Xi'an China
| | - Dangxia Zhou
- Department of PathologyXi'an Jiaotong University Xi'an China
- Key Laboratory of Environment and Genes Related to DiseasesMinistry of Education of ChinaXi'an Jiaotong University Xi'an China
| | - Chen Huang
- Department of Cell Biology and GeneticsSchool of Basic Medical SciencesXi'an Jiaotong University Xi'an China
- Key Laboratory of Environment and Genes Related to DiseasesMinistry of Education of ChinaXi'an Jiaotong University Xi'an China
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine ResearchCollege of StomatologyXi'an Jiaotong University Xi'an China
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Ferrer-Mayorga G, Larriba MJ, Crespo P, Muñoz A. Mechanisms of action of vitamin D in colon cancer. J Steroid Biochem Mol Biol 2019; 185:1-6. [PMID: 29981368 DOI: 10.1016/j.jsbmb.2018.07.002] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 06/20/2018] [Accepted: 07/03/2018] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is the neoplasia that is most frequently associated with vitamin D deficiency in epidemiological and observational studies in terms of incidence and mortality. Many mechanistic studies show that the active vitamin D metabolite (1α,25-dihydroxyvitamin D3 or calcitriol) inhibits proliferation and promotes epithelial differentiation of human colon carcinoma cell lines that express vitamin D receptor (VDR) via the regulation of a high number of genes. A key action underlining this effect is the multilevel inhibition of the Wnt/β-catenin signaling pathway, whose abnormal activation in colon epithelial cells initiates and promotes CRC. Recently, our group has shown that calcitriol modulates gene expression and inhibits protumoral properties of patient-derived colon cancer-associated fibroblasts (CAFs). Accordingly, high VDR expression in tumor stromal fibroblasts is associated with longer survival of CRC patients. Moreover, many types of immune cells express VDR and are regulated by calcitriol, which probably contributes to its action against CRC. Given the role attributed to the intestinal microbiota in CRC and the finding that it is altered by vitamin D deficiency, an indirect antitumoral effect of calcitriol is also plausible at this level. In summary, calcitriol has an array of potential protective effects against CRC by acting on carcinoma cells, CAFs, immune cells and probably also the gut microbiota.
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Affiliation(s)
- Gemma Ferrer-Mayorga
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas - Universidad Autónoma de Madrid, IdiPAZ and CIBERONC, Arturo Duperier, 4, E-28029 Madrid, Spain.
| | - María Jesús Larriba
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas - Universidad Autónoma de Madrid, IdiPAZ and CIBERONC, Arturo Duperier, 4, E-28029 Madrid, Spain.
| | - Piero Crespo
- Instituto de Biomedicina y Biotecnología de Cantabria and CIBERONC, E-39011 Santander, Spain.
| | - Alberto Muñoz
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas - Universidad Autónoma de Madrid, IdiPAZ and CIBERONC, Arturo Duperier, 4, E-28029 Madrid, Spain.
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Leucine promotes porcine myofibre type transformation from fast-twitch to slow-twitch through the protein kinase B (Akt)/forkhead box 1 signalling pathway and microRNA-27a. Br J Nutr 2018; 121:1-8. [DOI: 10.1017/s000711451800301x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
AbstractMuscle fibre types can transform from slow-twitch (slow myosin heavy chain (MyHC)) to fast-twitch (fast MyHC) or vice versa. Leucine plays a vital effect in the development of skeletal muscle. However, the role of leucine in porcine myofibre type transformation and its mechanism are still unclear. In this study, effects of leucine and microRNA-27a (miR-27a) on the transformation of porcine myofibre type were investigatedin vitro. We found that leucine increased slow MyHC protein level and decreased fast MyHC protein level, increased the levels of phospho-protein kinase B (Akt)/Akt and phospho-forkhead box 1 (FoxO1)/FoxO1 and decreased the FoxO1 protein level. However, blocking the Akt/FoxO1 signalling pathway by wortmannin attenuated the role of leucine in porcine myofibre type transformation. Over-expression of miR-27a decreased slow MyHC protein level and increased fast MyHC protein level, whereas inhibition of miR-27a had an opposite effect. We also found that expression of miR-27a was down-regulated following leucine treatment. Moreover, over-expression of miR-27a repressed transformation from fast MyHC to slow MyHC caused by leucine, suggesting that miR-27a is interdicted by leucine and then contributes to porcine muscle fibre type transformation. Our finding provided the first evidence that leucine promotes porcine myofibre type transformation from fast MyHC to slow MyHC via the Akt/FoxO1 signalling pathway and miR-27a.
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Neve B, Jonckheere N, Vincent A, Van Seuningen I. Epigenetic Regulation by lncRNAs: An Overview Focused on UCA1 in Colorectal Cancer. Cancers (Basel) 2018; 10:E440. [PMID: 30441811 PMCID: PMC6266399 DOI: 10.3390/cancers10110440] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 11/06/2018] [Accepted: 11/08/2018] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancers have become the second leading cause of cancer-related deaths. In particular, acquired chemoresistance and metastatic lesions occurring in colorectal cancer are a major challenge for chemotherapy treatment. Accumulating evidence shows that long non-coding (lncRNAs) are involved in the initiation, progression, and metastasis of cancer. We here discuss the epigenetic mechanisms through which lncRNAs regulate gene expression in cancer cells. In the second part of this review, we focus on the role of lncRNA Urothelial Cancer Associated 1 (UCA1) to integrate research in different types of cancer in order to decipher its putative function and mechanism of regulation in colorectal cancer cells. UCA1 is highly expressed in cancer cells and mediates transcriptional regulation on an epigenetic level through the interaction with chromatin modifiers, by direct regulation via chromatin looping and/or by sponging the action of a diversity of miRNAs. Furthermore, we discuss the role of UCA1 in the regulation of cell cycle progression and its relation to chemoresistance in colorectal cancer cells.
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Affiliation(s)
- Bernadette Neve
- Inserm UMR-S 1172, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc), Team "Mucins, Epithelial Differentiation and Carcinogenesis"; University Lille; CHU Lille,59045, Lille CEDEX, France.
| | - Nicolas Jonckheere
- Inserm UMR-S 1172, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc), Team "Mucins, Epithelial Differentiation and Carcinogenesis"; University Lille; CHU Lille,59045, Lille CEDEX, France.
| | - Audrey Vincent
- Inserm UMR-S 1172, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc), Team "Mucins, Epithelial Differentiation and Carcinogenesis"; University Lille; CHU Lille,59045, Lille CEDEX, France.
| | - Isabelle Van Seuningen
- Inserm UMR-S 1172, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc), Team "Mucins, Epithelial Differentiation and Carcinogenesis"; University Lille; CHU Lille,59045, Lille CEDEX, France.
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Malcomson FC. Mechanisms underlying the effects of nutrition, adiposity and physical activity on colorectal cancer risk. NUTR BULL 2018. [DOI: 10.1111/nbu.12359] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Kim DH, Kim KS, Ramakrishna S. NFAT5 promotes in vivo development of murine melanoma metastasis. Biochem Biophys Res Commun 2018; 505:748-754. [PMID: 30293684 DOI: 10.1016/j.bbrc.2018.09.171] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 09/17/2018] [Accepted: 09/26/2018] [Indexed: 10/28/2022]
Abstract
Malignant melanoma is one of the most fatal and aggressive skin cancers, originating from pigment-containing melanocytes. Despite progress in clinical research, treatment options for malignant melanoma have been limited. The nuclear factor of activated T-cell 5 (NFAT5), originally identified as tonicity regulated transcription factor Ton/EBP, is now known as a carcinogenic gene in several types of cancer pathology. In this study, we knocked down NFAT5 to investigate its role in melanoma cancer. shRNA-mediated knockdown of NFAT5 led to a significant decrease in cell proliferation in vitro. Additionally, depletion of NFAT5 inhibited the cell migratory ability of B16BL6 melanoma cells and led to more accumulation at the G2/M phase of the cell cycle. Furthermore, NFAT5 was essential for the development of melanoma cancer pathophysiology in an in vivo mouse model. NFAT5 knockdown-induced tumor growth was slow and tumor volume was significantly reduced compared to mock controls. Moreover, NFAT5 knockdown was associated with a low number of metastatic nodules on the lung and liver. To our knowledge, our data demonstrate for the first time a role of NFAT5 in the development of melanoma. We provide evidence for NFAT5 as a marker of cell migration and metastasis, indicating that NFAT5 represents a novel therapeutic target in melanoma.
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Affiliation(s)
- Dong-Ho Kim
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea
| | - Kye-Seong Kim
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea; College of Medicine, Hanyang University, Seoul, South Korea.
| | - Suresh Ramakrishna
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea; College of Medicine, Hanyang University, Seoul, South Korea.
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Hu Y, French SW, Chau T, Liu HX, Sheng L, Wei F, Stondell J, Garcia JC, Du Y, Bowlus CL, Wan YJY. RARβ acts as both an upstream regulator and downstream effector of miR-22, which epigenetically regulates NUR77 to induce apoptosis of colon cancer cells. FASEB J 2018; 33:2314-2326. [PMID: 30252536 DOI: 10.1096/fj.201801390r] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
This study investigates the mechanism and consequences of microRNA-22 ( miR-22) induction. Our data revealed for the first time that retinoic acid (RA) and histone deacetylase (HDAC) inhibitors, including short-chain fatty acids and suberanilohydroxamic acid (SAHA), could individually or in combination induce miR-22. This induction was mediated via RA receptor β (RARβ) binding to a direct repeat 5 (DR5) motif. In addition, we uncovered HDAC1 as a novel miR-22 target. In an miR-22-dependent manner, HDAC inhibitors and RA reduced HDAC1, HDAC4, and sirtuin 1 (SIRT1), which were involved in chromatin remodeling of the RARβ and nerve growth factor IB ( NUR77). Thus, HDAC inhibitors and RA-induced miR-22 resulted in simultaneous induction of cytoplasmic RARβ and NUR77, leading to apoptosis of colon cancer cells. In mice, miR-22 and its inducers inhibited the growth of xenograft colon cancer. Moreover, tumor size reduction was accompanied by elevated miR-22, NUR77, and RARβ and by reduced HDACs. In human colon polyps and adenocarcinomas, miR-22 and RARβ were consistently reduced, which was associated with elevated HDAC1, HDAC4, and SIRT1 in colon adenocarcinomas. Results from this study revealed a novel anticancer mechanism of RARβ via miR-22 induction to epigenetically regulate itself and NUR77, providing a promising cancer treatment modality using miR-22 and its inducers.-Hu, Y., French, S. W., Chau, T., Liu, H.-X., Sheng, L., Wei, F., Stondell, J., Garcia, J. C., Du, Y., Bowlus, C. L., Wan, Y.-J. Y. RARβ acts as both an upstream regulator and downstream effector of miR-22, which epigenetically regulates NUR77 to induce apoptosis of colon cancer cells.
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Affiliation(s)
- Ying Hu
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health System, Sacramento, California, USA
| | - Samuel W French
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Thinh Chau
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health System, Sacramento, California, USA
| | - Hui-Xin Liu
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health System, Sacramento, California, USA
| | - Lili Sheng
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health System, Sacramento, California, USA
| | - Fang Wei
- Department of Gastroenterology and Hepatology, First Municipal People's Hospital of Guangzhou, Guangzhou Medical College, Guangzhou, China
| | - Jesse Stondell
- Division of Gastroenterology, University of California, Davis Health System, Sacramento, California, USA
| | - Juan C Garcia
- Division of Gastroenterology, University of California, Davis Health System, Sacramento, California, USA
| | - Yanlei Du
- Department of Gastroenterology and Hepatology, First Municipal People's Hospital of Guangzhou, Guangzhou Medical College, Guangzhou, China
| | - Christopher L Bowlus
- Division of Gastroenterology, University of California, Davis Health System, Sacramento, California, USA
| | - Yu-Jui Yvonne Wan
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health System, Sacramento, California, USA
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Fadaka AO, Ojo BA, Adewale OB, Esho T, Pretorius A. Effect of dietary components on miRNA and colorectal carcinogenesis. Cancer Cell Int 2018; 18:130. [PMID: 30202241 PMCID: PMC6127951 DOI: 10.1186/s12935-018-0631-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 08/31/2018] [Indexed: 12/14/2022] Open
Abstract
Background Colorectal cancer (CRC) is one of the most common cancers diagnosed and among the commonest causes of cancer-related mortality globally. Despite the various available treatment options, millions of people still suffer from this illness and most of these treatment options have several limitations. Therefore, a less expensive, non-invasive or a treatment that requires the use of dietary products remains a focal point in this review. Main body Aberrant microRNA expression has been revealed to have a functional role in the initiation and progression of CRC. These has shown significant promise in the diagnosis and prognosis of CRC, owing to their unique expression profile associated with cancer types and malignancies. Moreover, microRNA therapeutics show a great promise in preclinical studies, and these encourage further development of their clinical use in CRC patients. Additionally, emerging studies show the chemo-preventive potential of dietary components in microRNA modulation using several CRC models. This review examines the dietary interplay between microRNAs and CRC incidence. Improving the understanding of the interactions between microRNAs and dietary components in the carcinogenesis of CRC will assist the study of CRC progression and finally, in developing personalized approaches for cancer prevention and therapy. Conclusion Although miRNA research is still at its infancy, it could serve as a promising predictive biomarkers and therapeutic targets for CRC. Given the ever-expanding number of miRNAs, understanding their functional aspects represents a promising option for further research.
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Affiliation(s)
- Adewale Oluwaseun Fadaka
- 1Department of Biotechnology, Faculty of Natural Sciences, University of the Western Cape, Cape Town, South Africa.,3Department of Biochemistry, Afe Babalola University, P.M.B. 5454, Ado-Ekiti, Ekiti State Nigeria
| | - Babajide A Ojo
- 2Department of Nutritional Science, Oklahoma State University, 301, Human Sciences, Stillwater, OK 74075 USA
| | - Olusola Bolaji Adewale
- 3Department of Biochemistry, Afe Babalola University, P.M.B. 5454, Ado-Ekiti, Ekiti State Nigeria
| | - Temitope Esho
- 4Institute of Biochemistry II, Medical Faculty, University of Cologne, Joseph-Stelzmann Str. 52, 50931 Cologne, Germany
| | - Ashley Pretorius
- Biotechnology Innovation Division, Aminotek PTY LTD, Suite 2C, Oude Westhof Village Square Bellville, 7530 South Africa
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Zhao CN, Li Y, Meng X, Li S, Liu Q, Tang GY, Gan RY, Li HB. Insight into the roles of vitamins C and D against cancer: Myth or truth? Cancer Lett 2018; 431:161-170. [DOI: 10.1016/j.canlet.2018.05.039] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 05/17/2018] [Accepted: 05/24/2018] [Indexed: 02/07/2023]
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Wang Y, Liu J, Wu H, Cai Y. Combined Biomarkers Composed of Environment and Genetic Factors in Stroke. Biosci Trends 2018; 12:360-368. [PMID: 30158363 DOI: 10.5582/bst.2018.01150] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
It was widely accepted that stroke onset was the result of interactions between environment and genetic factors. However, the combined biomarkers covering environment and genetic factors and their interplay information in stroke were still lacking. In this study, we proposed a framework to identify the targeting or indicating role each factor played in the combined stroke biomarkers. A combined set of 36 biomarkers were identified based on evaluation and importance scores. Validations on three independent microarray data sets justified that the obtained markers were pervasively effective in discriminating stroke patients of different stages from healthy people on genetic levels. 8 and 3 genetic factors were identified as biomarkers in the acute and recovery phases of stroke, respectively. For example, the expression changing of SERPINH1 only appeared in the acute phase of stroke showing its targeting role in the combined biomarker. Compared with this, 11 genetic factors such as MMP9 were found to be differentially expressed in both acute and recovery phases of stroke showing their indicating roles in stroke. Functional analyses further revealed that the biomarkers could be grouped into 4 closely related processes of stroke including prevention, occurrence, processing, and recovery, respectively. These results indicated that the adoption of interactions between environment and genetic factors would be helpful in selecting robust and biologically relevant biomarkers, which cast a new insight for stroke biomarker identification.
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Affiliation(s)
- Yingying Wang
- Research Center for Biomedical Information Technology, Shenzhen Institutes of Advanced Technologies, Chinese Academy of Sciences
| | - Jianfeng Liu
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University
| | - Hongyan Wu
- Research Center for Biomedical Information Technology, Shenzhen Institutes of Advanced Technologies, Chinese Academy of Sciences
| | - Yunpeng Cai
- Research Center for Biomedical Information Technology, Shenzhen Institutes of Advanced Technologies, Chinese Academy of Sciences
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Guan Y, He Y, Lv S, Hou X, Li L, Song J. Overexpression of HOXC10 promotes glioblastoma cell progression to a poor prognosis via the PI3K/AKT signalling pathway. J Drug Target 2018; 27:60-66. [PMID: 29768063 DOI: 10.1080/1061186x.2018.1473408] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVE The HOX gene is expressed in neoplasias occurred in multiple tissues, such as the colon, lung and breast. However, the effects of the HOX gene on glioblastoma (GBM) remain poorly understood. We examined HOXC10 expression in GBM tissues and cells, analysed its effect on GBM prognosis, and finally assessed its possible underlying mechanisms in this study. METHODS HOXC10 expression levels and its prognostic effects on GBM tissues were analysed based on The Cancer Genome Atlas (TCGA) and ONCOMINE database. Overall survival (OS) analysis was performed using the Kaplan-Meier method and log rank test. Then, the expression of HOXC10 was detected in four GBM cell lines using quantitative real-time reverse transcription-PCR (qRT-PCR). In addition, small interfering RNA (si-RNA) was utilised in the U87 cell line with the highest HOXC10 expression to facilitate subsequent in vitro cell experiment. Cell proliferation, migration and invasion were assessed using the Cell Counting Kit-8 (CCK-8) and colony formation assay, wound healing, Transwell assay, respectively in GBM U87 cell after HOXC10 knockdown. Key proteins related to the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signalling pathway were measured by western blotting. RESULTS HOXC10 expression was significantly increased in GBM tissues and cell lines, leading a poor OS in GBM patients. Knockdown of HOXC10 could inhibit the GBM U87 cells proliferation, migration and invasion, as well as decreased expression levels of key proteins in PI3K/AKT signalling pathway. CONCLUSION HOXC10 was overexpressed in GBM tissues and cells, and associated with poor prognosis in GBM patients. Moreover, HOXC10 knockdown inhibited U87 cell proliferation, migration and invasion, which were potentially related to PI3K/AKT signalling pathway activation. Our findings revealed that HOXC10 represent a promising biological target for GBM treatment in the future.
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Affiliation(s)
- Yong Guan
- a Department of Neurosurgery , Qingdao Minicipal Hospital , Qingdao , Shandong , PR China
| | - Yajie He
- a Department of Neurosurgery , Qingdao Minicipal Hospital , Qingdao , Shandong , PR China
| | - Shaoping Lv
- b Department of Rehabilitation , Qingdao Central Hospital , Qingdao , Shandong , PR China
| | - Xiaoqun Hou
- a Department of Neurosurgery , Qingdao Minicipal Hospital , Qingdao , Shandong , PR China
| | - Luo Li
- a Department of Neurosurgery , Qingdao Minicipal Hospital , Qingdao , Shandong , PR China
| | - Jianjun Song
- a Department of Neurosurgery , Qingdao Minicipal Hospital , Qingdao , Shandong , PR China
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