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Zhai F, Yun B, Ming J, Yu T, Li B, Liu X, Wang X, Chen ZH, Song C, Zhao M, Li W, Liu Z, Liang A, Li J, Zhang F. Non-Invasive Diagnosis of Early Colorectal Cancerization via Amplified Sensing of MicroRNA-21 in NIR-II Window. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025; 37:e2501378. [PMID: 40123304 DOI: 10.1002/adma.202501378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 03/04/2025] [Indexed: 03/25/2025]
Abstract
Accurate, sensitive, and in situ visualization of aberrant expression level of low-abundant biomolecules is crucial for early colorectal cancer (CRC) detection ahead of tumor morphology change. However, the clinical used colonoscopy and biopsy methods are invasive and lack of sensitivity at early-stage of cancerization. Here, an amplified sensing strategy is developed in the second near-infrared long-wavelength subregion (NIR-II-L, 1500-1900 nm) by integrating DNAzyme-triggered signal amplification technology and lanthanide-dye hybrid system. In the early-stage of CRC, the overexpressed biomarker microRNA-21 initiates the NIR-II-L luminescence ratiometric signal amplification of the CRCsensor. The high sensitivity with a limit of detection (LOD) of 1.26 pm allows non-invasive visualization of orthotopic colorectal cancerization via rectal administration, which achieves early and accurate in situ diagnosis at 2 weeks ahead of the in vitro histological results. This innovative approach offers a promising tool for early diagnosis and long-term monitoring of carcinogenesis progression, with potential applications in other cancer-related biomarkers.
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Affiliation(s)
- Fuheng Zhai
- Department of Oncology, Huadong Hospital, Fudan University, Shanghai, 200040, P. R. China
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials and iChem, Fudan University, Shanghai, 200433, P. R. China
| | - Baofeng Yun
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials and iChem, Fudan University, Shanghai, 200433, P. R. China
| | - Jiang Ming
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials and iChem, Fudan University, Shanghai, 200433, P. R. China
| | - Tianyu Yu
- Department of Oncology, Huadong Hospital, Fudan University, Shanghai, 200040, P. R. China
| | - Benhao Li
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials and iChem, Fudan University, Shanghai, 200433, P. R. China
| | - Xiao Liu
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials and iChem, Fudan University, Shanghai, 200433, P. R. China
| | - Xusheng Wang
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials and iChem, Fudan University, Shanghai, 200433, P. R. China
| | - Zi-Han Chen
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials and iChem, Fudan University, Shanghai, 200433, P. R. China
| | - Changfeng Song
- Department of Oncology, Huadong Hospital, Fudan University, Shanghai, 200040, P. R. China
| | - Mengyao Zhao
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials and iChem, Fudan University, Shanghai, 200433, P. R. China
| | - Wenlin Li
- Department of Cell Biology, Naval Medical University, Shanghai, 200433, P. R. China
| | - Zhebin Liu
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200433, P. R. China
| | - Aibin Liang
- Department of Hematology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, P. R. China
| | - Jiyu Li
- Department of Oncology, Huadong Hospital, Fudan University, Shanghai, 200040, P. R. China
- Department of Oncology, Pudong Hospital, Fudan University, Shanghai, 201399, P. R. China
| | - Fan Zhang
- Department of Oncology, Huadong Hospital, Fudan University, Shanghai, 200040, P. R. China
- Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials and iChem, Fudan University, Shanghai, 200433, P. R. China
- Department of Hematology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, P. R. China
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Wang Y, Wang S, He H, Bai Y, Liu Z, Sabihi SS. Mechanisms of apoptosis-related non-coding RNAs in ovarian cancer: a narrative review. Apoptosis 2025; 30:553-578. [PMID: 39833637 DOI: 10.1007/s10495-024-02074-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/27/2024] [Indexed: 01/22/2025]
Abstract
Ovarian cancer remains a major challenge in oncology due to its complex biology and late-stage diagnosis. Recent advances in molecular biology have highlighted the crucial role of non-coding RNAs (ncRNAs) in regulating apoptosis and cancer progression. NcRNAs, including microRNAs, long non-coding RNAs, and circular RNAs, have emerged as significant players in the molecular networks governing ovarian cancer. Despite these insights, the precise mechanisms by which ncRNAs influence ovarian cancer pathology are not fully understood. This complexity, combined with the heterogeneity of the disease and the development of treatment resistance, poses substantial obstacles to effective therapeutic development. Additionally, the lack of reliable early detection methods further complicates treatment strategies. This manuscript reviews the current state of research on ncRNAs in ovarian cancer, discusses the challenges in translating these findings into clinical applications, and outlines potential future directions. Emphasis is placed on the need for integrated approaches to unravel the intricate roles of ncRNAs, improve early detection, and develop personalized treatment strategies to address the diverse and evolving nature of ovarian cancer. While these findings provide valuable insights, it is crucial to recognize that many results are based on preclinical studies and require further validation to establish their clinical applicability.
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Affiliation(s)
- Yue Wang
- Department of Obstetrics and Gynecology, Tang Du Hospital, The Air Force Military Medical University, Xi'an, 710038, China
| | - Shirui Wang
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710038, China
| | - Haiyan He
- Department of Obstetrics and Gynecology, Tang Du Hospital, The Air Force Military Medical University, Xi'an, 710038, China
| | - Yingying Bai
- Department of Obstetrics and Gynecology, Tang Du Hospital, The Air Force Military Medical University, Xi'an, 710038, China
| | - Zhuo Liu
- Department of Obstetrics and Gynecology, Xi'an International Medical Center Hospital, Xi'an, 710038, China
| | - Sima-Sadat Sabihi
- Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
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Fathi S, Aazzane O, Guendaoui S, Tawfiq N, Sahraoui S, Guessous F, Karkouri M. A miRNA Signature for Non-Invasive Colorectal Cancer Diagnosis in Morocco: miR-21, miR-29a and miR-92a. Noncoding RNA 2025; 11:26. [PMID: 40126350 PMCID: PMC11932314 DOI: 10.3390/ncrna11020026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 03/08/2025] [Accepted: 03/10/2025] [Indexed: 03/25/2025] Open
Abstract
Colorectal cancer (CRC) is the third most diagnosed cancer and a leading cause of cancer-related mortality in Morocco, often detected at late stages. Circulating microRNAs (miRNAs) have emerged as promising non-invasive biomarkers for CRC detection, with miR-21, miR-29a, and miR-92a showing significant diagnostic potential. This study aimed to evaluate the expression levels of these miRNAs in a Moroccan population and their efficacy as diagnostic biomarkers. METHODS A prospective study was conducted using blood samples from 50 CRC patients and 50 healthy controls. Circulating miRNA expression levels were quantified through reverse transcription quantitative PCR (RT-qPCR), with normalization to miR-1228-3p. Statistical analyses, including the Mann-Whitney U test, Receiver Operating Characteristic (ROC) curve analysis, sensitivity (Sen), and specificity (Spe) evaluations, were performed to assess the diagnostic accuracy of individual miRNAs and their combined performance as panels. RESULTS The expression levels of miR-21, miR-29a, and miR-92a were significantly elevated in CRC patients compared to healthy controls (all p < 0.001). ROC analysis demonstrated that miR-92a exhibited the highest individual diagnostic performance (AUC: 0.938), followed by miR-21 (AUC: 0.907) and miR-29a (AUC: 0.898). Sensitivity and specificity were 88% and 90%, 92% and 56%, and 76% and 94%, respectively. Combinatorial analysis revealed that the miR-29a and miR-92a panel achieved the highest diagnostic accuracy (AUC: 0.976), surpassing individual miRNAs and other combinations, highlighting its potential as a robust, non-invasive biomarker panel for CRC. CONCLUSIONS This study highlights the potential of the miR-29a and miR-92a combination, which achieved excellent diagnostic efficiency (AUC: 0.976). These findings underscore miRNA utility in enhancing early detection and reducing CRC-related mortality in Morocco.
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Affiliation(s)
- Sofia Fathi
- Laboratory of Cellular and Molecular Pathology, Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Casablanca 20250, Morocco
- Laboratory of Pathology, Ibn Rochd University Hospital, Casablanca 20100, Morocco
| | - Oussama Aazzane
- Laboratory of Cellular and Molecular Pathology, Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Casablanca 20250, Morocco
- Laboratory of Pathology, Ibn Rochd University Hospital, Casablanca 20100, Morocco
| | - Salma Guendaoui
- Mohamed VI Center for Cancer Treatment, Ibn Rochd University Hospital, Casablanca 20100, Morocco
| | - Nezha Tawfiq
- Mohamed VI Center for Cancer Treatment, Ibn Rochd University Hospital, Casablanca 20100, Morocco
| | - Souha Sahraoui
- Mohamed VI Center for Cancer Treatment, Ibn Rochd University Hospital, Casablanca 20100, Morocco
| | - Fadila Guessous
- Laboratory of Oncopathology, Environment and Cancer Biology, Faculty of Medicine, Mohammed VI University of Health Sciences, Casablanca 82403, Morocco
- Department of Microbiology, Immunology and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA
| | - Mehdi Karkouri
- Laboratory of Cellular and Molecular Pathology, Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Casablanca 20250, Morocco
- Laboratory of Pathology, Ibn Rochd University Hospital, Casablanca 20100, Morocco
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Tahghighi A, Seyedhashemi E, Mohammadi J, Moradi A, Esmaeili A, Pornour M, Jafarifar K, Ganji SM. Epigenetic marvels: exploring the landscape of colorectal cancer treatment through cutting-edge epigenetic-based drug strategies. Clin Epigenetics 2025; 17:34. [PMID: 39987205 PMCID: PMC11847397 DOI: 10.1186/s13148-025-01844-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 02/14/2025] [Indexed: 02/24/2025] Open
Abstract
Epigenetics is currently considered the investigation of inheritable changes in gene expression that do not rely on DNA sequence alteration. Significant epigenetic procedures are involved, such as DNA methylations, histone modifications, and non-coding RNA actions. It is confirmed through several investigations that epigenetic changes are associated with the formation, development, and metastasis of various cancers, such as colorectal cancer (CRC). The difference between epigenetic changes and genetic mutations is that the former could be reversed or prevented; therefore, cancer treatment and prevention could be achieved by restoring abnormal epigenetic events within the neoplastic cells. These treatments, consequently, cause the anti-tumour effects augmentation, drug resistance reduction, and host immune response stimulation. In this article, we begin our survey by exploring basic epigenetic mechanisms to understand epigenetic tools and strategies for treating colorectal cancer in monotherapy and combination with chemotherapy or immunotherapy.
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Affiliation(s)
- Azar Tahghighi
- Medicinal Chemistry Laboratory, Clinical Research Department, Pasteur Institute of Iran, Tehran, Iran
| | - Effat Seyedhashemi
- Department of Molecular Medicine, Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Shahrak-E Pajoohesh, Km 15, P.O. Box 14965/161, Tehran, Iran
| | - Javad Mohammadi
- Department of Molecular Medicine, Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Shahrak-E Pajoohesh, Km 15, P.O. Box 14965/161, Tehran, Iran
- Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran
| | - Arash Moradi
- Department of Molecular Medicine, Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Shahrak-E Pajoohesh, Km 15, P.O. Box 14965/161, Tehran, Iran
| | - Aria Esmaeili
- Department of Molecular Medicine, Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Shahrak-E Pajoohesh, Km 15, P.O. Box 14965/161, Tehran, Iran
| | - Majid Pornour
- Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD, USA
| | - Kimia Jafarifar
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Shahla Mohammad Ganji
- Department of Molecular Medicine, Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Shahrak-E Pajoohesh, Km 15, P.O. Box 14965/161, Tehran, Iran.
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Liu F, Ai F, Tang A, Yang Z, Li Z, Liu S. Macrophage-Derived Exosomes Promoted the Development and Stemness of Inflammatory Bowel Disease-Related Colorectal Cancer via nuclear paraspeckle assembly transcript 1-Mediated miRNA-34a-5p/phosphoprotein enriched in astrocytes 15 Axis. Inflamm Bowel Dis 2025; 31:524-538. [PMID: 39425913 DOI: 10.1093/ibd/izae212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Indexed: 10/21/2024]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is closely associated with the development of colorectal cancer (CRC) due to the chronic inflammatory response. Macrophages play critical roles in regulating the microenvironment to facilitate tumor progression. Exosomes are key modulators for the communication between macrophages and tumor cells. The mechanism of macrophage-derived exosomes in IBD-related CRC development remains unclear. METHODS The macrophages were isolated using fluorescence activating cell sorter (FACS). The RNA and protein expressions in exosomes and CRC cells were examined by quantitative real-time polymerase chain reaction and western blot assays, respectively. CRC cell development was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, BrdU staining, Transwell assay, and spheroid formation assay. The level of stemness was determined by detecting the proportion of leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5)-positive CRC cells and the expression of LGR5, CD133, and CD44. Molecular interaction experiments were done using luciferase reporter assay and RNA immunoprecipitation assay. Xenograft tumor model in vivo and immunohistochemistry were used to observe the pathological changes. RESULTS Macrophage-derived exosomes from IBD-related CRC tissues were enriched with nuclear paraspeckle assembly transcript 1 (NEAT1) and able to promote the progression and stemness of CRC both in vitro and in vivo. The exosomal NEAT1 could sponge miR-34a-5p, leading to the restoration of PEA15 expression in CRC cells and promoting the development of CRC. Inhibition of NEAT1 in exosomes could effectivity inhibit the tumor growth in the CRC xenograft model. CONCLUSIONS These findings provide novel insights into how macrophages affect CRC development and highlight exosomal NEAT1 as a therapeutic target for CRC treatment.
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Affiliation(s)
- Fen Liu
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, P.R. China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, P.R. China
| | - Feiyan Ai
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, P.R. China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, P.R. China
| | - Anliu Tang
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, P.R. China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, P.R. China
| | - Zhenyu Yang
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, P.R. China
| | - Zhaoqi Li
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, P.R. China
| | - Shaojun Liu
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, P.R. China
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Wu Y, Xiao Y, Ding Y, Ran R, Wei K, Tao S, Mao H, Wang J, Pang S, Shi J, Zhu C, Wan W, Yang Q, Chen C. Colorectal cancer cell-derived exosomal miRNA-372-5p induces immune escape from colorectal cancer via PTEN/AKT/NF-κB/PD-L1 pathway. Int Immunopharmacol 2024; 143:113261. [PMID: 39353381 DOI: 10.1016/j.intimp.2024.113261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 09/22/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024]
Abstract
Tumor cells can escape immune surveillance by changing their own escape or expressing abnormal genes and proteins, resulting in unlimited proliferation and invasive growth of cells. These changes are related to microRNAs (miRNAs), which reduce the killing effect of immune cells, devastate the immune response, and interfere with apoptosis through the aberrant expression of relevant miRNAs. In the preliminary phase of this study, miRNAs in clinical plasma exosomes of colorectal cancer patients were differentially analyzed by RNA sequencing technology, and miR-372-5p derived from extracellular vesicles (sEVs) was found to be a key signaling molecule mediating the regulation of macrophages by colorectal cancer (CRC). miRNA-372-5p is upregulated in colorectal cancer patient tissues and serum, as well as colorectal cancer cell lines and their exosomes. Subsequently, we found that macrophages could take up sEV secreted by colorectal cancer cells HCT116, affecting the expression of the immune checkpoint PD-L1, resulting in the generation of a tumor-immunosuppressive microenvironment and suppression of T cell activation in CRC. Gene enrichment mapping and database revealed that miR-372-5p regulates PD-L1 expression in colorectal cancer through the homologous phosphatase-tensin (PTEN)-phosphatidylinositol 3-kinase-protein kinase B (AKT)-nuclear factor-κB (NF-κB) pathway. Further studies confirmed that miRNA-372-5p-treated macrophages co-cultured with T cells affected the regulation of PD-L1 expression through the PTEN/AKT/NF-κB signaling pathway, resulting in decreased CD3+CD8+ T cell activity, decreased cytokine IL-2 and increased IFN-γ. And miRNA-372-5p could down-regulate the expression of PD-L1 in HCT116 through the PTEN/AKT/NF-κB pathway, inhibit tumor cell proliferation and promote apoptosis. Conclusion: Colorectal cancer cell-derived exosome miR-372-5p can be phagocytosed by colorectal cancer and macrophage cells, regulate the expression of PD-L1 in colorectal cancer cells and macrophages by targeting the PTEN/AKT/NF-κB pathway, and induce the immunosuppressive microenvironment of CRC to promote CRC development. This suggests that inhibiting the secretion of HCT116-specific sEV-miR-372-5p or targeting PD-L1 in tumor-associated macrophages could be a novel approach for CRC treatment and possibly a sensitizing approach for CRC anti-PD-L1 therapy.
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Affiliation(s)
- Yulun Wu
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China; Department of Life Sciences, Bengbu Medical University, Anhui 233030, China.
| | - Yuhan Xiao
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China; School of Laboratory Medicine, Bengbu Medical University, Anhui 233030, China.
| | - Yongxing Ding
- The Third the Pople's Hospital of Bengbu, Anhui 233000, China.
| | - Ruorong Ran
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Ke Wei
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Shuang Tao
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Huilan Mao
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Jing Wang
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Siyan Pang
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Jiwen Shi
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Chengle Zhu
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu medical university, 2600 Donghai Avenue, Bengbu, Anhui 233030, China.
| | - Wenrui Wan
- Department of Biotechnology, Bengbu Medical University, Anhui 233030, China.
| | - Qingling Yang
- Department of Biochemistry and Molecular Biology, Bengbu Medical University, Anhui 233030, China.
| | - Changjie Chen
- Department of Biochemistry and Molecular Biology, Bengbu Medical University, Anhui 233030, China.
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Gatti CR, Schibert F, Taylor VS, Capobianco E, Montero V, Higa R, Jawerbaum A. Maternal dietary olive oil protects diabetic rat offspring from impaired uterine decidualization. Placenta 2024:S0143-4004(24)00776-8. [PMID: 39609224 DOI: 10.1016/j.placenta.2024.11.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 11/13/2024] [Accepted: 11/19/2024] [Indexed: 11/30/2024]
Abstract
INTRODUCTION Maternal diabetes increases the risk of adverse maternal, perinatal and offspring outcomes. This study aimed to address whether alterations in uterine decidualization are programmed in the prepubertal offspring from diabetic rats fed diets enriched or not in extra virgin olive oil (EVOO). METHODS Control and mild pregestational diabetic female rats (F0) were mated with control males and fed diets enriched or not with 6 % EVOO during pregnancy. Offspring (F1) were evaluated on postnatal day 30, after induction of uterine decidualization (PMSG 50 IU- hCG 50 IU). Signaling pathways involved in decidualization, including prolactin, PPAR and mTOR pathways as well as microRNAs (miRs) regulating these pathways were evaluated by Western blot or qPCR in the decidualized uteri. RESULTS The offspring from diabetic rats evidenced reduced prolactin and prolactin receptor levels in the decidualized uteri. Additionally, these tissues showed increased PPARγ levels and reduced levels of its negative regulators miR-19b and miR-155. MiR-21, a microRNA that targets both PPARα and mTOR pathway regulators was reduced, whereas PPARα, PTEN and FOXO1 mRNA levels were increased in the decidualized uteri of the offspring from diabetic rats. The mTOR pathway activity was reduced in the decidualized uteri of the offspring from diabetic rats. Most of the observed alterations were prevented by the EVOO-enriched maternal diet. DISCUSSION Impaired pathways relevant to decidualization are programmed in the uteri of prepubertal offspring from diabetic dams, alterations capable of being prevented by maternal diets enriched in EVOO.
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Affiliation(s)
- Cintia Romina Gatti
- Universidad de Buenos Aires (UBA). Facultad de Medicina, Argentina; CONICET - UBA. Laboratory of Reproduction and Metabolism, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Buenos Aires, Argentina
| | - Florencia Schibert
- Universidad de Buenos Aires (UBA). Facultad de Medicina, Argentina; CONICET - UBA. Laboratory of Reproduction and Metabolism, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Buenos Aires, Argentina
| | - Virginia Soledad Taylor
- Universidad de Buenos Aires (UBA). Facultad de Medicina, Argentina; CONICET - UBA. Laboratory of Reproduction and Metabolism, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Buenos Aires, Argentina
| | - Evangelina Capobianco
- Universidad de Buenos Aires (UBA). Facultad de Medicina, Argentina; CONICET - UBA. Laboratory of Reproduction and Metabolism, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Buenos Aires, Argentina
| | | | - Romina Higa
- Universidad de Buenos Aires (UBA). Facultad de Medicina, Argentina; CONICET - UBA. Laboratory of Reproduction and Metabolism, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Buenos Aires, Argentina
| | - Alicia Jawerbaum
- Universidad de Buenos Aires (UBA). Facultad de Medicina, Argentina; CONICET - UBA. Laboratory of Reproduction and Metabolism, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Buenos Aires, Argentina.
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Yadav V, Singh T, Sharma D, Garg VK, Chakraborty P, Ghatak S, Satapathy SR. Unraveling the Regulatory Role of HuR/microRNA Axis in Colorectal Cancer Tumorigenesis. Cancers (Basel) 2024; 16:3183. [PMID: 39335155 PMCID: PMC11430344 DOI: 10.3390/cancers16183183] [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: 08/07/2024] [Revised: 09/04/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
Colorectal cancer (CRC) remains a significant global health burden with high incidence and mortality. MicroRNAs (miRNAs) are small non-protein coding transcripts, conserved throughout evolution, with an important role in CRC tumorigenesis, and are either upregulated or downregulated in various cancers. RNA-binding proteins (RBPs) are known as essential regulators of miRNA activity. Human antigen R (HuR) is a prominent RBP known to drive tumorigenesis with a pivotal role in CRC. In this review, we discuss the regulatory role of the HuR/miRNA axis in CRC. Interestingly, miRNAs can directly target HuR, altering its expression and activity. However, HuR can also stabilize or degrade miRNAs, forming complex feedback loops that either activate or block CRC-associated signaling pathways. Dysregulation of the HuR/miRNA axis contributes to CRC initiation and progression. Additionally, HuR-miRNA regulation by other small non-coding RNAs, circular RNA (circRNAs), or long-non-coding RNAs (lncRNAs) is also explored here. Understanding this HuR-miRNA interplay could reveal novel biomarkers with better diagnostic or prognostic accuracy.
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Affiliation(s)
- Vikas Yadav
- Department of Translational Medicine, Clinical Research Centre, Lund University, 221 00 Malmö, Sweden;
| | - Tejveer Singh
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, University of Delhi, New Delhi 110021, India; (T.S.); (D.S.)
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences (INMAS-DRDO), New Delhi 110054, India
| | - Deepika Sharma
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, University of Delhi, New Delhi 110021, India; (T.S.); (D.S.)
| | - Vivek Kumar Garg
- Department of Medical Lab Technology, Chandigarh University, Gharuan, Mohali 140413, Punjab, India;
| | - Payel Chakraborty
- Amity Institute of Biotechnology, Amity University Kolkata, Kolkata 700135, West Bengal, India; (P.C.); (S.G.)
| | - Souvik Ghatak
- Amity Institute of Biotechnology, Amity University Kolkata, Kolkata 700135, West Bengal, India; (P.C.); (S.G.)
| | - Shakti Ranjan Satapathy
- Department of Translational Medicine, Clinical Research Centre, Lund University, 221 00 Malmö, Sweden;
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El-Korany WA, Zahran WE, Alm El-Din MA, Al-Shenawy HA, Soliman AF. Rs12039395 Variant Influences the Expression of hsa-miR-181a-5p and PTEN Toward Colorectal Cancer Risk. Dig Dis Sci 2024; 69:3318-3332. [PMID: 38940971 DOI: 10.1007/s10620-024-08517-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 05/31/2024] [Indexed: 06/29/2024]
Abstract
BACKGROUND Single nucleotide polymorphisms (SNPs) in microRNA (miRNA) genes could alter miRNA expression levels or processing and, thus, may contribute to colorectal cancer (CRC) development. Therefore, this study aimed to examine whether the MIR181A1 genomic sequence possesses SNPs that can affect the expression of hsa-miR-181a-5p and, subsequently, impact its targets and associate with CRC risk. METHODS The NCBI dbSNP database was searched for possible SNPs associated with MIR181A1. One SNP with a minor allele frequency > 5%, rs12039395 G > T was identified. In silico analyses determined the effect of the SNP on the secondary structure of the miRNA and predicted the hsa-miR-181a-5p target genes. The SNP was genotyped using allelic discrimination assay, the relative hsa-miR-181a-5p expression level was determined using quantitative real-time PCR, and immunohistochemical staining was used to detect target genes in 192 paraffin-embedded specimens collected from 160 CRC patients and 32 healthy subjects. RESULTS The rs6505162 SNP conferred protection against CRC, and the G-allele presence provides may provide accessibility for the transcriptional machinery. Hsa-miR-181a-5p was significantly over-expressed in the CRC group compared to controls and in samples carrying the G-allele compared to those with T-allele. PTEN, identified as the only hsa-miR-181a-5p target implicated in CRC, was significantly diminished in the CRC group compared to controls and showed an inverse relationship with hsa-miR-181a-5p expression level as well as negatively associated with the G-allele presence in CRC. CONCLUSION This study highlights that rs12039395 G > T may protect against CRC by influencing the expression of hsa-mir-181a-5p and its target gene, PTEN.
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Affiliation(s)
- Wael A El-Korany
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Walid E Zahran
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Mohamed A Alm El-Din
- Clinical Oncology Department, Faculty of Medicine, Tanta University, Gharbia, Egypt
| | - Hanan A Al-Shenawy
- Pathology Department, Faculty of Medicine, Tanta University, Gharbia, Egypt
| | - Ahmed F Soliman
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt.
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10
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Tohidast M, Amini M, Doustvandi MA, Hosseini SS, Bilan F, Mozammel N, Sameti P, Mokhtarzadeh AA, Baradaran B. Simultaneous effect of miR-21 suppression and miR-143 restoration on inhibition of proliferation and migration in SW-480 colorectal cancer cells. BIOIMPACTS : BI 2024; 15:30255. [PMID: 39963562 PMCID: PMC11830141 DOI: 10.34172/bi.30255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 02/10/2024] [Accepted: 02/20/2024] [Indexed: 02/20/2025]
Abstract
Introduction Colorectal cancer (CRC) is regarded as a serious global issue and is presently ranked second in the classification of gastrointestinal (GI) malignancies, with fast incidence and high mortality patterns. As the key "gene expression regulators", miRNAs critically contribute to tumor progression and development. For example, miR-21 (an oncomiR) and miR-143 (a tumor suppressor) are dysregulated through colorectal tumorigenesis. Accordingly, this study assesses the concomitant therapeutic impacts of "miR-21 suppression" (anti-miR-21) and "miR-143 restoration" (miR-143) on CRC cell proliferation and migration. Methods SW-480 cell lines (with overexpressed "miR-21" and downregulated "miR-143") were transfected via "anti-miR-21" and "miR-143" mimics, either independently or in combination. Next, cell viability assessment was performed through MTT assay. Then, apoptosis induction was examined with "Annexin V-FITC Kit", and via Propidium Iodide (PI) assay and DAPI staining. In the next step, "cell cycle condition" and "autophagy induction" were studied through flow cytometry. "Wound-healing assay" and "clonogenic assay" were employed to investigate the migration and proliferation of tumor cells. Ultimately, qRT-PCR was utilized to quantify the intensity of the effects of "anti-miR-21" and "miR-143" on gene expression profiles. Results Downregulation of "miR-21" expression and overexpression of "miR-143" were found to synergistically reduce the viability (while elevating apoptosis) of SW-480 cells by modulating Bcl-2 and Bax expression profiles. Combined therapy increased the number of cells in the sub-G1 phase and reduced cell proliferation by modulating expression levels of PTEN and AKT-1. Additionally, miR-21 suppression and miR-143 restoration concomitantly reduced cell migration by modulating the expression of MMP-9. Conclusion Considering anti-cancer effects on cell growth, survival, and migration, it can be concluded that the concomitant suppression of "anti-miR-21" and "miR-143 restoration" might be introduced as a promising method for the therapy of CRC.
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Affiliation(s)
- Maryam Tohidast
- Department of Biotechnology, Higher Education Institute of Rab-Rashid, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Amini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Farzaneh Bilan
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nazila Mozammel
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Pouryia Sameti
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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11
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Chawra HS, Agarwal M, Mishra A, Chandel SS, Singh RP, Dubey G, Kukreti N, Singh M. MicroRNA-21's role in PTEN suppression and PI3K/AKT activation: Implications for cancer biology. Pathol Res Pract 2024; 254:155091. [PMID: 38194804 DOI: 10.1016/j.prp.2024.155091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 12/31/2023] [Accepted: 01/01/2024] [Indexed: 01/11/2024]
Abstract
MicroRNA-21 (miR-21) was recognized as a key figure in the intricate web of tumor biology, with a prominent role in regulating the PTEN tumor suppressor gene and the PI3K/AKT cascade. This review elucidates the multifaceted interactions between miR-21, PTEN, and the PI3K/AKT signaling, shedding light on their profound implications in cancer initiation, progression, and therapeutic strategies. The core of this review delves into the mechanical intricacies of miR-21-mediated PTEN suppression and its consequent impact on PI3K/AKT pathway activation. It explores how miR-21, as an oncogenic miRNA, targets PTEN directly or indirectly, resulting in uncontrolled activation of PI3K/AKT, fostering cancerous cell survival, proliferation, and evasion of apoptosis. Furthermore, the abstract emphasizes the clinical relevance of these molecular interactions, discussing their implications in various cancer types, prognostic significance, and potential as therapeutic targets. The review provides insights into ongoing research efforts to develop miR-21 inhibitors and strategies to restore PTEN function, offering new avenues for cancer treatment. This article illuminates the critical function of miR-21 in PTEN suppression and PI3K/AKT activation, offering profound insights into its implications for cancer biology and the potential for targeted interventions.
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Affiliation(s)
| | - Mohit Agarwal
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, India
| | - Anurag Mishra
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, India
| | | | | | - Gaurav Dubey
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, India
| | - Neelima Kukreti
- School of Pharmacy, Graphic Era Hill University, Dehradun 248007, India
| | - Mithilesh Singh
- NIMS Institute of Pharmacy, NIMS University Rajasthan, Jaipur, India.
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12
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Mohammadi M, Fazilat A, Mamalo AS, Ojarudi M, Hemmati-Dinarvand M, Beilankouhi EAV, Valilo M. Correlation of PTEN signaling pathway and miRNA in breast cancer. Mol Biol Rep 2024; 51:221. [PMID: 38281224 DOI: 10.1007/s11033-023-09191-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Accepted: 12/21/2023] [Indexed: 01/30/2024]
Abstract
Breast cancer (BC) is one of the most common cancers among women and can be fatal if not diagnosed and treated on time. Various genetic and environmental factors play a significant role in the development and progression of BC. Within the body, different signaling pathways have been identified that contribute to cancer progression, or conversely, cancer prevention. Phosphatase and tensin homolog (PTEN) is one of the proteins that prevent cancer by inhibiting the oncogenic PI3K/Akt/mTOR signaling pathway. MicroRNAs (miRNAs) are molecules with about 18 to 28 base pairs, which regulate about 30% of human genes after transcription. miRNAs play a key role in the progression or prevention of cancer through different signaling pathway and mechanisms, e.g., apoptosis, angiogenesis, and proliferation. miRNAs, which are upstream mediators of PTEN, can reinforce or suppress the effect of PTEN signaling on BC cells, and suppressing the PTEN signaling, linked to weakness of the cancer cells to chemotherapeutic drugs. However, the precise mechanism and function of miRNAs on PTEN in BC are not yet fully understood. Therefore, in the present study, has been focused on miRNAs regulating PTEN function in BC.
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Affiliation(s)
- Mahya Mohammadi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ahmad Fazilat
- Department of Genetics, Motamed Cancer Institute, ACECR, Tehran, Iran
| | | | - Masoud Ojarudi
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Mohsen Hemmati-Dinarvand
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Mohammad Valilo
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
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13
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Sado AI, Batool W, Ahmed A, Zafar S, Patel SK, Mohan A, Zia U, Aminpoor H, Kumar V, Tejwaney U. Role of microRNA in colorectal carcinoma (CRC): a narrative review. Ann Med Surg (Lond) 2024; 86:308-318. [PMID: 38222721 PMCID: PMC10783342 DOI: 10.1097/ms9.0000000000001494] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 11/01/2023] [Indexed: 01/16/2024] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs that play a critical role in regulating gene expression by binding to target messenger RNAs (mRNAs). They were first discovered around 8 years after the identification of the first miRNA in 1993, and since then, there has been a significant increase in miRNA-related research and discoveries. MiRNAs have been implicated in various biological processes, including cancer, particularly in colorectal cancer (CRC). In CRC, miRNAs act as either oncogenes or tumor suppressors, influencing essential cellular functions such as cell proliferation, apoptosis, angiogenesis, and metastasis. The dysregulation of miRNAs in CRC can arise from different factors, leading to abnormal expression levels of their target mRNAs and subsequently affecting protein production. Consequently, miRNAs may directly target oncogenes or tumor suppressor genes, thereby contributing to cancer initiation and progression. Notably, tumors often exhibit reduced expression of mature miRNAs. In CRC research, miRNAs offer potential as diagnostic biomarkers and therapeutic targets. Specific miRNA profiles could serve as non-invasive tools for early CRC detection and risk assessment. Additionally, miRNA-based therapies present a promising approach for targeted cancer treatment by modulating miRNA expression. However, challenges related to delivery systems and long-term safety must be addressed to fully harness their therapeutic potential.
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Affiliation(s)
| | | | | | | | | | | | - Umar Zia
- Khyber Medical University, Peshawar, Pakistan
| | | | - Vikash Kumar
- The Brooklyn Hospital Center, Brooklyn, New York
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14
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Ebrahimi N, Hakimzadeh A, Bozorgmand F, Speed S, Manavi MS, Khorram R, Farahani K, Rezaei-Tazangi F, Mansouri A, Hamblin MR, Aref AR. Role of non-coding RNAs as new therapeutic targets in regulating the EMT and apoptosis in metastatic gastric and colorectal cancers. Cell Cycle 2023; 22:2302-2323. [PMID: 38009668 PMCID: PMC10730205 DOI: 10.1080/15384101.2023.2286804] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 05/11/2023] [Accepted: 08/01/2023] [Indexed: 11/29/2023] Open
Abstract
Colorectal cancer (CRC) and gastric cancer (GC), are the two most common cancers of the gastrointestinal tract, and are serious health concerns worldwide. The discovery of more effective biomarkers for early diagnosis, and improved patient prognosis is important. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), can regulate cellular processes such as apoptosis and the epithelial-mesenchymal transition (EMT) leading to progression and resistance of GC and CRC tumors. Moreover these pathways (apoptosis and EMT) may serve as therapeutic targets, to prevent metastasis, and to overcome drug resistance. A subgroup of ncRNAs is common to both GC and CRC tumors, suggesting that they might be used as biomarkers or therapeutic targets. In this review, we highlight some ncRNAs that can regulate EMT and apoptosis as two opposite mechanisms in cancer progression and metastasis in GC and CRC. A better understanding of the biological role of ncRNAs could open up new avenues for the development of personalized treatment plans for GC and CRC patients.
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Affiliation(s)
- Nasim Ebrahimi
- Genetics Division, Department of Cell and Molecular Biology and Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran
| | - Ali Hakimzadeh
- Department of Medical Biotechnologies, University of Siena, Tuscany, Italy
| | - Farima Bozorgmand
- Department of Medical Nanotechnology, Faculty of Advanced Sciences and Technology, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Sepehr Speed
- Medical Campus, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | | | - Roya Khorram
- Bone and Joint Diseases Research Center, Department of Orthopedic Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Kobra Farahani
- Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Atena Mansouri
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, South Africa
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Amir Reza Aref
- Xsphera Biosciences, Translational Medicine group, Boston, MA, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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15
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Gupta J, Tayyib NA, Jalil AT, Hlail SH, Zabibah RS, Vokhidov UN, Alsaikhan F, Ramaiah P, Chinnasamy L, Kadhim MM. Angiogenesis and prostate cancer: MicroRNAs comes into view. Pathol Res Pract 2023; 248:154591. [PMID: 37343381 DOI: 10.1016/j.prp.2023.154591] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/01/2023] [Accepted: 06/03/2023] [Indexed: 06/23/2023]
Abstract
Angiogenesis, the formation of new blood vessels, is an important stage in the growth of cancer. Extracellular matrix, endothelial cells, and soluble substances must be carefully coordinated during the multistep procedure of angiogenesis. Inducers and inhibitors have been found to control pretty much every phase. In addition to benign prostatic hyperplasia, prostatic intraepithelial neoplasia, and angiogenesis have a critical role in the initiation and progression of prostate cancer. MicroRNA (miRNA) is endogenous, short, non-coding RNA molecules of almost 22 nucleotides play a role in regulating cellular processes and regulating several genes' expression. Through controlling endothelial migration, differentiation, death, and cell proliferation, miRNAs have a significant function in angiogenesis. A number of pathological and physiological processes, particularly prostate cancer's emergence, depend on the regulation of angiogenesis. Investigating the functions played with miRNAs in angiogenesis is crucial because it might result in the creation of novel prostate cancer therapies that entail regulating angiogenesis. The function of several miRNAs and its targeting genes engaged in cancer of the prostate angiogenesis will be reviewed in this review in light of the most recent developments. The potential clinical utility of miRNAs potentially a novel therapeutic targets will also be explored, as well as their capacity to control prostate cancer angiogenesis and the underlying mechanisms.
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Affiliation(s)
- Jitendra Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura 281406, U.P., India.
| | - Nahla A Tayyib
- Faculty of Nursing, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Hilla 51001, Babylon, Iraq.
| | | | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Ulug'bek N Vokhidov
- Department of ENT Diseases, Head of the Department of Quality Education, Tashkent State Dental Institute, Tashkent, Uzbekistan; Research scholar, Department of Scientific affairs, Samarkand State Medical Institute, Amir Temur Street 18, Samarkand, Uzbekistan
| | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia.
| | | | | | - Mustafa M Kadhim
- Department of Dentistry, Kut University College, Kut, Wasit 52001, Iraq; Medical Laboratory Techniques Department, Al-Farahidi University, Baghdad 10022 Iraq
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16
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Sameti P, Tohidast M, Amini M, Bahojb Mahdavi SZ, Najafi S, Mokhtarzadeh A. The emerging role of MicroRNA-182 in tumorigenesis; a promising therapeutic target. Cancer Cell Int 2023; 23:134. [PMID: 37438760 DOI: 10.1186/s12935-023-02972-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 06/13/2023] [Indexed: 07/14/2023] Open
Abstract
A wide range of studies have indicated that microRNAs (miRNAs), a type of small single-stranded regulatory RNAs, are dysregulated in a different variety of human cancers. Therefore, they are expected to play important roles in tumorigenesis by functioning as oncogenic (oncomiRs) or tumor-suppressive miRNAs. Subsequently, their potential as diagnostic and therapeutic targets for malignancies has attracted attention in recent years. In particular, studies have revealed the aberrant expression of miR-182 through tumorigenesis and its important roles in various aspects of malignancies, including proliferation, metastasis, and chemoresistance. Accumulating reports have illustrated that miR-182, as a dual-role regulator, directly or indirectly regulates the expression of a wide range of genes and modulates the activity of various signaling pathways involved in tumor progression, such as JAK / STAT3, Wnt / β-catenin, TGF-β, and P13K / AKT. Therefore, considering the high therapeutic and diagnostic potential of miR-182, this review aims to point out the effects of miR-182 dysregulation on the signaling pathways involved in tumorigenesis.
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Affiliation(s)
- Pouriya Sameti
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Tohidast
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Amini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Souzan Najafi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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17
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Genc S, Yagci T, Vageli DP, Dundar R, Doukas PG, Doukas SG, Tolia M, Chatzakis N, Tsatsakis A, Taghizadehghalehjoughi A. Exosomal MicroRNA-223, MicroRNA-146, and MicroRNA-21 Profiles and Biochemical Changes in Laryngeal Cancer. ACS Pharmacol Transl Sci 2023; 6:820-828. [PMID: 37200807 PMCID: PMC10186621 DOI: 10.1021/acsptsci.3c00038] [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: 02/23/2023] [Indexed: 05/20/2023]
Abstract
Laryngeal squamous cell carcinoma (LSCC) is one of the most aggressive cancers, and its early diagnosis is urgent. Exosomes are believed to have diagnostic significance in cancer. However, the role of serum exosomal microRNAs, miR-223, miR-146, and miR-21, and phosphatase and tensin homologue (PTEN) and hemoglobin subunit delta (HBD) mRNAs in LSCC is unclear. Exosomes were isolated from the blood serum of 10 LSCC patients and 10 healthy controls to perform scanning electron microscopy and liquid chromatography quadrupole time-of-flight mass spectrometry analyses to characterize them and to undergo reverse transcription polymerase chain reaction to identify miR-223, miR-146, miR-21, and PTEN and HBD mRNA expression phenotypes. Biochemical parameters, including serum C-reactive protein (CRP) and vitamin B12, were also obtained. Serum exosomes of 10-140 nm were isolated from LSCC and controls. Serum exosomal miR-223, miR-146, and PTEN were found to be significantly decreased (p < 0.05), in contrast to serum exosomal miRNA-21 (p < 0.01), and serum vitamin B12 and CRP (p < 0.05) were found to be significantly increased, in LSCC vs controls. Our novel data show that the combination of reduced serum exosomal miR-223, miR-146, and miR-21 profiles and biochemical alterations in CRP and vitamin B12 levels may be useful indicators of LSCC that could be validated by large studies. Our findings also suggest a possible negative regulatory effect of miR-21 on PTEN in LSCC, encouraging a more extensive investigation of its role.
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Affiliation(s)
- Sidika Genc
- Faculty
of Medicine, Department of Medical Pharmacology, Bilecik Seyh Edebali University, Bilecik 11230, Turkey
| | - Tarik Yagci
- Faculty
of Medicine, Department of ENT, Bilecik
Seyh Edebali University, Bilecik 11230, Turkey
| | - Dimitra P. Vageli
- Yale
Larynx Laboratory, Department of Surgery (Otolaryngology), Yale School of Medicine, New Haven, Connecticut 06510, United States
| | - Riza Dundar
- Faculty
of Medicine, Department of ENT, Bilecik
Seyh Edebali University, Bilecik 11230, Turkey
| | - Panagiotis G. Doukas
- Yale
Larynx Laboratory, Department of Surgery (Otolaryngology), Yale School of Medicine, New Haven, Connecticut 06510, United States
| | - Sotirios G. Doukas
- Department
of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Peter University Hospital, New Brunswick New Jersey 08901-1780, United States
- Department
of Forensic Sciences and Toxicology, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Maria Tolia
- Department
of Radiology, Faculty of Medicine, University
of Crete, 71003 Heraklion, Greece
| | - Nikolaos Chatzakis
- Otorhinolaryngologist
Consultant, ENT Department of University
Hospital of Crete, 71003 Heraklion, Greece
| | - Aristidis Tsatsakis
- Department
of Forensic Sciences and Toxicology, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Ali Taghizadehghalehjoughi
- Faculty
of Medicine, Department of Medical Pharmacology, Bilecik Seyh Edebali University, Bilecik 11230, Turkey
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18
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Farasati Far B, Vakili K, Fathi M, Yaghoobpoor S, Bhia M, Naimi-Jamal MR. The role of microRNA-21 (miR-21) in pathogenesis, diagnosis, and prognosis of gastrointestinal cancers: A review. Life Sci 2023; 316:121340. [PMID: 36586571 DOI: 10.1016/j.lfs.2022.121340] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/16/2022] [Accepted: 12/26/2022] [Indexed: 12/29/2022]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs regulating the expression of several target genes. miRNAs play a significant role in cancer biology, as they can downregulate their corresponding target genes by impeding the translation of mRNA (at the mRNA level) as well as degrading mRNAs by binding to the 3'-untranslated (UTR) regions (at the protein level). miRNAs may be employed as cancer biomarkers. Therefore, miRNAs are widely investigated for early detection of cancers which can lead to improved survival rates and quality of life. This is particularly important in the case of gastrointestinal cancers, where early detection of the disease could substantially impact patients' survival. MicroRNA-21 (miR-21 or miRNA-21) is one of the most frequently researched miRNAs, where it is involved in the pathophysiology of cancer and the downregulation of several tumor suppressor genes. In gastrointestinal cancers, miR-21 regulates phosphatase and tensin homolog (PTEN), programmed cell death 4 (PDCD4), mothers against decapentaplegic homolog 7 (SMAD7), phosphatidylinositol 3-kinase /protein kinase B (PI3K/AKT), matrix metalloproteinases (MMPs), β-catenin, tropomyosin 1, maspin, and ras homolog gene family member B (RHOB). In this review, we investigate the functions of miR-21 in pathogenesis and its applications as a diagnostic and prognostic cancer biomarker in four different gastrointestinal cancers, including colorectal cancer (CRC), pancreatic cancer (PC), gastric cancer (GC), and esophageal cancer (EC).
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Affiliation(s)
- Bahareh Farasati Far
- Department of Chemistry, Iran University of Science and Technology, Tehran, Iran
| | - Kimia Vakili
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mobina Fathi
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shirin Yaghoobpoor
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohammed Bhia
- Student Research Committee, Department of Pharmaceutics and Nanotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - M Reza Naimi-Jamal
- Department of Chemistry, Iran University of Science and Technology, Tehran, Iran.
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19
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Ghaemi Z, Mowla SJ, Soltani BM. Novel splice variants of LINC00963 suppress colorectal cancer cell proliferation via miR-10a/miR-143/miR-217/miR-512-mediated regulation of PI3K/AKT and Wnt/β-catenin signaling pathways. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2023; 1866:194921. [PMID: 36804476 DOI: 10.1016/j.bbagrm.2023.194921] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 01/28/2023] [Accepted: 02/10/2023] [Indexed: 02/18/2023]
Abstract
Emerging evidence has shown lncRNAs play important roles in signaling pathways involved in colorectal cancer (CRC) carcinogenesis. However, only a few functional lncRNAs have been extensively researched, especially in CRC-related signaling pathways. Looking for novel candidate regulators of CRC incidence and progression, using available RNA-seq and microarray datasets, LINC00963 was introduced as a bona fide oncogenic-lncRNA. Consistently, RT-qPCR results showed that LINC00963 was up-regulated in CRC tissues. However, our attempt to amplify the full-length lncRNA from cDNA resulted in the discovery of two novel variants (LINC00963-v2 & LINC00963-v3) that surprisingly, were downregulated in CRC tissues, detected by RT-qPCR. Overexpression of LINC00963-v2/-v3 in HCT116 and SW480 cells resulted in downregulation of the major oncogenes and upregulation of the main tumor suppressor genes involved in PI3K and Wnt signaling, verified through RT-qPCR, western blotting, and TOPFlash assays. Mechanistic studies revealed that LINC00963-v2/-v3 exert their effect on PI3K and Wnt signaling through sponging miR-10a-5p, miR-143-3p, miR-217, and miR-512-3p, which in turn these miRNAs are fine-regulators of PTEN, APC1, and Axin1 tumor suppressor genes verified by dual-luciferase assay and RT-qPCR. At cellular levels, LINC00963-v2/-v3 overexpression suppressed cell proliferation, viability, and migration while increasing the apoptosis of CRC cell lines, detected by PI flow cytometry, colony formation, MTT, RT-qPCR, wound-healing, Transwell, AnnexinV-PE/7AAD, caspase3/7 activity assays, and Hoechst/PI-AO/EB staining. Overall, our results indicate that LINC00963-v2 & -v3 are novel tumor suppressor ceRNAs that attenuate the PI3K and Wnt pathways during CRC incidence and these lncRNAs may serve as potential targets for CRC therapy.
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Affiliation(s)
- Zahra Ghaemi
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Seyed Javad Mowla
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Bahram Mohammad Soltani
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
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20
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Hosseinzadeh R, Bahadori A, Ghorbani M, Mohammadimehr M. Lactobacillus casei condition medium downregulates miR-21 relative expression in HT-29 colorectal cancer cell line. FEMS Microbiol Lett 2023; 370:fnad089. [PMID: 37697675 DOI: 10.1093/femsle/fnad089] [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: 06/14/2023] [Revised: 08/17/2023] [Accepted: 09/07/2023] [Indexed: 09/13/2023] Open
Abstract
Previous research has demonstrated promising outcomes regarding the advantageous impact of probiotics in both cancer prevention and treatment. Nevertheless, the precise molecular mechanisms underpinning these effects remain elusive. Recent investigations have proposed a potential involvement of micro ribonucleic acids (miRNAs) in mediating the favorable influence of probiotics on cancerous cells. This study was designed to evaluate the effect of Lactobacillus casei condition medium on miR-21 relative expression in HT-29 colorectal cancer cells. Lactobacillus casei condition medium mixed with RPMI in different proportions (1:1, 1:3, and 1:7) and utilized to treat HT-29 cells for 24 and 48 h. Subsequently, percentage of early and late apoptotic cells were identified using a flow cytometry instrument. A real-time polymerase chain reaction was carried out to determine the relative expression of miR-21. Our findings revealed that L. casei condition medium induces apoptosis in a time- and dose-dependent manner in HT-29 cells. Furthermore, we found a significantly downregulated miR-21 after treatment with high doses of L. casei condition medium after 48 h. Overall, our results provide valuable insights into a potential mechanism through which L. casei condition medium mediates its apoptotic effect in colorectal cancer cells through downregulation of miR-21. However, further investigations are required to unravel its therapeutic, diagnostic, and treatment monitoring potential.
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Affiliation(s)
- Ramin Hosseinzadeh
- Research Center for Cancer Screening and Epidemiology, Aja University of Medical Sciences, Tehran 1411718541, Iran
| | - Ali Bahadori
- Department of Medical Microbiology, Sarab Faculty of Medical Sciences, Sarab 4543154717, Iran
| | - Mahdi Ghorbani
- Research Center for Cancer Screening and Epidemiology, Aja University of Medical Sciences, Tehran 1411718541, Iran
| | - Mojgan Mohammadimehr
- Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran 1411718541, Iran
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21
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Ko B, Hanna M, Yu M, Grady WM. Epigenetic Alterations in Colorectal Cancer. EPIGENETICS AND HUMAN HEALTH 2023:331-361. [DOI: 10.1007/978-3-031-42365-9_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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22
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Zhang Z, Huang Y, Li J, Su F, Kuo JC, Hu Y, Zhao X, Lee RJ. Antitumor Activity of Anti-miR-21 Delivered through Lipid Nanoparticles. Adv Healthc Mater 2023; 12:e2202412. [PMID: 36412002 PMCID: PMC11468686 DOI: 10.1002/adhm.202202412] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/17/2022] [Indexed: 11/23/2022]
Abstract
The ability of lipid nanoparticles (LNPs) to deliver nucleic acids have shown a great therapeutic potential to treat a variety of diseases. Here, an optimized formulation of QTsome lipid nanoparticles (QTPlus) is utilized to deliver an anti-miR-21 (AM21) against cancer. The miR-21 downstream gene regulation and antitumor activity is evaluated using mouse and human cancer cells and macrophages. The antitumor activity of QTPlus encapsulating AM21 (QTPlus-AM21) is further evaluated in combination with erlotinib and atezolizumab (ATZ). QTPlus-AM21 demonstrates a superior miR-21-dependent gene regulation and eventually inhibits A549 non-small cell lung cancer growth in vitro. QTPlus-AM21 further induces chemo-sensitization of A549 cells to erlotinib with a combination index of 0.6 in inhibiting A549 cell growth. When systemically administers to MC38 tumor-bearing mouse model, QTPlus-AM21 exhibits an antitumor immune response with over 80% tumor growth inhibition (TGI%) and over twofold and fourfold PD-1 and PD-L1 upregulation in tumors and spleens. The combination therapy of QTPlus-AM21 and ATZ further shows a higher antitumor response (TGI% over 90%) and successfully increases M1 macrophages and CD8 T cells into TME. This study provides new insights into the antitumor mechanism of AM21 and shows great promise of QTPlus-AM21 in combination with chemotherapies and immunotherapies.
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Affiliation(s)
- Zhongkun Zhang
- Division of Pharmaceutics and PharmacologyCollege of PharmacyThe Ohio State University500 W 12th AvenueColumbusOH43210USA
| | - Yirui Huang
- Division of Pharmaceutics and PharmacologyCollege of PharmacyThe Ohio State University500 W 12th AvenueColumbusOH43210USA
| | - Jing Li
- Zhejiang Haichang Biotechnology Co., Ltd.HangzhouZhejiang310000P. R. China
| | - Fei Su
- Zhejiang Haichang Biotechnology Co., Ltd.HangzhouZhejiang310000P. R. China
| | - Jimmy Chun‐Tien Kuo
- Division of Pharmaceutics and PharmacologyCollege of PharmacyThe Ohio State University500 W 12th AvenueColumbusOH43210USA
| | - Yingwen Hu
- The Whiteoak Group, Inc.RockvilleMD20855USA
| | | | - Robert J. Lee
- Division of Pharmaceutics and PharmacologyCollege of PharmacyThe Ohio State University500 W 12th AvenueColumbusOH43210USA
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23
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Essex AL, Deosthale P, Huot JR, Davis HM, Momeni N, Bonetto A, Plotkin LI. miR21 deletion in osteocytes has direct and indirect effects on skeletal muscle in a sex-dimorphic manner in mice. Biol Sex Differ 2022; 13:56. [PMID: 36183096 PMCID: PMC9526971 DOI: 10.1186/s13293-022-00465-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 09/26/2022] [Indexed: 11/25/2022] Open
Abstract
Background Osteocytic microRNA21 (miR21) removal alters cytokine production and bone mass by modulating osteoclast and osteoblast differentiation and activity. Removing osteocytic miR21 increases osteoclast/osteoblast numbers and bone mass in male mice, whereas it decreases osteoclasts/osteoblasts without affecting bone mass in female mice. On the other hand, it leads to sex-independent increases in bone mechanical properties. Because changes in bone remodeling and strength affect skeletal muscle through bone–muscle crosstalk, we investigated whether osteocytic miR21 deletion influences skeletal muscle. Methods miR21fl/fl mice and 8kbDMP1-Cre mice were mated to obtain miR21-deficient mice primarily in the osteocyte (OtmiR21Δ) and littermate controls (miR21fl/fl). Four-month-old male and female mice were analyzed. Body composition was examined by DXA/Piximus and gene expression was assessed by qPCR. Ex vivo cultures of long bones devoid of bone-marrow cells from male and female 4-month-old were maintained for 48 h. Conditioned media were collected and used for the C2C12 assays. Two-way ANOVA analyses were performed to determine the contributions of genotype and sex and their interaction to the effects of miR21 deficiency. Results Lean body mass was increased only in female OtmiR21Δ mice, although miR21 levels in soleus muscle were similar in miR21fl/fl (0.05 ± 0.02) and OtmiR21Δ (0.09 ± 0.04) mice. Female, but not male, OtmiR21Δ mice exhibited increased soleus (42%) and gastrocnemius (21%) muscle weight compared to miR21fl/fl littermates. However, muscle strength and gastrocnemius muscle fiber cross-sectional area were unaltered for either sex. Kinase phosphorylation (phospho/total protein ratio) in soleus muscle, measured as a surrogate for kinase activity by means of multiplex analysis, was also selectively changed depending on the mouse sex. Thus, female OtmiR21Δ mice had higher T185/Y187-ERK1/2 but lower S473-Akt phosphorylation than miR21fl/fl controls, while male OtmiR21Δ mice had higher S473-Akt phosphorylation, suggesting sex-dimorphic shifts in anabolic vs. catabolic signaling. Consistently, levels of FOXO3 and MuRF-1, known to be regulated by Akt, were only increased in male OtmiR21Δ mice. Atrogin-1 mRNA levels were upregulated in female OtmiR21Δ mice, suggesting a potential shift in protein regulation. Sex-specific effects were also found by exposing myotube cultures to conditioned media from 48-h-cultured marrow-flushed bones. Thus 5-day differentiated C2C12 myotubes treated with conditioned media of female OtmiR21Δ mice exhibit 12% higher average diameter compared to cells exposed to miR21fl/fl bone conditioned media. Yet, conditioned media from male bones had no effect on myotube size. Conclusions We present a novel aspect of bone–muscle crosstalk in which osteocyte-derived miR21 influences skeletal muscle size, but not strength, in female but not male mice; whereas, intracellular signaling alterations resulting from loss of miR21 seem to alter protein dynamics in a sex-dimorphic fashion. Supplementary Information The online version contains supplementary material available at 10.1186/s13293-022-00465-9.
Osteocytic microRNA21 (miR21) removal in OtmiR21Δ mice alters cytokine production and bone mass by modulating osteoclast and osteoblast differentiation and activity. Only female, but not male, OtmiR21Δ mice exhibit higher lean body mass and soleus and gastrocnemius muscle weight compared to miR21fl/fl littermates. Sex-dependent consequences of osteocytic miR21 deletion on skeletal muscle were also found at protein and gene expression level. We conclude that osteocyte-derived miR21 influences skeletal muscle size, but not strength, in female but not male mice; whereas, intracellular signaling alterations resulting from loss of miR21 seem to alter protein dynamics in a sex-dimorphic fashion.
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Affiliation(s)
- Alyson L Essex
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.,Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA.,Indiana Center for Musculoskeletal Health, Indiana University, Indianapolis, IN, USA
| | - Padmini Deosthale
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.,Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
| | - Joshua R Huot
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.,Indiana Center for Musculoskeletal Health, Indiana University, Indianapolis, IN, USA.,Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Hannah M Davis
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.,Ely Lilly and Company, Indianapolis, IN, USA
| | - Nicholas Momeni
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Andrea Bonetto
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA. .,Indiana Center for Musculoskeletal Health, Indiana University, Indianapolis, IN, USA. .,Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA. .,Simon Comprehensive Cancer Center, Indianapolis, IN, USA. .,University of Colorado Anschutz Medical Campus and University of Colorado Comprehensive Cancer Center, Aurora, CO, USA.
| | - Lilian I Plotkin
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA. .,Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA. .,Indiana Center for Musculoskeletal Health, Indiana University, Indianapolis, IN, USA.
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24
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Wei S, Hu W, Feng J, Geng Y. Promotion or remission: a role of noncoding RNAs in colorectal cancer resistance to anti-EGFR therapy. Cell Commun Signal 2022; 20:150. [PMID: 36131281 PMCID: PMC9490904 DOI: 10.1186/s12964-022-00960-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 08/16/2022] [Indexed: 11/10/2022] Open
Abstract
Anti-epidermal-growth-factor-receptor (EGFR) monoclonal antibodies (mAbs) are of great significance for RAS and BRAF wild-type metastatic colorectal cancer (mCRC) patients. However, the generation of primary and secondary resistance to anti-EGFR mAbs has become an important factor restricting its efficacy. Recent studies have revealed that non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are implicated in anti-EGFR antibodies resistance, affecting the sensitivity of CRC cells to Cetuximab and Panitumumab. This paper briefly reviewed the research advance of the expression, signaling network and functional mechanism of ncRNAs related to anti-EGFR mAbs resistance in CRC, as well as their relationship with clinical prognosis and the possibility of therapeutic targets. In addition, some ncRNAs that are involved in the regulation of signaling pathways or genes related to anti-EGFR resistance, but need to be further verified by resistance experiments were also included in this review, thereby providing more ideas and basis for ncRNAs as CRC prognostic markers and anti-EGFR therapy sensitizers. Video Abstract.
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Affiliation(s)
- Shanshan Wei
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, Jiangsu, China
| | - Wenwei Hu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, Jiangsu, China.,Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Jun Feng
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, Jiangsu, China
| | - Yiting Geng
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, Jiangsu, China.
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25
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Bartolomeu AR, Romualdo GR, Lisón CG, Besharat ZM, Corrales JAM, Chaves MÁG, Barbisan LF. Caffeine and Chlorogenic Acid Combination Attenuate Early-Stage Chemically Induced Colon Carcinogenesis in Mice: Involvement of oncomiR miR-21a-5p. Int J Mol Sci 2022; 23:ijms23116292. [PMID: 35682971 PMCID: PMC9181067 DOI: 10.3390/ijms23116292] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/27/2022] [Accepted: 05/28/2022] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is one of most common cancers worldwide, with high rates of mortality. Epidemiological findings demonstrate that coffee consumption reduces the risk of developing CRC by ~13%. In general, in vivo and in vitro findings demonstrate the antiproliferative, antioxidant and proapoptotic effects of brewed coffee or major bioavailable coffee compounds. Thus, it was assessed whether caffeine (CAF) and/or chlorogenic acid (CGA) attenuates the early-stage of chemically induced mouse colon carcinogenesis. Male Swiss mice were submitted to a 1,2-dimethylhydrazine/deoxycholic acid (DMH/DCA)-induced colon carcinogenesis model. These animals received CAF (50 mg/kg), CGA (25 mg/kg) or CAF+CGA (50 + 25 mg/kg) intragastrically for five times/week for ten weeks. CAF+CGA had the most pronounced effects on decreasing epithelial cell proliferation (Ki-67) and increasing apoptosis (cleaved caspase-3) in colonic crypts. This treatment also decreased the levels of proinflammatory cytokines IL-6, IL-17 and TNF-α, and downregulated the oncomiR miR-21a-5p in the colon. Accordingly, the analysis of miR-21a-5p targets demonstrated the genes involved in the negative regulation of proliferation and inflammation, and the positive regulation of apoptosis. Ultimately, CAF+CGA attenuated preneoplastic aberrant crypt foci (ACF) development. Our findings suggest that a combination of coffee compounds reduces early-stage colon carcinogenesis by the modulation of miR-21a-5p expression, highlighting the importance of coffee intake to prevent CRC.
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Affiliation(s)
- Ariane Rocha Bartolomeu
- Department of Pathology, Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil; (A.R.B.); (G.R.R.)
| | - Guilherme Ribeiro Romualdo
- Department of Pathology, Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil; (A.R.B.); (G.R.R.)
- Department of Structural and Functional Biology, Biosciences Institute, São Paulo State University (UNESP), Botucatu 18618-689, SP, Brazil
| | - Carmen Griñán Lisón
- Biosanitary Research Institute of Granada (ibs.GRANADA), University Hospitals of Granada, University of Granada, 18012 Granada, Spain; (C.G.L.); (J.A.M.C.); (M.Á.G.C.)
- GENYO (Centre for Genomics and Oncological Research), Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain
- UGC de Oncología Médica, Complejo Hospitalario de Jaen, 23007 Jaen, Spain
| | - Zein Mersini Besharat
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy;
| | - Juan Antonio Marchal Corrales
- Biosanitary Research Institute of Granada (ibs.GRANADA), University Hospitals of Granada, University of Granada, 18012 Granada, Spain; (C.G.L.); (J.A.M.C.); (M.Á.G.C.)
- Department of Human Anatomy and Embryology, School of Medicine, University of Granada, 18016 Granada, Spain
| | - Maria Ángel García Chaves
- Biosanitary Research Institute of Granada (ibs.GRANADA), University Hospitals of Granada, University of Granada, 18012 Granada, Spain; (C.G.L.); (J.A.M.C.); (M.Á.G.C.)
- Department of Biochemistry and Molecular Biology III and Immunology, University of Granada, 18016 Granada, Spain
| | - Luís Fernando Barbisan
- Department of Structural and Functional Biology, Biosciences Institute, São Paulo State University (UNESP), Botucatu 18618-689, SP, Brazil
- Correspondence:
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Yang F, Xuan G, Chen Y, Cao L, Zhao M, Wang C, Chen E. MicroRNAs Are Key Molecules Involved in the Gene Regulation Network of Colorectal Cancer. Front Cell Dev Biol 2022; 10:828128. [PMID: 35465317 PMCID: PMC9023807 DOI: 10.3389/fcell.2022.828128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 03/07/2022] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common types of cancer and one of the leading causes of mortality worldwide. MicroRNAs (miRNAs) play central roles in normal cell maintenance, development, and other physiological processes. Growing evidence has illustrated that dysregulated miRNAs can participate in the initiation, progression, metastasis, and therapeutic resistance that confer miRNAs to serve as clinical biomarkers and therapeutic targets for CRC. Through binding to the 3′-untranslated region (3′-UTR) of target genes, miRNAs can lead to target mRNA degradation or inhibition at a post-transcriptional level. During the last decade, studies have found numerous miRNAs and their potential targets, but the complex network of miRNA/Targets in CRC remains unclear. In this review, we sought to summarize the complicated roles of the miRNA-target regulation network (Wnt, TGF-β, PI3K-AKT, MAPK, and EMT related pathways) in CRC with up-to-date, high-quality published data. In particular, we aimed to discuss the downstream miRNAs of specific pathways. We hope these data can be a potent supplement for the canonical miRNA-target regulation network.
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Affiliation(s)
- Fangfang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, China
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an, China
| | - Guoyun Xuan
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi’an, China
| | - Yixin Chen
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, China
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an, China
| | - Lichao Cao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, China
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an, China
| | - Min Zhao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, China
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an, China
| | - Chen Wang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, China
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an, China
| | - Erfei Chen
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an, China
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an, China
- *Correspondence: Erfei Chen,
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27
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Jorgensen BG, Ro S. MicroRNAs and 'Sponging' Competitive Endogenous RNAs Dysregulated in Colorectal Cancer: Potential as Noninvasive Biomarkers and Therapeutic Targets. Int J Mol Sci 2022; 23:2166. [PMID: 35216281 PMCID: PMC8876324 DOI: 10.3390/ijms23042166] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 01/28/2022] [Accepted: 02/02/2022] [Indexed: 12/13/2022] Open
Abstract
The gastrointestinal (GI) tract in mammals is comprised of dozens of cell types with varied functions, structures, and histological locations that respond in a myriad of ways to epigenetic and genetic factors, environmental cues, diet, and microbiota. The homeostatic functioning of these cells contained within this complex organ system has been shown to be highly regulated by the effect of microRNAs (miRNA). Multiple efforts have uncovered that these miRNAs are often tightly influential in either the suppression or overexpression of inflammatory, apoptotic, and differentiation-related genes and proteins in a variety of cell types in colorectal cancer (CRC). The early detection of CRC and other GI cancers can be difficult, attributable to the invasive nature of prophylactic colonoscopies. Additionally, the levels of miRNAs associated with CRC in biofluids can be contradictory and, therefore, must be considered in the context of other inhibiting competitive endogenous RNAs (ceRNA) such as lncRNAs and circRNAs. There is now a high demand for disease treatments and noninvasive screenings such as testing for bloodborne or fecal miRNAs and their inhibitors/targets. The breadth of this review encompasses current literature on well-established CRC-related miRNAs and the possibilities for their use as biomarkers in the diagnoses of this potentially fatal GI cancer.
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Affiliation(s)
| | - Seungil Ro
- Department of Physiology & Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA;
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28
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Fragiadaki M. Lessons from microRNA biology: Top key cellular drivers of Autosomal Dominant Polycystic Kidney Disease. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166358. [PMID: 35150832 DOI: 10.1016/j.bbadis.2022.166358] [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: 09/30/2021] [Revised: 02/02/2022] [Accepted: 02/03/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND Numerous microRNAs (miRs), small RNAs that target several pathways, have been implicated in the development of Autosomal Dominant Polycystic Kidney Disease (ADPKD), which is the most common genetic cause of kidney failure. The hallmark of ADPKD is tissue overgrowth and hyperproliferation, eventually leading to kidney failure. SCOPE OF THE REVIEW Many miRs are dysregulated in disease, yet the intracellular pathways regulated by miRs are less well described in ADPKD. Here, I summarise all the differentially expressed miRs in ADPKD and highlight the top miR-regulated cellular driver of disease. MAJOR CONCLUSIONS Literature review has identified 53 abnormally expressed miRs in ADPKD. By performing bioinformatics analysis of their target genes I present 10 key intracellular pathways that drive ADPKD progression. The top key drivers are divided into three main areas: (i) hyperproliferation and the role of JAK/STAT and PI3K pathways (ii) DNA damage and (iii) inflammation and NFκB. GENERAL SIGNIFICANCE The description of the 10 top cellular drivers of ADPKD, derived by analysis of miR signatures, is of paramount importance in better understanding the key processes resulting in pathophysiological changes that underlie disease.
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Affiliation(s)
- Maria Fragiadaki
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, S10 2RX, United Kingdom of Great Britain and Northern Ireland.
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29
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Sanaei MJ, Baghery Saghchy Khorasani A, Pourbagheri-Sigaroodi A, Shahrokh S, Zali MR, Bashash D. The PI3K/Akt/mTOR axis in colorectal cancer: Oncogenic alterations, non-coding RNAs, therapeutic opportunities, and the emerging role of nanoparticles. J Cell Physiol 2021; 237:1720-1752. [PMID: 34897682 DOI: 10.1002/jcp.30655] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 11/02/2021] [Accepted: 11/24/2021] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one of the deadliest human malignancies worldwide. Several molecular pathways have been demonstrated to be involved in the initiation and development of CRC which among them, the overactivation of the phosphatidyl-inositol 3-kinase (PI3K)/Akt/mTOR axis is of importance. The current review aims to unravel the mechanisms by which the PI3K/Akt/mTOR pathway affects CRC progression; and also, to summarize the original data obtained from international research laboratories on the oncogenic alterations and polymorphisms affecting this pathway in CRC. Besides, we provide a special focus on the regulatory role of noncoding RNAs targeting the PI3K/Akt/mTOR pathway in this malignancy. Questions on how this axis is involved in the inhibition of apoptosis, in the induction of drug resistance, and the angiogenesis, epithelial to mesenchymal transition, and metastasis are also responded. We also discussed the PI3K/Akt pathway-associated prognostic and predictive biomarkers in CRC. In addition, we provide a general overview of PI3K/Akt/mTOR pathway inhibition whether by chemical-based drugs or by natural-based medications in the context of CRC, either as monotherapy or in combination with other therapeutic agents; however, those treatments might have life-threatening side effects and toxicities. To the best of our knowledge, the current review is one of the first ones highlighting the emerging roles of nanotechnology to overcome challenges related to CRC therapy in the hope that providing a promising platform for the treatment of CRC.
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Affiliation(s)
- Mohammad-Javad Sanaei
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Shahrokh
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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30
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Zhang Y, Huang S, Yang G, Zou L, Huang X, Liu S. The Role of miRNAs during Endoplasmic Reticulum Stress Induced Apoptosis in Digestive Cancer. J Cancer 2021; 12:6787-6795. [PMID: 34659567 PMCID: PMC8517994 DOI: 10.7150/jca.62352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 09/18/2021] [Indexed: 11/10/2022] Open
Abstract
Digestive cancer is one of the leading causes of cancer mortality in the world. Despite a number of studies being conducted, the exact mechanism for treating digestive cancer has not yet been fully understood. To survive, digestive cancer cells are subjected to various internal and external adverse factors, such as hypoxia, nutritional deficiencies or drug toxicity, resulting in accumulation of misfolded and unfolded protein in endoplasmic reticulum (ER) lumen further leading to ER stress and the unfolded protein response (UPR). During the last years, studies on the relationship between ER stress and microRNAs (miRNAs) has burst on the scene. miRNAs are non-coding RNAs with a length of 21~22nucleotides involved in post-transcriptional regulation of gene expression, which could be regarded as oncomiRs (tumor inducers) and tumor suppressors regulating cancer cell proliferation, invasion, and apoptosis by differently affecting the expression of genes related to cancer cell signaling. Therefore, investigating the interaction between ER stress and miRNAs is crucial for developing effective cancer treatment and prevention strategies. In this review, we mainly discuss miRNAs focusing on its regulation, role in ER stress induced apoptosis in Digestive cancer, expound the underlying mechanism, thus provides a theoretical foundation for finding new therapeutic targets of digestive cancer.
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Affiliation(s)
- Yujing Zhang
- Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, 410081, China.,Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Hunan Normal University, Changsha, 410081, China
| | - Shuai Huang
- Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, 410081, China.,Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Hunan Normal University, Changsha, 410081, China
| | - Gang Yang
- Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, 410081, China.,Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Hunan Normal University, Changsha, 410081, China
| | - Lianhong Zou
- Hunan Provincial Institute of Emergency Medicine, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, 410015, China
| | - Xin Huang
- Key Laboratory of Molecular Epidemiology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, 410081, China.,Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Hunan Normal University, Changsha, 410081, China
| | - Sulai Liu
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, 410015, China
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31
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Abstract
MicroRNAs (miRNAs), a class of small noncoding RNA, posttranscriptionally regulate the expression of genes. Aberrant expression of miRNA is reported in various types of cancer. Since the first report of oncomiR-21 involvement in the glioma, its upregulation was reported in multiple cancers and was allied with high oncogenic property. In addition to the downregulation of tumor suppressor genes, the miR-21 is also associated with cancer resistance to various chemotherapy. The recent research is appraising miR-21 as a promising cancer target and biomarker for early cancer detection. In this review, we briefly explain the biogenesis and regulation of miR-21 in cancer cells. Additionally, the review features the assorted genes/pathways regulated by the miR-21 in various cancer and cancer stem cells.
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32
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Karimi F, Mollaei H. Potential of miRNAs in cervical cancer chemoresistance. GENE REPORTS 2021. [DOI: 10.1016/j.genrep.2021.101109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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33
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Moafian Z, Maghrouni A, Soltani A, Hashemy SI. Cross-talk between non-coding RNAs and PI3K/AKT/mTOR pathway in colorectal cancer. Mol Biol Rep 2021; 48:4797-4811. [PMID: 34057685 DOI: 10.1007/s11033-021-06458-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 05/27/2021] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is the third commonest cancer globally, with metastasis being the reason for cancer-associated mortality. Much is still unknown biochemically about CRC, and with current treatments that are not wholly effective over time, new therapeutics are urgently needed. Emerging evidence has shown the importance of non-coding RNAs such as lncRNAs and miRNAs functions in the development and progression of CRC. However, the exact underlying mechanism of these types of RNAs in CRC is still mostly unknown. PI3K/AKT/mTOR pathway contributes to many cellular processes, and dysregulation of this pathway frequently occurs in cancers. In this review, the authors have mostly focused on the significant non-coding RNAs regulators of the PI3K/AKT/mTOR pathway and their contribution to the development or inhibition of CRC and their potential as diagnostic or therapeutic targets in CRC treatment.
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Affiliation(s)
- Zeinab Moafian
- Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abolfazl Maghrouni
- Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Arash Soltani
- Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Isaac Hashemy
- Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. .,Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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34
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Roberti SL, Gatti CR, Fornes D, Higa R, Jawerbaum A. Diets enriched in PUFAs at an early postimplantation stage prevent embryo resorptions and impaired mTOR signaling in the decidua from diabetic rats. J Nutr Biochem 2021; 95:108765. [PMID: 33965535 DOI: 10.1016/j.jnutbio.2021.108765] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 02/24/2021] [Accepted: 04/29/2021] [Indexed: 12/28/2022]
Abstract
Maternal diabetes increases the risk of embryo resorptions and impairs embryo development. Decidualization is crucial for embryo development and regulated by mTOR signaling. However, little is known about how maternal diabetes affects the decidua at early postimplantation stages and whether dietary treatments enriched in polyunsaturated fatty acids (PUFAs) can prevent decidual alterations. Here, we determined resorption rates, decidual mTOR pathways and markers of decidual function and remodeling in diabetic rats fed or not with diets enriched in PUFAs exclusively during the early postimplantation period. Pregestational streptozotocin-induced diabetic Albino Wistar rats and controls were fed or not with diets enriched in 6% sunflower oil or 6% chia oil (enriched in n-6 or n-3 PUFAs, respectively) on days 7, 8 and 9 of pregnancy and evaluated on day 9 of pregnancy. Maternal diabetes induced an 11-fold increase in embryo resorptions, which was prevented by both PUFAs-enriched diets despite no changes in maternal glycemia. The activity of mTOR pathway was decreased in the decidua from diabetic rats, an alteration prevented by the PUFAs-enriched diets. PUFAs-enriched diets prevented increased expression of Foxo1 (a negative regulator of mTOR) and reduced expression of miR-21 (a negative regulator of Foxo1). These diets also prevented reduced markers of decidual function (leukemia inhibitory factor and IGFBP1 expression and MMPs activity) in diabetic rat decidua. We identified the early post implantation as a crucial stage for pregnancy success, in which dietary PUFAs can protect diabetic pregnancies from embryo resorptions, decidual mTOR signaling impairments, and altered markers of decidual function and remodeling.
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Affiliation(s)
- Sabrina Lorena Roberti
- Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Laboratory of Reproduction and Metabolism, CEFYBO, Buenos Aires, Argentina
| | - Cintia Romina Gatti
- Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Laboratory of Reproduction and Metabolism, CEFYBO, Buenos Aires, Argentina
| | - Daiana Fornes
- Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Laboratory of Reproduction and Metabolism, CEFYBO, Buenos Aires, Argentina
| | - Romina Higa
- Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Laboratory of Reproduction and Metabolism, CEFYBO, Buenos Aires, Argentina
| | - Alicia Jawerbaum
- Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Laboratory of Reproduction and Metabolism, CEFYBO, Buenos Aires, Argentina.
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35
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Im J, Nam SK, Lee HS. MicroRNA-552 expression in colorectal cancer and its clinicopathological significance. J Pathol Transl Med 2021; 55:125-131. [PMID: 33596633 PMCID: PMC7987523 DOI: 10.4132/jptm.2021.01.17] [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: 11/13/2020] [Accepted: 01/17/2021] [Indexed: 12/24/2022] Open
Abstract
Background MicroRNA-552 (miR-552) has been reported to correlate with the development and progression of various cancers, including colorectal cancer (CRC). This study aimed to investigate miR-552 expression in cancer tissue samples compared to normal mucosal tissue and its role as a diagnostic or prognostic marker in CRC patients. Methods Normal mucosal tissues and primary cancer tissues from 80 surgically resected CRC specimens were used. Quantitative real-time polymerase chain reaction was performed for miR-552 and U6 small nuclear RNA to analyze miR-552 expression and its clinicopathological significance. Immunohistochemistry for p53 and phosphatase and tension homolog (PTEN) was performed to evaluate their association with miR-552 expression. Results miR-552 expression was significantly higher in primary cancer tissues compared to normal mucosal tissues (p<.001). The expression level of miR552 was inversely correlated with that of PTEN (p=.068) and p53 (p=.004). Survival analysis showed that high miR-552 expression was associated with worse prognosis but this was not statistically significant (p=.255). However, patients with CRC having high miR-552 expression and loss of PTEN expression had significantly worse prognosis than others (p=.029). Conclusions Our results suggest that high miR-552 expression might be a potential diagnostic biomarker for CRC, and its combined analysis with PTEN expression can possibly be used as a prognostic marker.
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Affiliation(s)
- Joon Im
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Soo Kyung Nam
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
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36
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Rodriguez-Casanova A, Costa-Fraga N, Bao-Caamano A, López-López R, Muinelo-Romay L, Diaz-Lagares A. Epigenetic Landscape of Liquid Biopsy in Colorectal Cancer. Front Cell Dev Biol 2021; 9:622459. [PMID: 33614651 PMCID: PMC7892964 DOI: 10.3389/fcell.2021.622459] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 01/05/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies and is a major cause of cancer-related deaths worldwide. Thus, there is a clinical need to improve early detection of CRC and personalize therapy for patients with this disease. In the era of precision oncology, liquid biopsy has emerged as a major approach to characterize the circulating tumor elements present in body fluids, including cell-free DNA and RNA, circulating tumor cells, and extracellular vesicles. This non-invasive tool has allowed the identification of relevant molecular alterations in CRC patients, including some indicating the disruption of epigenetic mechanisms. Epigenetic alterations found in solid and liquid biopsies have shown great utility as biomarkers for early detection, prognosis, monitoring, and evaluation of therapeutic response in CRC patients. Here, we summarize current knowledge of the most relevant epigenetic mechanisms associated with cancer development and progression, and the implications of their deregulation in cancer cells and liquid biopsy of CRC patients. In particular, we describe the methodologies used to analyze these epigenetic alterations in circulating tumor material, and we focus on the clinical utility of epigenetic marks in liquid biopsy as tumor biomarkers for CRC patients. We also discuss the great challenges and emerging opportunities of this field for the diagnosis and personalized management of CRC patients.
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Affiliation(s)
- Aitor Rodriguez-Casanova
- Cancer Epigenomics Laboratory, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela, Spain.,Roche-Chus Joint Unit, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), Santiago de Compostela, Spain
| | - Nicolás Costa-Fraga
- Cancer Epigenomics Laboratory, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela, Spain
| | - Aida Bao-Caamano
- Cancer Epigenomics Laboratory, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela, Spain
| | - Rafael López-López
- Roche-Chus Joint Unit, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), Santiago de Compostela, Spain.,Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela, Spain.,Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain
| | - Laura Muinelo-Romay
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain.,Liquid Biopsy Analysis Unit, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela, Spain
| | - Angel Diaz-Lagares
- Cancer Epigenomics Laboratory, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela, Spain.,Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain
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37
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Jiang R, Chen X, Ge S, Wang Q, Liu Y, Chen H, Xu J, Wu J. MiR-21-5p Induces Pyroptosis in Colorectal Cancer via TGFBI. Front Oncol 2021; 10:610545. [PMID: 33614494 PMCID: PMC7892456 DOI: 10.3389/fonc.2020.610545] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 12/18/2020] [Indexed: 12/24/2022] Open
Abstract
Pyroptosis is a distinct form of programmed cell death in eukaryotic cells that has garnered increasing attention in cancer-related research. Moreover, although miR-21 has been reported as abnormally expressed in colorectal cancer, due to a lack of in-depth research on the transcriptional regulation mechanisms of miR-21, its clinical usage remains limited. Our study is the first, to our knowledge, to compare the clinical manifestations and laboratory phenotypes associated with miR-21-3p and miR-21-5p. Morphologically, the transfection of miR-21-3p or miR-21-5p inhibitors, as well as miR-21-5p mimics into HCT-116 and HT-29 cell lines, induced cell death. Surprisingly, overexpression of miR-21-5p induced cell death more strongly than its knockdown. Mechanistic studies of miR-21-5p overexpression revealed that various inflammatory factors including IL-1β and IL-18 were released, while pyroptosis-associated mRNAs were upregulated and proteins were activated. Moreover, miR-21-5p was found to act as a downstream factor to significantly and directly regulate transforming growth factor beta-induced (TGFB1). Specifically, miR-21-5p overexpression caused downregulation of TGFBI, which may have led to pyroptosis. Collectively, we revealed that miR-21-5p induces pyroptosis in colorectal cancer via TGFBI regulation, thereby providing important mechanistic insights into its antitumor effects and expanding its potential for clinical applications.
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Affiliation(s)
- Rilei Jiang
- School of Basic Medicine Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaolei Chen
- School of Basic Medicine Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shaohua Ge
- Department of Oncology, Kunshan Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Kunshan, China
| | - Qin Wang
- First Clinical Medical College, Nanjing Medical University, Nanjing, China
| | - Yichang Liu
- Department of Oncology, Kunshan Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Kunshan, China
| | - Haijun Chen
- Department of Oncology, Kunshan Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Kunshan, China
| | - Jiatuo Xu
- School of Basic Medicine Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiang Wu
- Department of Oncology, Kunshan Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Kunshan, China
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38
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Peruhova M, Peshevska-Sekulovska M, Krastev B, Panayotova G, Georgieva V, Konakchieva R, Nikolaev G, Velikova TV. What could microRNA expression tell us more about colorectal serrated pathway carcinogenesis? World J Gastroenterol 2020; 26:6556-6571. [PMID: 33268946 PMCID: PMC7673963 DOI: 10.3748/wjg.v26.i42.6556] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 09/24/2020] [Accepted: 10/20/2020] [Indexed: 02/06/2023] Open
Abstract
In the last two decades, the vision of a unique carcinogenesis model for colorectal carcinoma (CRC) has completely changed. In addition to the adenoma to carcinoma transition, colorectal carcinogenesis can also occur via the serrated pathway. Small non-coding RNA, known as microRNAs (miRNAs), were also shown to be involved in progression towards malignancy. Furthermore, increased expression of certain miRNAs in premalignant sessile serrated lesions (SSLs) was found, emphasizing their role in the serrated pathway progression towards colon cancer. Since miRNAs function as post-transcriptional gene regulators, they have enormous potential to be used as useful biomarkers for CRC and screening in patients with SSLs particularly. In this review, we have summarized the most relevant information about the specific role of miRNAs and their relevant signaling pathways among different serrated lesions and polyps as well as in serrated adenocarcinoma. Additional focus is put on the correlation between gut immunity and miRNA expression in the serrated pathway, which remains unstudied.
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Affiliation(s)
- Milena Peruhova
- Department of Gastroenterology, University Hospital Lozenetz, Sofia 1407, Bulgaria
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | | | - Boris Krastev
- Department of Clinical Oncology, MHAT Hospital for Women Health Nadezhda, Sofia 1330, Bulgaria
| | - Gabriela Panayotova
- Department of Gastroenterology, University Hospital Lozenetz, Sofia 1407, Bulgaria
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | - Viktoriya Georgieva
- Department of Gastroenterology, University Hospital Lozenetz, Sofia 1407, Bulgaria
| | | | - Georgi Nikolaev
- Faculty of Biology, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | - Tsvetelina Veselinova Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
- Department of Clinical Immunology, University Hospital Lozenetz, Sofia 1407, Bulgaria
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39
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Akbari G. Emerging roles of microRNAs in intestinal ischemia/reperfusion-induced injury: a review. J Physiol Biochem 2020; 76:525-537. [PMID: 33140255 DOI: 10.1007/s13105-020-00772-y] [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: 04/29/2020] [Accepted: 10/06/2020] [Indexed: 02/06/2023]
Abstract
Intestinal ischemia/reperfusion (II/R) injury is a serious pathological phenomenon in underlying hemorrhagic shock, trauma, strangulated intestinal obstruction, and acute mesenteric ischemia which associated with high morbidity and mortality. MicroRNAs (miRNAs, miRs) are endogenous non-coding RNAs that regulate post-transcriptionally target mRNA translation via degrading it and/or suppressing protein synthesis. This review discusses on the role of some miRNAs in underlying II/R injury. Some of these miRNAs can have protective action through agomiR or specific antagomiR, and others can have destructive effects in the basal level of II/R insult. Based on these literature reviews, II/R injury affects several miRNAs and their specific target genes. Some miRNAs upregulate under condition of II/R injury, and multiple miRNAs downregulate following II/R damage. Data of this review have been collected from the scientific articles published in databases such as Science Direct, Scopus, PubMed, Web of Science, and Scientific Information Database from 2000 to 2020. It is shown a correlation between changes in the expression of miRNAs and autophagy, inflammation, oxidative stress, apoptosis, and epithelial barrier function. Taken together, agomiR or antagomiR of some miRNAs can be considered as one new target for the research and development of innovative drugs to the prevention or treatment of II/R damage.
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Affiliation(s)
- Ghaidafeh Akbari
- Medicinal Plants Research Center, Department of Physiology, School of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran.
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40
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Pérez-Machado G, Berenguer-Pascual E, Bovea-Marco M, Rubio-Belmar PA, García-López E, Garzón MJ, Mena-Mollá S, Pallardó FV, Bas T, Viña JR, García-Giménez JL. From genetics to epigenetics to unravel the etiology of adolescent idiopathic scoliosis. Bone 2020; 140:115563. [PMID: 32768685 DOI: 10.1016/j.bone.2020.115563] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/24/2020] [Accepted: 07/24/2020] [Indexed: 12/11/2022]
Abstract
Scoliosis is defined as the three-dimensional (3D) structural deformity of the spine with a radiological lateral Cobb angle (a measure of spinal curvature) of ≥10° that can be caused by congenital, developmental or degenerative problems. However, those cases whose etiology is still unknown, and affect healthy children and adolescents during growth, are the commonest form of spinal deformity, known as adolescent idiopathic scoliosis (AIS). In AIS management, early diagnosis and the accurate prediction of curve progression are most important because they can decrease negative long-term effects of AIS treatment, such as unnecessary bracing, frequent exposure to radiation, as well as saving the high costs of AIS treatment. Despite efforts made to identify a method or technique capable of predicting AIS progression, this challenge still remains unresolved. Genetics and epigenetics, and the application of machine learning and artificial intelligence technologies, open up new avenues to not only clarify AIS etiology, but to also identify potential biomarkers that can substantially improve the clinical management of these patients. This review presents the most relevant biomarkers to help explain the etiopathogenesis of AIS and provide new potential biomarkers to be validated in large clinical trials so they can be finally implemented into clinical settings.
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Affiliation(s)
| | | | | | - Pedro Antonio Rubio-Belmar
- Institute for Health Research La Fe, IISLaFe, Valencia, Spain; Spine Surgery Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - Eva García-López
- EpiDisease S.L., University of Valencia. Scientific Park. Paterna, Valencia, Spain
| | - María José Garzón
- EpiDisease S.L., University of Valencia. Scientific Park. Paterna, Valencia, Spain
| | - Salvador Mena-Mollá
- EpiDisease S.L., University of Valencia. Scientific Park. Paterna, Valencia, Spain; Department of Physiology, University of Valencia, Faculty of Medicine and Dentistry, Valencia, Spain
| | - Federico V Pallardó
- EpiDisease S.L., University of Valencia. Scientific Park. Paterna, Valencia, Spain; Department of Physiology, University of Valencia, Faculty of Medicine and Dentistry, Valencia, Spain; Consortium Center for Biomedical Network Research ISCIII. Instituto de Salud Carlos III, Valencia, Spain; INCLIVA Health Research Institute, Valencia, Spain
| | - Teresa Bas
- Institute for Health Research La Fe, IISLaFe, Valencia, Spain; Spine Surgery Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - Juan R Viña
- INCLIVA Health Research Institute, Valencia, Spain; Department of Biochemistry, University of Valencia, Faculty of Medicine and Dentistry, Valencia, Spain
| | - José Luis García-Giménez
- EpiDisease S.L., University of Valencia. Scientific Park. Paterna, Valencia, Spain; Department of Physiology, University of Valencia, Faculty of Medicine and Dentistry, Valencia, Spain; Consortium Center for Biomedical Network Research ISCIII. Instituto de Salud Carlos III, Valencia, Spain; INCLIVA Health Research Institute, Valencia, Spain.
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41
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Arasi MB, Pedini F, Valentini S, Felli N, Felicetti F. Advances in Natural or Synthetic Nanoparticles for Metastatic Melanoma Therapy and Diagnosis. Cancers (Basel) 2020; 12:cancers12102893. [PMID: 33050185 PMCID: PMC7601614 DOI: 10.3390/cancers12102893] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/05/2020] [Accepted: 10/07/2020] [Indexed: 12/17/2022] Open
Abstract
Advanced melanoma is still a major challenge in oncology. In the early stages, melanoma can be treated successfully with surgery and the survival rate is high, nevertheless the survival rate drops drastically after metastasis dissemination. The identification of parameters predictive of the prognosis to support clinical decisions and of new efficacious therapies are important to ensure patients the best possible prognosis. Recent progress in nanotechnology allowed the development of nanoparticles able to protect drugs from degradation and to deliver the drug to the tumor. Modification of the nanoparticle surface by specific molecules improves retention and accumulation in the target tissue. In this review, we describe the potential role of nanoparticles in advanced melanoma treatment and discuss the current efforts of designing polymeric nanoparticles for controlled drug release at the site upon injection. In addition, we highlight the advances as well as the challenges of exosome-based nanocarriers as drug vehicles. We place special focus on the advantages of these natural nanocarriers in delivering various cargoes in advanced melanoma treatment. We also describe the current advances in knowledge of melanoma-related exosomes, including their biogenesis, molecular contents and biological functions, focusing our attention on their utilization for early diagnosis and prognosis in melanoma disease.
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42
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Petkovic M, Sørensen AE, Leal EC, Carvalho E, Dalgaard LT. Mechanistic Actions of microRNAs in Diabetic Wound Healing. Cells 2020; 9:E2228. [PMID: 33023156 PMCID: PMC7601058 DOI: 10.3390/cells9102228] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 09/25/2020] [Accepted: 09/30/2020] [Indexed: 02/06/2023] Open
Abstract
Wound healing is a complex biological process that is impaired under diabetes conditions. Chronic non-healing wounds in diabetes are some of the most expensive healthcare expenditures worldwide. Early diagnosis and efficacious treatment strategies are needed. microRNAs (miRNAs), a class of 18-25 nucleotide long RNAs, are important regulatory molecules involved in gene expression regulation and in the repression of translation, controlling protein expression in health and disease. Recently, miRNAs have emerged as critical players in impaired wound healing and could be targets for potential therapies for non-healing wounds. Here, we review and discuss the mechanistic background of miRNA actions in chronic wounds that can shed the light on their utilization as specific wound healing biomarkers.
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Affiliation(s)
- Marija Petkovic
- Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark; (A.E.S.); (L.T.D.)
- Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; (E.C.L.); (E.C.)
- Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
| | - Anja Elaine Sørensen
- Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark; (A.E.S.); (L.T.D.)
| | - Ermelindo Carreira Leal
- Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; (E.C.L.); (E.C.)
- Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
| | - Eugenia Carvalho
- Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; (E.C.L.); (E.C.)
- Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
- Department of Geriatrics, University of Arkansas for Medical Sciences, and Arkansas Children’s Research Institute, Little Rock, AR 72205, USA
| | - Louise Torp Dalgaard
- Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark; (A.E.S.); (L.T.D.)
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Galvão MLTDC, Coimbra EC. Long noncoding RNAs (lncRNAs) in cervical carcinogenesis: New molecular targets, current prospects. Crit Rev Oncol Hematol 2020; 156:103111. [PMID: 33080526 DOI: 10.1016/j.critrevonc.2020.103111] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 07/15/2020] [Accepted: 09/09/2020] [Indexed: 12/11/2022] Open
Abstract
Aberrant expression of lncRNAs has been seen as a key factor in a wide range of diseases including cancer. The role of lncRNAs in cervical cancer has not been clearly explained, and has been the subject of recent studies. In this review, we have compiled an updated list of previously reported lncRNAs and established a general profile of these transcripts in accordance with the role they play in cervical carcinogenesis. Thus, information here includes the influence of lncRNAs on cervical tumorigenic process through a disturbance of cellular activities. Additionally, we described recent discoveries about how HPV contributes to lncRNAs expression in cervical cancer and we summarized exploratory studies of strategies adopted to modulate the expression levels of lncRNAs to treat cervical neoplasia, by drawing attention to radio and chemo-resistance. Finally, this paper provides a broad overview that sets out new research directions about the role of lncRNAs in cervical cancer.
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Affiliation(s)
- Maria Luiza Tabosa de Carvalho Galvão
- Faculty of Medical Sciences, University of Pernambuco, Brazil; Laboratory of Molecular Biology of Viruses, Biological Sciences Institute, University of Pernambuco, Brazil
| | - Eliane Campos Coimbra
- Laboratory of Molecular Biology of Viruses, Biological Sciences Institute, University of Pernambuco, Brazil.
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44
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miR-21-5p: A viable therapeutic strategy for regulating intraocular pressure. Exp Eye Res 2020; 200:108197. [PMID: 32871166 DOI: 10.1016/j.exer.2020.108197] [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: 02/12/2020] [Revised: 08/03/2020] [Accepted: 08/13/2020] [Indexed: 12/20/2022]
Abstract
Lowering intraocular pressure (IOP) is the most effective treatment of glaucoma, however most of the current available glaucoma drugs target a single molecule. MicroRNAs (miRNAs) are noncoding RNAs that target a network of molecules. This study aims to investigate the role of miR-21-5p in regulating IOP and the mechanism of function. miR-21-5p mimics was topically applied to C57/BL6 mouse eyes, which significantly increased miR-21-5p expression in the conventional outflow tissue and reduced IOP by a maximum of 17.77% at 24 h after treatment. The conventional outflow facility measured by ex vivo moue eye perfusion of miR-21-5p was significantly increased by 60.14%. Moreover, miR-21-5p overexpression significantly reduced the transendothelial electrical resistance in porcine angular aqueous plexus cells. Transcriptome analysis and further quantification by Western blot and PCR revealed that SMAD7 and FGF18 might be the downstream target of miR-21-5p in regulating aqueous humor outflow. The predicted functional pathways PTEN/eNOS, RhoB/pMLC and TIMP3/MMP9 were significantly altered after miR-21-5p transfection. Dual luciferase assay verified the direct targets of miR-21-5p. In conclusion, miR-21-5p seems to regulate IOP by modulating multiple genes that are associated with aqueous humor outflow, including genes those regulating cell adhesion, cytoskeletal dynamics and extracellular matrix turnover. Thus, miR-21-5p represents a new therapeutic strategy for glaucoma and a viable alternative to existing multidrug regimens.
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45
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Mehrgou A, Ebadollahi S, Seidi K, Ayoubi-Joshaghani MH, Ahmadieh Yazdi A, Zare P, Jaymand M, Jahanban-Esfahlan R. Roles of miRNAs in Colorectal Cancer: Therapeutic Implications and Clinical Opportunities. Adv Pharm Bull 2020; 11:233-247. [PMID: 33880345 PMCID: PMC8046386 DOI: 10.34172/apb.2021.029] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/03/2020] [Accepted: 07/26/2020] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most disseminated diseases across the globe engaging the digestive system. Various therapeutic methods from traditional to the state-of-the-art ones have been applied in CRC patients, however, the attempts have been unfortunate to lead to a definite cure. MiRNAs are a smart group of non-coding RNAs having the capabilities of regulating and controlling coding genes. By utilizing this stock-in-trade biomolecules, not only disease’s symptoms can be eliminated, there may also be a good chance for the complete cure of the disease in the near future. Herein, we provide a comprehensive review delineating the therapeutic relationship between miRNAs and CRC. To this, various clinical aspects of miRNAs which act as a tumor suppressor and/or an oncogene, their underlying cellular processes and clinical outcomes, and, in particular, their effects and expression level changes in patients treated with chemo- and radiotherapy are discussed. Finally, based on the results deducted from scientific research studies, therapeutic opportunities based on targeting/utilizing miRNAs in the preclinical as well as clinical settings are highlighted.
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Affiliation(s)
- Amir Mehrgou
- Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shima Ebadollahi
- Department of Biochemistry and Biophysics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Khaled Seidi
- Biotechnology Research Center, Tabriz University of Medical Sciences, 9841 Tabriz, Iran
| | - Mohammad Hosein Ayoubi-Joshaghani
- Drug Applied Research Center, Tabriz University of Medical Sciences, 9841 Tabriz, Iran.,Student Research Committees, Tabriz University of Medical Sciences, 9841 Tabriz, Iran
| | | | - Peyman Zare
- Dioscuri Center of Chromatin Biology and Epigenomics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.,Faculty of Medicine, Cardinal Stefan Wyszyński University in Warsaw, 01-938 Warsaw, Poland
| | - Mehdi Jaymand
- Nano Drug Delivery Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Rana Jahanban-Esfahlan
- Stem Cell Research Center, Tabriz University of Medical Sciences, 9841 Tabriz, Iran.,Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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Circular RNA-9119 suppresses in ovarian cancer cell viability via targeting the microRNA-21-5p-PTEN-Akt pathway. Aging (Albany NY) 2020; 12:14314-14328. [PMID: 32675386 PMCID: PMC7425477 DOI: 10.18632/aging.103470] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 05/27/2020] [Indexed: 12/24/2022]
Abstract
We aimed to assess the regulatory role of circular RNA (circRNA)-9119 (circ9119) in ovarian cancer (OC) cell viability. The expression of circ9119 was clearly reduced in OC tissues and cell lines, whereas the microRNA-21-5p (miR-21) levels were elevated compared with those in normal healthy control tissues and immortalized fallopian epithelial cell line FTE187. Further, circ9119 was overexpressed, causing a notable decrease in the viability and proliferation of OC cells and an increase in apoptosis. Further study showed that circ9119 upregulation resulted in a decrease in miR-21 levels. Bioinformatics forecasting (starBase and TargetScan) and dual luciferase reporter assay demonstrated that circ9119 acts as an miR-21 sponge. Recovery of miR-21 expression in circ9119-overexpressing OC cells showed that miR-21 exhibited the opposite effect on circ9119; moreover, its recovery could suppress the effects of circ9119 overexpression, recover cell proliferation, and reduce apoptosis. Furthermore, miR-21 was found to target phosphatase and tensin homologue (PTEN) 3′ untranslated region. PTEN protein and mRNA expression was reduced in OC tissues and cells, whereas it was increased on transfection with an miR-21 inhibitor. Thus, circ9119 could regulate cell proliferation and apoptosis of OC cells via by acting as an miR-21 sponge and targeting the PTEN–Akt pathway.
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Eshghifar N, Badrlou E, Pouresmaeili F. The roles of miRNAs' clinical efficiencies in the colorectal cancer pathobiology: A review article. Hum Antibodies 2020; 28:273-285. [PMID: 32623393 DOI: 10.3233/hab-200417] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
MiRNAs (microRNAs) are defined as micro directors and regulators of gene expression. Since altered miRNA expression is signified in the pathobiology of diverse cancers such as colorectal cancers (CRCs), these molecules are described as therapeutic targets, either. Manipulation of miRNAs could lead to further therapy for chemo and radio-resistant CRCs. The usage of microRNAs has indicated prominent promise in the prognosis and diagnosis of CRC, because of their unique expression pattern associated with cancer types and malignancies. Nowadays, many researchers are analyzing the correlation between miRNA polymorphisms and cancer risk. With continuous incompatibility in colorectal cancer (CRC) miRNAs expression data, it is critical to move toward the content of a "pre-laboratory" analysis to speed up efficient accuracy medicine and translational study. Pathway study for the highest expressed miRNAs- regulated target genes resulted in the identification of a considerable number of genes associated with CRC pathway including PI3K, TGFβ, and APC. In this review, we aimed to collect fruitful information about miRNAs and their potential roles in CRC, and provide a meta-analysis of the most frequently studied miRNAs in association with the disease.
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Affiliation(s)
- Nahal Eshghifar
- Department of Molecular and Cellular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elham Badrlou
- Medical Genetics Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farkhondeh Pouresmaeili
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Lv Y, Wang Z, Zhao K, Zhang G, Huang S, Zhao Y. Role of noncoding RNAs in cholangiocarcinoma (Review). Int J Oncol 2020; 57:7-20. [PMID: 32319584 DOI: 10.3892/ijo.2020.5047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 03/16/2020] [Indexed: 11/06/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a malignant tumour originating from biliary epithelial cells, and is increasing in incidence. Radical surgery is the main treatment. However, the pathogenesis of CCA is unclear. Noncoding RNAs (ncRNAs) are non‑protein‑coding RNAs produced by genomic transcription that include microRNAs (miRNAs), circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs). They play important roles in gene expression, epigenetic modification, cell proliferation, differentiation and reproduction. ncRNAs also serve key roles in cancer development. Numerous studies have been carried out on ncRNAs, and associated publications have shown that ncRNAs are closely associated with the physiological and pathological mechanisms of CCA. The findings of these studies can provide new insights into the diagnosis, treatment and prognosis of CCA. The present review summarizes the pathophysiological mechanisms of different types of ncRNAs, including miRNAs, circRNAs and lncRNAs in CCA, and their applications in the diagnosis and treatment of CCA.
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Affiliation(s)
- Yinghao Lv
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 476100, P.R. China
| | - Zhenzhen Wang
- Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 476100, P.R. China
| | - Kun Zhao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 476100, P.R. China
| | - Guokun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 476100, P.R. China
| | - Shuai Huang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 476100, P.R. China
| | - Yongfu Zhao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 476100, P.R. China
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Liu J, Ke F, Chen T, Zhou Q, Weng L, Tan J, Shen W, Li L, Zhou J, Xu C, Cheng H, Zhou J. MicroRNAs that regulate PTEN as potential biomarkers in colorectal cancer: a systematic review. J Cancer Res Clin Oncol 2020; 146:809-820. [PMID: 32146564 DOI: 10.1007/s00432-020-03172-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 02/27/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE MicroRNAs (miRNAs) participate in a variety of biological processes, including tumorigenesis, progression, invasion, and drug resistance to multiple cancers. Phosphatase and tensin homolog (PTEN) is a cancer suppressor gene that has been certified to be regulated by miRNAs in various tumors, including colorectal cancer (CRC). In this review, we screened articles focusing on low PTEN expression in CRC, observed the expression of related miRNAs, analyzed their correlation and relationship with clinicopathological features, and discussed the possibility of these miRNAs as prognostic molecules. METHODS We conducted a systematic search for articles published in the Web of Science, PubMed and EBSCO databases between January 1, 2002, and July 18, 2019. We identified these studies by using combinations of the following index entries and key words: 'colorectal tumor OR colorectal neoplasm OR colorectal carcinoma OR colorectal cancer OR CRC', 'protein tyrosine phosphatase OR PTEN', and 'microRNA OR MiRNA OR miRNA OR MicroRNA'. Moreover, we evaluated the underlying association between alterations in PTEN and CRC prognosis. RESULTS PTEN expression was obviously lower in CRC tissues than in normal mucosa. However, PTEN expression did not differ significantly between adenoma and normal tissues. PTEN tends to be negatively associated with tumor size and metastasis. MiR-21, miR-200a, miR-543, miR-32, miR-92a, miR-26a, miR-106a and miR-181a were correlated with the downregulation of PTEN. MiR-26a, miR-106a and miR-181a were obviously higher in CRC tissues than in normal tissues, while PTEN was downregulated in CRC tissues. Additionally, miRNAs were mainly positively correlated with distant metastasis, followed by TNM stage. The relationship between miRNAs and tumor differentiation is controversial. However, there were no significant differences between miRNAs and either sex or age. CONCLUSIONS The loss of PTEN may be a diagnostic factor for CRC patients. The above-mentioned miRNAs may function as oncogenes in CRC and represent potential targets for CRC therapy. However, further prospective clinical studies are necessary.
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Affiliation(s)
- Jianrong Liu
- School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, People's Republic of China
| | - Fei Ke
- Pathology Department, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People's Republic of China
| | - Tingting Chen
- Jiangsu Collaborative Innovation Center of TCM Prevention and Treatment of Tumor, The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, People's Republic of China
| | - Qing Zhou
- Jiangsu Collaborative Innovation Center of TCM Prevention and Treatment of Tumor, The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, People's Republic of China
| | - Lingling Weng
- Imaging Department, Nanjing Hospital of Chinese Medicine, Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People's Republic of China
| | - Jiani Tan
- Jiangsu Collaborative Innovation Center of TCM Prevention and Treatment of Tumor, The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, People's Republic of China
| | - Weixing Shen
- Jiangsu Collaborative Innovation Center of TCM Prevention and Treatment of Tumor, The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, People's Republic of China
| | - Liu Li
- Jiangsu Collaborative Innovation Center of TCM Prevention and Treatment of Tumor, The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, People's Republic of China
| | - Jinyong Zhou
- Central Laboratory, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People's Republic of China
| | - Changliang Xu
- Jiangsu Collaborative Innovation Center of TCM Prevention and Treatment of Tumor, The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, People's Republic of China
| | - Haibo Cheng
- Jiangsu Collaborative Innovation Center of TCM Prevention and Treatment of Tumor, The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, People's Republic of China.
| | - Jinrong Zhou
- School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210046, Jiangsu, People's Republic of China.
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50
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Pu X, Ding G, Wu M, Zhou S, Jia S, Cao L. Elevated expression of exosomal microRNA-21 as a potential biomarker for the early diagnosis of pancreatic cancer using a tethered cationic lipoplex nanoparticle biochip. Oncol Lett 2020; 19:2062-2070. [PMID: 32194703 PMCID: PMC7039151 DOI: 10.3892/ol.2020.11302] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 11/13/2019] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) has a poor prognosis due to the lack of effective molecular biomarkers for early diagnosis. Recent studies have investigated the use of exosomal microRNAs (exmiRs) as diagnostic biomarkers in cancer. The present study examined exmiR-21, exmiR-10b and exmiR-212-3p expression in patients with PC and healthy individuals. The expression levels of exmiR-21, exmiR-10b and exmiR-212-3p were examined in the peripheral blood plasma of 36 patients with PC and 65 healthy controls, using tethered cationic lipoplex nanoparticle biochip. The levels of exmiR-21 in the plasma of 34 mice were also evaluated. The expression levels of exmiR-21 and exmiR-10b were significantly greater in patients with PC compared with the control group. The receiver operating characteristic (ROC) analysis indicated that exmiR-21 had better diagnostic performance (P=0.0003; AUC, 0.7171) compared with the other two exmiRs. The diagnostic value of exmiR-21 improved when combined with exmiR-10b (P<0.0001; AUC, 0.791). Furthermore, exmiR-21 was capable of distinguishing patients with early-stage PC from controls and advanced-stage PC (P<0.05, early stage vs. healthy; P<0.001, early stage vs. advanced stage). The results of the present study revealed that the plasma levels of exmiR-21 and exmiR-10b were upregulated in patients with PC. The ROC analyses indicated that exmiR-21 had the best diagnostic performance among the three exmiRs. Furthermore, exmiR-21 was capable of discriminating patients with early-stage PC from healthy controls. These findings indicate the potential of determining the expression of exmiR-21 from serum using a tethered cationic lipoplex nanoparticle biochip as a novel non-invasive strategy for the early diagnosis of PC.
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Affiliation(s)
- Xiaofan Pu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
| | - Guoping Ding
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
| | - Mingjie Wu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
| | - Senhao Zhou
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
| | - Shengnan Jia
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
| | - Liping Cao
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
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