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Su Z, Liu M, Krohn M, Schwarz S, Linnebacher M. The impact of SEC23A on 5-FU chemotherapy sensitivity and its involvement in endoplasmic reticulum stress-induced apoptosis in colorectal cancer. Apoptosis 2025; 30:976-990. [PMID: 39904858 PMCID: PMC11946983 DOI: 10.1007/s10495-025-02084-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/24/2025] [Indexed: 02/06/2025]
Abstract
BACKGROUND Colorectal cancer (CRC) represents a significant global health burden, with chemotherapy resistance representing a significant challenge to effective treatment. SEC23A, a core component of the COPII vesicle trafficking system, is of critical importance with regard to protein transport and cellular homeostasis. Nevertheless, its function in CRC progression and chemoresistance remains uncertain. The present study investigates the correlation between SEC23A expression and sensitivity to 5-fluorouracil (5-FU), a widely used chemotherapeutic agent, with particular emphasis on ER stress-induced apoptosis. METHODS A bioinformatic analysis was conducted to evaluate SEC23A expression in CRC and its association with patient prognosis. Chemotherapy sensitivity was predicted using GDSC data and validated experimentally using CRC cell lines with manipulated SEC23A expression. In order to explore the role of SEC23A in acquired drug resistance, patient-derived xenograft (PDX) models and 5-FU-resistant cell lines were employed. Apoptosis assays, cell cycle analysis, and ER stress modulation experiments were performed to elucidate the underlying mechanisms. RESULTS SEC23A expression was significantly reduced in CRC samples compared to normal tissues. This reduction was linked to a poorer prognosis, including both overall and disease-specific survival. A correlation was observed between low SEC23A expression and increased resistance to 5-FU, as evidenced by both bioinformatic predictions and in vitro experiments. In PDX models, metastatic lesions exhibited decreased SEC23A expression following 5-FU treatment in comparison to primary tumors. Overexpression of SEC23A in 5-FU-resistant cell lines restored sensitivity to the drug and increased apoptosis. Bioinformatic and experimental analyses revealed a robust correlation between SEC23A and ER stress-related apoptotic pathways. Elevated expression of SEC23A was observed to facilitate the accumulation of misfolded proteins in response to 5-FU treatment, which in turn resulted in increased ER stress and apoptosis. CONCLUSIONS SEC23A plays a crucial role in modulating the sensitivity of CRC cells to 5-FU by regulating ER stress-induced apoptosis. Its downregulation contributes to chemoresistance, indicating that SEC23A may serve as a prognostic marker and therapeutic target in CRC. Strategies aimed at upregulating SEC23A or enhancing ER stress may provide new avenues for overcoming chemoresistance and improving treatment outcomes for CRC patients.
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Affiliation(s)
- Zhaoran Su
- Department of Gastrointestinal Surgery, People's Hospital of Tongling City, Tongling, 244000, China
- Molecular Oncology and Immunotherapy, Clinic of General Surgery, University Medical Center Rostock, 18057, Rostock, Germany
| | - Menglan Liu
- Molecular Oncology and Immunotherapy, Clinic of General Surgery, University Medical Center Rostock, 18057, Rostock, Germany
| | - Mathias Krohn
- Molecular Oncology and Immunotherapy, Clinic of General Surgery, University Medical Center Rostock, 18057, Rostock, Germany
| | - Sandra Schwarz
- Molecular Oncology and Immunotherapy, Clinic of General Surgery, University Medical Center Rostock, 18057, Rostock, Germany
| | - Michael Linnebacher
- Molecular Oncology and Immunotherapy, Clinic of General Surgery, University Medical Center Rostock, 18057, Rostock, Germany.
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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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Cheng W, Pan H, Chen J, He M, Wang Z, Xiang Y. Enzyme-Free and Triple Sensitivity Amplification for Electrochemical Detection of Exosomal microRNA. Anal Chem 2025; 97:5244-5250. [PMID: 40017114 DOI: 10.1021/acs.analchem.4c06879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2025]
Abstract
Exosomal miRNAs, particularly miRNA-21, are promising cancer biomarkers. Current enzyme-dependent detection methods face challenges, such as environmental limitations and high costs. In contrast, enzyme-independent sensors are highly desirable for on-site, miniaturized, and cost-effective miRNA detection. To address these limitations, we developed a nonenzymatic electrochemical sensor featuring a triple-signal amplification system for ultrasensitive detection of miRNA-21. This sensor utilizes cascade toehold-mediated strand displacement reactions to activate molecular machines triggered by target miRNA, generating biotinylated-and-thiol-modified double-stranded DNA for stable immobilization on a gold electrode. Preprepared biotinylated tetrahedron DNA (TDNA)-mediated hybridization chain reaction probes are then linked to the electrode via streptavidin-biotin binding. This amplification process allows for significant DNA duplex immobilization, with electroactive [Ru(NH3)6]3+ (RuHex) adsorbed onto them, producing a robust electrochemical signal. This approach enables accurate detection of miRNA-21 at concentrations as low as 0.43 fM, with a linear range from 1 fM to 1 nM. Clinical testing demonstrates its potential for cancer diagnostics.
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Affiliation(s)
- Wenting Cheng
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China
| | - Han Pan
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China
| | - Jinhua Chen
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China
| | - Miao He
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China
| | - Zhongyun Wang
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, P. R. China
| | - Yang Xiang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P. R. China
- State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, P. R. China
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4
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Gao X, Yuan J, Zhang X, Wang R, Yang J, Li Y, Li J. Exploration of the Prognostic Markers of Multiple Myeloma Based on Cuproptosis-Related Genes. Cancer Rep (Hoboken) 2025; 8:e70151. [PMID: 40042106 PMCID: PMC11880913 DOI: 10.1002/cnr2.70151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 01/28/2025] [Accepted: 02/04/2025] [Indexed: 05/12/2025] Open
Abstract
BACKGROUND The investigation of cuproptosis in relation to tumor development has been limited, particularly in multiple myeloma (MM), indicating the need for further research. Our study aimed to examine the impact of cuproptosis-related genes (CRGs) on the prognosis of MM. METHODS Using the datasets, we filtered cuproptosis score-related differentially expressed genes (CRDEGs) by overlapping the DEGs between the MM and normal groups and between the high and low cuproptosis score groups. Additionally, key module genes were identified through weighted gene co-expression network analysis. A univariate Cox algorithm and multivariate Cox analysis were employed to obtain biomarkers of MM and build a prognostic model before conducting independent prognostic analysis. RESULTS A total of 59 CRDEGs were filtered, demonstrating their involvement in the COPII vesicle coat and endoplasmic reticulum protein processing, and protein processing in the endoplasmic reticulum. Six prognosis-related biomarkers (PARP1, EDEM3, SEC23A, RSL24D1, TTC37, and SRP72) were obtained, and a prognostic model was developed. The performance of the model was verified using a test cohort (GSE136324 dataset) and a validation cohort (GSE24080 dataset). Risk score, age, albumin, International Staging System (ISS) score, and β2-microglobulin (B2M) were found to be significant predictors of prognosis independently. CONCLUSION As a result of this investigation, a set of six biomarkers associated with cuproptosis (PARP1, EDEM3, SEC23A, RSL24D1, TTC37, and SRP72) were screened to provide a basis for predicting the prognosis of MM.
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Affiliation(s)
- Xiao‐Han Gao
- Department of HematologyHebei General HospitalShijiazhuangChina
| | - Jun Yuan
- Department of HematologyHebei General HospitalShijiazhuangChina
| | - Xiao‐Xia Zhang
- Department of HematologyHebei General HospitalShijiazhuangChina
| | - Rui‐Cang Wang
- Department of HematologyHebei General HospitalShijiazhuangChina
| | - Jie Yang
- Department of HematologyHebei General HospitalShijiazhuangChina
| | - Yan Li
- Department of HematologyHebei General HospitalShijiazhuangChina
| | - Jie Li
- Department of HematologyHebei General HospitalShijiazhuangChina
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Ždralević M, Radović A, Raonić J, Popovic N, Klisic A, Vučković L. Advances in microRNAs as Emerging Biomarkers for Colorectal Cancer Early Detection and Diagnosis. Int J Mol Sci 2024; 25:11060. [PMID: 39456841 PMCID: PMC11507567 DOI: 10.3390/ijms252011060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 09/21/2024] [Accepted: 09/27/2024] [Indexed: 10/26/2024] Open
Abstract
Colorectal cancer (CRC) remains the second most common cause of cancer-related mortality worldwide, necessitating advancements in early detection and innovative treatment strategies. MicroRNAs (miRNAs), small non-coding RNAs involved in gene regulation, have emerged as crucial players in the pathogenesis of CRC. This review synthesizes the latest findings on miRNA deregulated in precancerous lesions and in CRC. By examining the deregulation patterns of miRNAs across different stages of CRC development, this review highlights their potential as diagnostic tools. We specifically analyse the roles and diagnostic relevance of four miRNAs-miR-15b, miR-21, miR-31, and miR-146a-that consistently exhibit altered expression in CRC. The current knowledge of their role in key oncogenic pathways, drug resistance, and clinical relevance is discussed. Despite challenges posed by the heterogeneity of the research findings on miRNA deregulation and their role in CRC, integrating miRNA diagnostics into current screening methods holds promise for enhancing personalized medicine approaches. This review emphasizes the transformative potential of miRNAs in CRC diagnosis, paving the way for improved patient outcomes and novel therapeutic paradigms.
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Affiliation(s)
- Maša Ždralević
- Institute for Advanced Studies, University of Montenegro, Cetinjska 2, 81000 Podgorica, Montenegro
| | - Andrijana Radović
- Faculty of Medicine, University of Montenegro, Kruševac bb, 81000 Podgorica, Montenegro (N.P.); (A.K.); (L.V.)
| | - Janja Raonić
- Center for Pathology, Clinical Center of Montenegro, Ljubljanska bb, 81000 Podgorica, Montenegro;
| | - Natasa Popovic
- Faculty of Medicine, University of Montenegro, Kruševac bb, 81000 Podgorica, Montenegro (N.P.); (A.K.); (L.V.)
| | - Aleksandra Klisic
- Faculty of Medicine, University of Montenegro, Kruševac bb, 81000 Podgorica, Montenegro (N.P.); (A.K.); (L.V.)
- Center for Laboratory Diagnostics, Primary Health Care Center, 81000 Podgorica, Montenegro
| | - Ljiljana Vučković
- Faculty of Medicine, University of Montenegro, Kruševac bb, 81000 Podgorica, Montenegro (N.P.); (A.K.); (L.V.)
- Center for Pathology, Clinical Center of Montenegro, Ljubljanska bb, 81000 Podgorica, Montenegro;
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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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Fei Y, Wu Y, Chen L, Yu H, Pan L. Comprehensive pan-carcinoma analysis of ITGB1 distortion and its potential clinical significance for cancer immunity. Discov Oncol 2024; 15:47. [PMID: 38402311 PMCID: PMC10894187 DOI: 10.1007/s12672-024-00901-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Accepted: 02/20/2024] [Indexed: 02/26/2024] Open
Abstract
The human protein-coding gene ITGB1 (Integrin 1), also known as CD29, has a length of 58048 base pairs. The Integrin family's most prevalent subunit, it participates in the transmission of numerous intracellular signaling pathways. A thorough examination of ITGB1's functions in human malignancies, however, is inadequate and many of their relationships to the onset and development of human cancers remain unknown. In this work, we examined ITGB1's role in 33 human cancers. Finally, a multi-platform analysis revealed that three of the 33 malignancies had significantly altered ITGB1 expression in tumor tissues in comparison to normal tissues. In addition, it was discovered through survival analysis that ITGB1 was a stand-alone prognostic factor in a number of cancers. ITGB1 expression was linked to immune cell infiltration in colon cancer, according to an investigation of immune infiltration in pan-cancer. In the gene co-expression research, ITGB1 showed a positive connection with the majority of the cell proliferation and EMT indicators, indicating that ITGB1 may have an essential function in controlling cancer metastasis and proliferation. Our pan-cancer analysis of ITGB1 gives evidence in favor of a further investigation into its oncogenic function in various cancer types.
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Affiliation(s)
- Yuchang Fei
- Department of Integrated Chinese and Western Medicine, The First People's Hospital of Jiashan, Jiashan Hospital Affiliated of Jiaxing University, Jiashan, Zhejiang, China.
| | - Yulun Wu
- Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Luting Chen
- Department of Integrated Chinese and Western Medicine, The First People's Hospital of Wenling, Wenling, Zhejiang, China
| | - Huan Yu
- The Department of Traditional Chinese Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Lei Pan
- Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
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Mohammadpour S, Noukabadi FN, Esfahani AT, Kazemi F, Esmaeili S, Zafarjafarzadeh N, Sarpash S, Nazemalhosseini-Mojarad E. Non-coding RNAs in Precursor Lesions of Colorectal Cancer: Their Role in Cancer Initiation and Formation. Curr Mol Med 2024; 24:565-575. [PMID: 37226783 DOI: 10.2174/1566524023666230523155719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 04/01/2023] [Accepted: 04/04/2023] [Indexed: 05/26/2023]
Abstract
Colorectal cancer (CRC) is one of the world's most common types of malignancy. The proliferation of precancerous lesions causes this type of cancer. Two distinct pathways for CRC carcinogenesis have been identified: the conventional adenoma-carcinoma pathway and the serrated neoplasia pathway. Recently, evidence has demonstrated the regulatory roles of noncoding RNAs (ncRNAs) in the initiation and progression of precancerous lesions, especially in the adenoma-carcinoma pathway and serrated neoplasia pathway. By expanding the science of molecular genetics and bioinformatics, several studies have identified dysregulated ncRNAs that function as oncogenes or tumor suppressors in cancer initiation and formation by diverse mechanisms via intracellular signaling pathways known to act on tumor cells. However, many of their roles are still unclear. This review summarizes the functions and mechanisms of ncRNAs (such as long non-coding RNAs, microRNAs, long intergenic non-coding RNAs, small interfering RNAs, and circRNAs) in the initiation and formation of precancerous lesions.
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Affiliation(s)
- Somayeh Mohammadpour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences. Tehran, Iran
| | - Fatemeh Naderi Noukabadi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences. Tehran, Iran
| | - Amir Torshizi Esfahani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences. Tehran, Iran
| | - Fatemeh Kazemi
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University Tehran, Tehran, Iran
| | - Sahar Esmaeili
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University Tehran, Tehran, Iran
| | - Nikta Zafarjafarzadeh
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University Tehran, Tehran, Iran
| | - SeyedKasra Sarpash
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University Tehran, Tehran, Iran
| | - Ehsan Nazemalhosseini-Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Zeng B, Chen Y, Chen H, Zhao Q, Sun Z, Liu D, Li X, Zhang Y, Wang J, Xing HR. Synergistic inhibition of NUDT21 by secretory S100A11 and exosomal miR-487a-5p promotes melanoma oligo- to poly-metastatic progression. Mol Oncol 2023; 17:2743-2766. [PMID: 37356089 DOI: 10.1002/1878-0261.13480] [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: 02/16/2023] [Revised: 06/03/2023] [Accepted: 06/23/2023] [Indexed: 06/27/2023] Open
Abstract
Although early diagnosis and therapeutic advances have transformed the living quality and outcome of cancer patients, the poor prognosis for metastatic patients has not been significantly improved. Mechanisms underlying the complexity of metastasis cannot be simply determined by the straightforward 'cause-and-effect relationships'. We have developed a 'dry-lab-driven knowledge discovery and wet-lab validation' approach to embrace the complexity of cancer and metastasis. We have revealed for the first time that polymetastatic (POL) melanoma cells can utilize both the secretory protein pathway (S100A11-Sec23a) and the exosomal crosstalk (miR-487a-5p) to transfer their 'polymetastatic competency' to the oligometastatic (OL) melanoma cells, via synergistic co-targeting of the tumor-suppressor Nudt21. The downstream deregulated glycolysis was verified to regulate metastatic colonization efficiency. Further, two gene sets conferring independent prognosis in melanoma were identified, which have the potential for clinical translation and merit future clinical validation.
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Affiliation(s)
- Bin Zeng
- Institute of Life Sciences, Chongqing Medical University, China
| | - Yuting Chen
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, China
| | - Hao Chen
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, China
| | - Qiting Zhao
- Institute of Life Sciences, Chongqing Medical University, China
| | - Zhiwei Sun
- Institute of Life Sciences, Chongqing Medical University, China
| | - Doudou Liu
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, China
| | - Xiaoshuang Li
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, China
| | - Yuhan Zhang
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, China
| | - Jianyu Wang
- Institute of Life Sciences, Chongqing Medical University, China
| | - H Rosie Xing
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, China
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Kim N, Kim TH, Kim C, Lee JE, Kang MG, Shin S, Jung M, Kim JS, Mun JY, Rhee HW, Park SY, Shin Y, Yoo JY. Intrinsically disordered region-mediated condensation of IFN-inducible SCOTIN/SHISA-5 inhibits ER-to-Golgi vesicle transport. Dev Cell 2023; 58:1950-1966.e8. [PMID: 37816329 DOI: 10.1016/j.devcel.2023.08.030] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 07/27/2023] [Accepted: 08/25/2023] [Indexed: 10/12/2023]
Abstract
Newly synthesized proteins in the endoplasmic reticulum (ER) are sorted by coat protein complex II (COPII) at the ER exit site en route to the Golgi. Under cellular stresses, COPII proteins become targets of regulation to control the transport. Here, we show that the COPII outer coat proteins Sec31 and Sec13 are selectively sequestered into the biomolecular condensate of SCOTIN/SHISA-5, which interferes with COPII vesicle formation and inhibits ER-to-Golgi transport. SCOTIN is an ER transmembrane protein with a cytosolic intrinsically disordered region (IDR), which is required and essential for the formation of condensates. Upon IFN-γ stimulation, which is a cellular condition that induces SCOTIN expression and condensation, ER-to-Golgi transport was inhibited in a SCOTIN-dependent manner. Furthermore, cancer-associated mutations of SCOTIN perturb its ability to form condensates and control transport. Together, we propose that SCOTIN impedes the ER-to-Golgi transport through its ability to form biomolecular condensates at the ER membrane.
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Affiliation(s)
- Nari Kim
- Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Republic of Korea.
| | - Tae-Hyeon Kim
- Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Republic of Korea
| | - Chaelim Kim
- Interdisciplinary Program in Bioengineering, Seoul National University, Seoul 08826, Republic of Korea
| | - Jee-Eun Lee
- Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Republic of Korea
| | - Myeong-Gyun Kang
- Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea
| | - Sanghee Shin
- School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea; Center for RNA Research, Institute for Basic Science (IBS), Seoul 08826, Republic of Korea
| | - Minkyo Jung
- Neural Circuit Research Group, Korea Brain Research Institute, Daegu 41062, Republic of Korea
| | - Jong-Seo Kim
- School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea; Center for RNA Research, Institute for Basic Science (IBS), Seoul 08826, Republic of Korea
| | - Ji Young Mun
- Neural Circuit Research Group, Korea Brain Research Institute, Daegu 41062, Republic of Korea
| | - Hyun-Woo Rhee
- Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea; School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Seung-Yeol Park
- Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Republic of Korea
| | - Yongdae Shin
- Interdisciplinary Program in Bioengineering, Seoul National University, Seoul 08826, Republic of Korea; Department of Mechanical Engineering, Seoul National University, Seoul 08826, Republic of Korea
| | - Joo-Yeon Yoo
- Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Republic of Korea.
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11
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Asl ER, Sarabandi S, Shademan B, Dalvandi K, sheikhansari G, Nourazarian A. MicroRNA targeting: A novel therapeutic intervention for ovarian cancer. Biochem Biophys Rep 2023; 35:101519. [PMID: 37521375 PMCID: PMC10382632 DOI: 10.1016/j.bbrep.2023.101519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/20/2023] [Accepted: 07/21/2023] [Indexed: 08/01/2023] Open
Abstract
Ovarian cancer, a perilous form of cancer affecting the female reproductive system, exhibits intricate communication networks that contribute to its progression. This study aims to identify crucial molecular abnormalities linked to the disease to enhance diagnostic and therapeutic strategies. In particular, we investigate the role of microRNAs (miRNAs) as diagnostic biomarkers and explore their potential in treating ovarian cancer. By targeting miRNAs, which can influence multiple pathways and genes, substantial therapeutic benefits can be attained. In this review we want to shed light on the promising application of miRNA-based interventions and provide insights into the specific miRNAs implicated in ovarian cancer pathogenesis.
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Affiliation(s)
- Elmira Roshani Asl
- Social Determinants of Health Research Center, Saveh University of Medical Sciences, Saveh, Iran
| | - Sajed Sarabandi
- Department of Veterinary, Faculty of Medicine Sciences, Islamic Azad University of Karaj, Karaj, Iran
| | - Behrouz Shademan
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Kourosh Dalvandi
- Ministry of Health and Medical Education, Health Department, Tehran, Iran
| | | | - Alireza Nourazarian
- Department of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, Iran
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12
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Zhu L, Yuhan J, Yu H, Zhang B, Zhu L, He X, Huang K, Xu W. Aptamer functionalized nucleic acid nano drug for targeted synergistic therapy for colon cancer. J Nanobiotechnology 2023; 21:182. [PMID: 37280622 DOI: 10.1186/s12951-023-01941-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 05/29/2023] [Indexed: 06/08/2023] Open
Abstract
Due to its complicated pathophysiology, propensity for metastasis, and poor prognosis, colon cancer is challenging to treat and must be managed with a combination of therapy. Using rolling circle transcription (RCT), this work created a nanosponge therapeutic medication system (AS1411@antimiR-21@Dox). Using the AS1411 aptamer, this approach accomplished targeted delivery to cancer cells. Furthermore, analysis of cell viability, cell apoptosis, cell cycle arrest, reactive oxygen species (ROS) content, and mitochondrial membrane potential (MMP) levels revealed that functional nucleic acid nanosponge drug (FND) can kill cancer cells. Moreover, transcriptomics uncovered a putative mechanism for the FND anti-tumor effect. These pathways, which included mitotic metaphase and anaphase as well as the SMAC-mediated dissociation of the IAP: caspase complexes, were principally linked to the cell cycle and cell death. In conclusion, by triggering cell cycle arrest and apoptosis, the nano-synergistic therapeutic system allowed for the intelligent and effective targeted administration of RNA and chemotherapeutic medicines for colon cancer treatment. The system allowed for payload efficiency while being customizable, targeted, reliable, stable, and affordable.
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Affiliation(s)
- Liye Zhu
- Food Laboratory of Zhongyuan, Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, No. 17 Qinghua Donglu, Beijing, 100083, China
- College of Veterinary Medicine, China Agricultural University, Beijing, 100094, China
| | - Jieyu Yuhan
- Food Laboratory of Zhongyuan, Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, No. 17 Qinghua Donglu, Beijing, 100083, China
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China
| | - Hao Yu
- Food Laboratory of Zhongyuan, Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, No. 17 Qinghua Donglu, Beijing, 100083, China
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China
| | - Boyang Zhang
- Food Laboratory of Zhongyuan, Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, No. 17 Qinghua Donglu, Beijing, 100083, China
| | - Longjiao Zhu
- Food Laboratory of Zhongyuan, Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, No. 17 Qinghua Donglu, Beijing, 100083, China
| | - Xiaoyun He
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China
| | - Kunlun Huang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China
| | - Wentao Xu
- Food Laboratory of Zhongyuan, Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, No. 17 Qinghua Donglu, Beijing, 100083, China.
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, 100083, China.
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13
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Smyth LJ, Cruise SM, Tang J, Young I, McGuinness B, Kee F, McKnight AJ. Differential methylation in CD44 and SEC23A is associated with time preference in older individuals. ECONOMICS AND HUMAN BIOLOGY 2023; 49:101233. [PMID: 36812724 DOI: 10.1016/j.ehb.2023.101233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/25/2022] [Accepted: 02/06/2023] [Indexed: 05/08/2023]
Abstract
Time preference is a measure used to ascertain the level of which individuals prefer smaller, immediate rewards over larger, delayed rewards. We explored how an individual's time preference associates with their epigenetic profile. Time preferences were ascertained by asking participants of the Northern Ireland COhort for the Longitudinal study of Ageing to make a series of choices between two hypothetical income scenarios. From these, eight 'time preference' categories were derived, ranging from "patient" to "impatient" on an ordinal scale. The Infinium High Density Methylation Assay, MethylationEPIC (Illumina) was used to evaluate the status of 862,927 CpGs. Time preference and DNA methylation data were obtained for 1648 individuals. Four analyses were conducted, assessing the methylation patterns at single site resolution between patient and impatient individuals using two adjustment models. In this discovery cohort analysis, two CpG sites were identified with significantly different levels of methylation (p < 9 × 10-8) between the individuals allocated to the patient group and the remaining population following adjustment for covariates; cg08845621 within CD44 and cg18127619 within SEC23A. Neither of these genes have previously been linked to time preference. Epigenetic modifications have not previously been linked to time preference using a population cohort but they may represent important biomarkers of accumulated, complex determinants of this trait. Further analysis is warranted of both the top-ranked results and of DNA methylation as an important link between measurable biomarkers and health behaviours.
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Affiliation(s)
- Laura J Smyth
- Epidemiology and Public Health Research Group, Centre for Public Health, Queen's University Belfast, BT12 6BJ Northern Ireland, United Kingdom
| | - Sharon M Cruise
- Epidemiology and Public Health Research Group, Centre for Public Health, Queen's University Belfast, BT12 6BJ Northern Ireland, United Kingdom
| | - Jianjun Tang
- School of Agricultural Economics and Rural Development, Renmin University of China, Beijing, China.
| | - Ian Young
- Epidemiology and Public Health Research Group, Centre for Public Health, Queen's University Belfast, BT12 6BJ Northern Ireland, United Kingdom
| | - Bernadette McGuinness
- Epidemiology and Public Health Research Group, Centre for Public Health, Queen's University Belfast, BT12 6BJ Northern Ireland, United Kingdom
| | - Frank Kee
- Epidemiology and Public Health Research Group, Centre for Public Health, Queen's University Belfast, BT12 6BJ Northern Ireland, United Kingdom
| | - Amy Jayne McKnight
- Epidemiology and Public Health Research Group, Centre for Public Health, Queen's University Belfast, BT12 6BJ Northern Ireland, United Kingdom
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14
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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: 49] [Impact Index Per Article: 24.5] [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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15
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Hu H, Zhang Z, Fang Y, Chen L, Wu J. Therapeutic poly(amino acid)s as drug carriers for cancer therapy. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2022.107953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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16
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Investigating the Role of Circulating miRNAs as Biomarkers in Colorectal Cancer: An Epidemiological Systematic Review. Biomedicines 2022; 10:biomedicines10092224. [PMID: 36140324 PMCID: PMC9496335 DOI: 10.3390/biomedicines10092224] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/01/2022] [Accepted: 09/03/2022] [Indexed: 11/20/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide. Primary and secondary preventions are key to reducing the global burden. MicroRNAs (miRNAs) are a group of small non-coding RNA molecules, which seem to have a role either as tumor suppressor genes or oncogenes and to be related to cancer risk factors, such as obesity and inflammation. We conducted a systematic review and meta-analysis to identify circulating miRNAs related to CRC diagnosis that could be selected as biomarkers in a meet-in-the-middle analysis. Forty-four studies were included in the systematic review and nine studies in the meta-analysis. The pooled sensitivity and specificity of miR-21 for CRC diagnosis were 77% (95% CI: 69–84) and 82% (95% CI: 70–90), respectively, with an AUC of 0.86 (95% CI: 0.82–0.88). Several miRNAs were found to be dysregulated, distinguishing patients with CRC from healthy controls. However, little consistency was present across the included studies, making it challenging to identify specific miRNAs, which were consistently validated. Understanding the mechanisms by which miRNAs become biologically embedded in cancer initiation and promotion may help better understand cancer pathways to develop more effective prevention strategies and therapy approaches.
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17
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Coronel-Hernández J, Delgado-Waldo I, Cantú de León D, López-Camarillo C, Jacobo-Herrera N, Ramos-Payán R, Pérez-Plasencia C. HypoxaMIRs: Key Regulators of Hallmarks of Colorectal Cancer. Cells 2022; 11:1895. [PMID: 35741024 PMCID: PMC9221210 DOI: 10.3390/cells11121895] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/03/2022] [Accepted: 06/07/2022] [Indexed: 01/27/2023] Open
Abstract
Hypoxia in cancer is a thoroughly studied phenomenon, and the logical cause of the reduction in oxygen tension is tumor growth itself. While sustained hypoxia leads to death by necrosis in cells, there is an exquisitely regulated mechanism that rescues hypoxic cells from their fatal fate. The accumulation in the cytoplasm of the transcription factor HIF-1α, which, under normoxic conditions, is marked for degradation by a group of oxygen-sensing proteins known as prolyl hydroxylases (PHDs) in association with the von Hippel-Lindau anti-oncogene (VHL) is critical for the cell, as it regulates different mechanisms through the genes it induces. A group of microRNAs whose expression is regulated by HIF, collectively called hypoxaMIRs, have been recognized. In this review, we deal with the hypoxaMIRs that have been shown to be expressed in colorectal cancer. Subsequently, using data mining, we analyze a panel of hypoxaMIRs expressed in both normal and tumor tissues obtained from TCGA. Finally, we assess the impact of these hypoxaMIRs on cancer hallmarks through their target genes.
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Affiliation(s)
- Jossimar Coronel-Hernández
- Genomics Laboratory, The National Cancer Institute of México, Tlalpan, Mexico City 14080, Mexico; (I.D.-W.); (D.C.d.L.)
- Functional Genomics Laboratory, Biomedicine Unit, FES-IZTACALA, UNAM, Tlalnepantla 54090, Mexico
| | - Izamary Delgado-Waldo
- Genomics Laboratory, The National Cancer Institute of México, Tlalpan, Mexico City 14080, Mexico; (I.D.-W.); (D.C.d.L.)
| | - David Cantú de León
- Genomics Laboratory, The National Cancer Institute of México, Tlalpan, Mexico City 14080, Mexico; (I.D.-W.); (D.C.d.L.)
| | - César López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Mexico City 03100, Mexico;
| | - Nadia Jacobo-Herrera
- Biochemistry Unit, Institute of Medical Sciences and Nutrition, Salvador Zubirán, Tlalpan, Mexico City 14080, Mexico;
| | - Rosalío Ramos-Payán
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacan City 80030, Mexico;
| | - Carlos Pérez-Plasencia
- Genomics Laboratory, The National Cancer Institute of México, Tlalpan, Mexico City 14080, Mexico; (I.D.-W.); (D.C.d.L.)
- Functional Genomics Laboratory, Biomedicine Unit, FES-IZTACALA, UNAM, Tlalnepantla 54090, Mexico
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18
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Davey MG, Feeney G, Annuk H, Paganga M, Holian E, Lowery AJ, Kerin MJ, Miller N. MicroRNA Expression Profiling Predicts Nodal Status and Disease Recurrence in Patients Treated with Curative Intent for Colorectal Cancer. Cancers (Basel) 2022; 14:cancers14092109. [PMID: 35565239 PMCID: PMC9106021 DOI: 10.3390/cancers14092109] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/13/2022] [Accepted: 04/20/2022] [Indexed: 12/12/2022] Open
Abstract
Background: Approximately one-third of colorectal cancer (CRC) patients will suffer recurrence. MiRNAs are small non-coding RNAs that play important roles in gene expression. We aimed to correlate miRNA expression with aggressive clinicopathological characteristics and survival outcomes in CRC. Methods: Tumour samples were extracted from 74 CRC patients. MiRNAs were quantified using real-time reverse transcriptase polymerase chain reaction. Descriptive statistics and Cox regression analyses were performed to correlate miRNA targets with clinicopathological and outcome data. Results: Aberrant miR-21 and miR-135b expression correlate with increased nodal stage (p = 0.039, p = 0.022). Using univariable Cox regression analyses, reduced miR-135b (β-coefficient −1.126, hazard ratio 0.324, standard error (SE) 0.4698, p = 0.017) and increased miR-195 (β-coefficient 1.442, hazard ratio 4.229, SE 0.446, p = 0.001) predicted time to disease recurrence. Survival regression trees analysis illustrated a relative cut-off of ≤0.488 for miR-195 and a relative cut-off of >−0.218 for miR-135b; both were associated with improved disease recurrence (p < 0.001, p = 0.015). Using multivariable analysis with all targets as predictors, miR-195 (β-coefficient 3.187, SE 1.419, p = 0.025) was the sole significant independent predictor of recurrence. Conclusion: MiR-195 has strong value in predicting time to recurrence in CRC patients. Additionally, miR-21 and miR-135b predict the degree nodal burden. Future studies may include these findings to personalize therapeutic and surgical decision making.
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Affiliation(s)
- Matthew G. Davey
- Department of Surgery, Lambe Institute for Translational Research, National University of Ireland, H91 YR71 Galway, Ireland; (G.F.); (H.A.); (A.J.L.); (M.J.K.); (N.M.)
- Correspondence:
| | - Gerard Feeney
- Department of Surgery, Lambe Institute for Translational Research, National University of Ireland, H91 YR71 Galway, Ireland; (G.F.); (H.A.); (A.J.L.); (M.J.K.); (N.M.)
| | - Heidi Annuk
- Department of Surgery, Lambe Institute for Translational Research, National University of Ireland, H91 YR71 Galway, Ireland; (G.F.); (H.A.); (A.J.L.); (M.J.K.); (N.M.)
| | - Maxwell Paganga
- School of Mathematical and Statistical Sciences, National University of Ireland, H91 H3CY Galway, Ireland; (M.P.); (E.H.)
| | - Emma Holian
- School of Mathematical and Statistical Sciences, National University of Ireland, H91 H3CY Galway, Ireland; (M.P.); (E.H.)
| | - Aoife J. Lowery
- Department of Surgery, Lambe Institute for Translational Research, National University of Ireland, H91 YR71 Galway, Ireland; (G.F.); (H.A.); (A.J.L.); (M.J.K.); (N.M.)
| | - Michael J. Kerin
- Department of Surgery, Lambe Institute for Translational Research, National University of Ireland, H91 YR71 Galway, Ireland; (G.F.); (H.A.); (A.J.L.); (M.J.K.); (N.M.)
| | - Nicola Miller
- Department of Surgery, Lambe Institute for Translational Research, National University of Ireland, H91 YR71 Galway, Ireland; (G.F.); (H.A.); (A.J.L.); (M.J.K.); (N.M.)
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19
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Nouri R, Hasani A, Asgharzadeh M, Sefidan FY, Hemmati F, Rezaee MA. Roles of gut microbiota in colorectal carcinogenesis providing a perspective for early diagnosis and treatment. Curr Pharm Biotechnol 2022; 23:1569-1580. [PMID: 35255786 DOI: 10.2174/1389201023666220307112413] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/29/2021] [Accepted: 01/03/2022] [Indexed: 12/02/2022]
Abstract
Colorectal cancer (CRC) is the third most prevalent malignant neoplasm in the world. CRC is influenced by both environmental and genetic factors. Through toxin-mediated DNA damage and promotion of persistent dysregulated inflammation, the gut microbiota plays a crucial role in the development of CRC. In this review, we discussed the correlation between the bacterial microbiota and CRC carcinogenesis as well as the mechanism by which Streptococcus bovis/gallolyticus, Fusobacterium nucleatum, Bacteroides fragilis, and Escherichia coli can cause CRC.
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Affiliation(s)
- Roghayeh Nouri
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alka Hasani
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Medical Microbiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Asgharzadeh
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Yeganeh Sefidan
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Hemmati
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Ahangarzadeh Rezaee
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Medical Microbiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
- Clinical Research Development Unit of Children Educational, Research and Treatment Center, Tabriz University of Medical Sciences, Tabriz, Iran
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20
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Chin A, Mariscal J, Kim M, Guerra G, Victor B, Qian C, Broseghini E, Posadas E, Freeman MR, Sharma S, Gandellini P, Zaffaroni N, You S, Chan KS, Guarnerio J, Fabbri M, Di Vizio D. miR-1227 Targets SEC23A to Regulate the Shedding of Large Extracellular Vesicles. Cancers (Basel) 2021; 13:5850. [PMID: 34831007 PMCID: PMC8616086 DOI: 10.3390/cancers13225850] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/09/2021] [Accepted: 11/11/2021] [Indexed: 11/23/2022] Open
Abstract
Cancer cells shed a heterogenous mixture of extracellular vesicles (EVs), differing in both size and composition, which likely influence physiological processes in different manners. However, how cells differentially control the shedding of these EV populations is poorly understood. Here, we show that miR-1227, which is enriched in prostate cancer EVs, compared to the cell of origin, but not in EVs derived from prostate benign epithelial cells, induces the shedding of large EVs (such as large oncosomes), while inhibiting the shedding of small EVs (such as exosomes). RNA sequencing from cells stably expressing miR-1227, a modified RISCTRAP assay that stabilizes and purifies mRNA-miR-1227 complexes for RNA sequencing, and in silico target prediction tools were used to identify miR-1227 targets that may mediate this alteration in EV shedding. The COPII vesicle protein SEC23A emerged and was validated by qPCR, WBlot, and luciferase assays as a direct target of miR-1227. The inhibition of SEC23A was sufficient to induce the shedding of large EVs. These results identify a novel mechanism of EV shedding, by which the inhibition of SEC23A by miR-1227 induces a shift in EV shedding, favoring the shedding of large EV over small EV.
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Affiliation(s)
- Andrew Chin
- Department of Surgery, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (A.C.); (J.M.); (M.K.); (G.G.); (B.V.); (C.Q.); (M.R.F.); (S.Y.)
| | - Javier Mariscal
- Department of Surgery, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (A.C.); (J.M.); (M.K.); (G.G.); (B.V.); (C.Q.); (M.R.F.); (S.Y.)
| | - Minhyung Kim
- Department of Surgery, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (A.C.); (J.M.); (M.K.); (G.G.); (B.V.); (C.Q.); (M.R.F.); (S.Y.)
| | - Giorgia Guerra
- Department of Surgery, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (A.C.); (J.M.); (M.K.); (G.G.); (B.V.); (C.Q.); (M.R.F.); (S.Y.)
| | - Blandine Victor
- Department of Surgery, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (A.C.); (J.M.); (M.K.); (G.G.); (B.V.); (C.Q.); (M.R.F.); (S.Y.)
| | - Chen Qian
- Department of Surgery, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (A.C.); (J.M.); (M.K.); (G.G.); (B.V.); (C.Q.); (M.R.F.); (S.Y.)
| | - Elisabetta Broseghini
- Cancer Biology Program, University of Hawai’i Cancer Center, Honolulu, HI 96813, USA; (E.B.); (M.F.)
| | - Edwin Posadas
- Department of Biomedical Sciences, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
- Samuel Oschin Comprehensive Cancer Institute, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (K.S.C.); (J.G.)
| | - Michael R. Freeman
- Department of Surgery, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (A.C.); (J.M.); (M.K.); (G.G.); (B.V.); (C.Q.); (M.R.F.); (S.Y.)
- Department of Biomedical Sciences, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;
- Samuel Oschin Comprehensive Cancer Institute, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (K.S.C.); (J.G.)
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Shivani Sharma
- Department of Pathology & Laboratory Medicine, California NanoSystems Institute, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA 90095, USA;
| | - Paolo Gandellini
- Department of Biosciences, University of Milan, 20122 Milan, Italy;
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy
| | - Nadia Zaffaroni
- Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy;
| | - Sungyong You
- Department of Surgery, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (A.C.); (J.M.); (M.K.); (G.G.); (B.V.); (C.Q.); (M.R.F.); (S.Y.)
| | - Keith Syson Chan
- Samuel Oschin Comprehensive Cancer Institute, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (K.S.C.); (J.G.)
| | - Jlenia Guarnerio
- Samuel Oschin Comprehensive Cancer Institute, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (K.S.C.); (J.G.)
| | - Muller Fabbri
- Cancer Biology Program, University of Hawai’i Cancer Center, Honolulu, HI 96813, USA; (E.B.); (M.F.)
| | - Dolores Di Vizio
- Department of Surgery, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (A.C.); (J.M.); (M.K.); (G.G.); (B.V.); (C.Q.); (M.R.F.); (S.Y.)
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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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Nguyen TT, Ung TT, Li S, Sah DK, Park SY, Lian S, Jung YD. Lithocholic Acid Induces miR21, Promoting PTEN Inhibition via STAT3 and ERK-1/2 Signaling in Colorectal Cancer Cells. Int J Mol Sci 2021; 22:10209. [PMID: 34638550 PMCID: PMC8508661 DOI: 10.3390/ijms221910209] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/15/2021] [Accepted: 09/17/2021] [Indexed: 11/19/2022] Open
Abstract
Micro-RNA-21 (miR-21) is a vital regulator of colorectal cancer (CRC) progression and has emerged as a potential therapeutic target in CRC treatment. Our study using real-time PCR assay found that a secondary bile acid, lithocholic acid (LCA), stimulated the expression of miR21 in the CRC cell lines. Promoter activity assay showed that LCA strongly stimulated miR21 promoter activity in HCT116 cells in a time- and dose-dependent manner. Studies of chemical inhibitors and miR21 promoter mutants indicated that Erk1/2 signaling, AP-1 transcription factor, and STAT3 are major signals involved in the mechanism of LCA-induced miR21 in HCT116 cells. The elevation of miR21 expression was upstream of the phosphatase and tensin homolog (PTEN) inhibition, and CRC cell proliferation enhancement that was shown to be possibly mediated by PI3K/AKT signaling activation. This study is the first to report that LCA affects miR21 expression in CRC cells, providing us with a better understanding of the cancer-promoting mechanism of bile acids that have been described as the very first promoters of CRC progression.
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Affiliation(s)
- Thinh-Thi Nguyen
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Korea; (T.-T.N.); (T.-T.U.); (S.L.); (D.K.S.); (S.-Y.P.)
- Nanogen Pharmaceutical Biotechnology Joint Stock Company, Ho Chi Minh City 71207, Vietnam
| | - Thuan-Trong Ung
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Korea; (T.-T.N.); (T.-T.U.); (S.L.); (D.K.S.); (S.-Y.P.)
- Nanogen Pharmaceutical Biotechnology Joint Stock Company, Ho Chi Minh City 71207, Vietnam
| | - Shinan Li
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Korea; (T.-T.N.); (T.-T.U.); (S.L.); (D.K.S.); (S.-Y.P.)
| | - Dhiraj Kumar Sah
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Korea; (T.-T.N.); (T.-T.U.); (S.L.); (D.K.S.); (S.-Y.P.)
| | - Sun-Young Park
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Korea; (T.-T.N.); (T.-T.U.); (S.L.); (D.K.S.); (S.-Y.P.)
| | - Sen Lian
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Young-Do Jung
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Korea; (T.-T.N.); (T.-T.U.); (S.L.); (D.K.S.); (S.-Y.P.)
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23
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Zeng B, Zhao Q, Sun Z, Liu D, Chen H, Li X, Wang J, Xing HR. SEC23A Is an Independent Prognostic Biomarker in Bladder Cancer Correlated With MAPK Signaling. Front Genet 2021; 12:672832. [PMID: 34456965 PMCID: PMC8385657 DOI: 10.3389/fgene.2021.672832] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 05/11/2021] [Indexed: 12/24/2022] Open
Abstract
Clinical data mining and bioinformatics analysis can be employed effectively to elucidate the function and underlying mechanisms of the gene of interest. Here, we have proposed a framework for the identification and validation of independent biomarkers in human cancer and for mechanistic profiling using gene sets enrichment analysis and pathway analysis. This is followed by validation with in vitro experiments. Using this framework to analyze the clinical relevance of SEC23A, we have discovered the prognostic potential of SEC23A in different cancers and identified SEC23A as an independent prognostic factor for poor prognosis in bladder cancer, which implicates SEC23A, for the first time, as an oncogene. Bioinformatic analyses have elucidated an association between SEC23A expression and the upregulation of the MAPK signaling pathway. Using the T24 human bladder cell line, we confirmed that knockdown of SEC23A expression could effectively impact the MAPK signaling pathway. Further, through PCR verification, we showed that MEF2A, one of the key genes of the MAPK signaling pathway, might be a downstream factor of the SEC23A gene.
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Affiliation(s)
- Bin Zeng
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Qiting Zhao
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Zhiwei Sun
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Doudou Liu
- State Key Laboratory of Ultrasound Engineering in Medicine Co-Founded By Chongqing and the Ministry of Science and Technology, School of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Hao Chen
- State Key Laboratory of Ultrasound Engineering in Medicine Co-Founded By Chongqing and the Ministry of Science and Technology, School of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Xiaoshuang Li
- State Key Laboratory of Ultrasound Engineering in Medicine Co-Founded By Chongqing and the Ministry of Science and Technology, School of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Jianyu Wang
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - H Rosie Xing
- State Key Laboratory of Ultrasound Engineering in Medicine Co-Founded By Chongqing and the Ministry of Science and Technology, School of Biomedical Engineering, Chongqing Medical University, Chongqing, China
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24
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Fodor A, Lazar AL, Buchman C, Tiperciuc B, Orasan OH, Cozma A. MicroRNAs: The Link between the Metabolic Syndrome and Oncogenesis. Int J Mol Sci 2021; 22:ijms22126337. [PMID: 34199293 PMCID: PMC8231835 DOI: 10.3390/ijms22126337] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/03/2021] [Accepted: 06/09/2021] [Indexed: 12/14/2022] Open
Abstract
Metabolic syndrome (MetS) represents a cluster of disorders that increase the risk of a plethora of conditions, in particular type two diabetes, cardiovascular diseases, and certain types of cancers. MetS is a complex entity characterized by a chronic inflammatory state that implies dysregulations of adipokins and proinflammatory cytokins together with hormonal and growth factors imbalances. Of great interest is the implication of microRNA (miRNA, miR), non-coding RNA, in cancer genesis, progression, and metastasis. The adipose tissue serves as an important source of miRs, which represent a novel class of adipokines, that play a crucial role in carcinogenesis. Altered miRs secretion in the adipose tissue, in the context of MetS, might explain their implication in the oncogenesis. The interplay between miRs expressed in adipose tissue, their dysregulation and cancer pathogenesis are still intriguing, taking into consideration the fact that miRNAs show both carcinogenic and tumor suppressor effects. The aim of our review was to discuss the latest publications concerning the implication of miRs dysregulation in MetS and their significance in tumoral signaling pathways. Furthermore, we emphasized the role of miRNAs as potential target therapies and their implication in cancer progression and metastasis.
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Affiliation(s)
- Adriana Fodor
- Department of Diabetes and Nutrtion, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Correspondence: (A.F.); (A.L.L.); (C.B.)
| | - Andrada Luciana Lazar
- Department of Dermatology, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Correspondence: (A.F.); (A.L.L.); (C.B.)
| | - Cristina Buchman
- Department of Oncology, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Correspondence: (A.F.); (A.L.L.); (C.B.)
| | - Brandusa Tiperciuc
- Department of Pharmaceutical Chemistry, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Olga Hilda Orasan
- Internal Medicine Department, 4th Medical Clinic “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (O.H.O.); (A.C.)
| | - Angela Cozma
- Internal Medicine Department, 4th Medical Clinic “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (O.H.O.); (A.C.)
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25
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Cancer-secreted exosomal miR-21-5p induces angiogenesis and vascular permeability by targeting KRIT1. Cell Death Dis 2021; 12:576. [PMID: 34088891 PMCID: PMC8178321 DOI: 10.1038/s41419-021-03803-8] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 04/27/2021] [Accepted: 04/27/2021] [Indexed: 12/12/2022]
Abstract
Cancer-secreted exosomes are critical mediators of cancer-host crosstalk. In the present study, we showed the delivery of miR-21-5p from colorectal cancer (CRC) cells to endothelial cells via exosomes increased the amount of miR-21-5p in recipient cells. MiR-21-5p suppressed Krev interaction trapped protein 1 (KRIT1) in recipient HUVECs and subsequently activated β-catenin signaling pathway and increased their downstream targets VEGFa and Ccnd1, which consequently promoted angiogenesis and vascular permeability in CRC. A strong inverse correlation between miR-21-5p and KRIT1 expression levels was observed in CRC-adjacent vessels. Furthermore, miR-21-5p expression in circulating exosomes was markedly higher in CRC patients than in healthy donors. Thus, our data suggest that exosomal miR-21-5p is involved in angiogenesis and vascular permeability in CRC and may be used as a potential new therapeutic target.
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26
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Shiragannavar VD, Sannappa Gowda NG, Santhekadur PK. Is circulating exosome carry Staphylococcal nuclease domain-containing protein 1, a component of RNA-induced silencing complex? Genes Dis 2021; 8:115-116. [PMID: 33997157 PMCID: PMC8099681 DOI: 10.1016/j.gendis.2020.03.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 03/19/2020] [Accepted: 03/20/2020] [Indexed: 11/17/2022] Open
Affiliation(s)
| | | | - Prasanna K. Santhekadur
- Corresponding author. Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagar, Mysore 570015, Karnataka, India.
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27
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Stecoza CE, Nitulescu GM, Draghici C, Caproiu MT, Olaru OT, Bostan M, Mihaila M. Synthesis and Anticancer Evaluation of New 1,3,4-Oxadiazole Derivatives. Pharmaceuticals (Basel) 2021; 14:438. [PMID: 34066442 PMCID: PMC8148175 DOI: 10.3390/ph14050438] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/01/2021] [Accepted: 05/03/2021] [Indexed: 12/24/2022] Open
Abstract
In order to develop novel chemotherapeutic agents with potent anticancer activities, a series of new 2,5-diaryl/heteroaryl-1,3,4-oxadiazoles were designed and synthesized. The structures of the new compounds were established using elemental analyses, IR and NMR spectral data. The compounds were evaluated for their anticancer potential on two standardized human cell lines, HT-29 (colon adenocarcinoma) and MDA-MB-231 (breast adenocarcinoma). Cytotoxicity was measured by MTS assay, while cell cycle arrest and apoptosis assays were conducted using a flow cytometer, the results showing that the cell line MDA-MB-231 is more sensitive to the compounds' action. The results of the predictive studies using the PASS application and the structural similarity analysis indicated STAT3 and miR-21 as the most probable pharmacological targets for the new compounds. The promising effect of compound 3e, 2-[2-(phenylsulfanylmethyl)phenyl]-5-(4-pyridyl)-1,3,4-oxadiazole, especially on the MDA-MB-231 cell line motivates future studies to improve the anticancer profile and to reduce the toxicological risks. It is worth noting that 3e produced a low toxic effect in the D. magna 24 h assay and the predictive studies on rat acute toxicity suggest a low degree of toxic risks.
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Affiliation(s)
- Camelia Elena Stecoza
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, 6 Traian Vuia Street, 020956 Bucharest, Romania; (C.E.S.); (O.T.O.)
| | - George Mihai Nitulescu
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, 6 Traian Vuia Street, 020956 Bucharest, Romania; (C.E.S.); (O.T.O.)
| | - Constantin Draghici
- “Costin D. Neniţescu” Centre of Organic Chemistry Romanian Academy, 202 B Splaiul Independenţei, 060023 Bucharest, Romania; (C.D.); (M.T.C.)
| | - Miron Teodor Caproiu
- “Costin D. Neniţescu” Centre of Organic Chemistry Romanian Academy, 202 B Splaiul Independenţei, 060023 Bucharest, Romania; (C.D.); (M.T.C.)
| | - Octavian Tudorel Olaru
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, 6 Traian Vuia Street, 020956 Bucharest, Romania; (C.E.S.); (O.T.O.)
| | - Marinela Bostan
- Center of Immunology, “Stefan S. Nicolau” Institute of Virology, 030304 Bucharest, Romania; (M.B.); (M.M.)
| | - Mirela Mihaila
- Center of Immunology, “Stefan S. Nicolau” Institute of Virology, 030304 Bucharest, Romania; (M.B.); (M.M.)
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28
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Bisnett BJ, Condon BM, Lamb CH, Georgiou GR, Boyce M. Export Control: Post-transcriptional Regulation of the COPII Trafficking Pathway. Front Cell Dev Biol 2021; 8:618652. [PMID: 33511128 PMCID: PMC7835409 DOI: 10.3389/fcell.2020.618652] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 12/14/2020] [Indexed: 11/13/2022] Open
Abstract
The coat protein complex II (COPII) mediates forward trafficking of protein and lipid cargoes from the endoplasmic reticulum. COPII is an ancient and essential pathway in all eukaryotes and COPII dysfunction underlies a range of human diseases. Despite this broad significance, major aspects of COPII trafficking remain incompletely understood. For example, while the biochemical features of COPII vesicle formation are relatively well characterized, much less is known about how the COPII system dynamically adjusts its activity to changing physiologic cues or stresses. Recently, post-transcriptional mechanisms have emerged as a major mode of COPII regulation. Here, we review the current literature on how post-transcriptional events, and especially post-translational modifications, govern the COPII pathway.
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Affiliation(s)
- Brittany J Bisnett
- Department of Biochemistry, Duke University School of Medicine, Durham, NC, United States
| | - Brett M Condon
- Department of Biochemistry, Duke University School of Medicine, Durham, NC, United States
| | - Caitlin H Lamb
- Department of Biochemistry, Duke University School of Medicine, Durham, NC, United States
| | - George R Georgiou
- Department of Biochemistry, Duke University School of Medicine, Durham, NC, United States
| | - Michael Boyce
- Department of Biochemistry, Duke University School of Medicine, Durham, NC, United States
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29
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Mollasalehi H, Shajari E. A colorimetric nano-biosensor for simultaneous detection of prevalent cancers using unamplified cell-free ribonucleic acid biomarkers. Bioorg Chem 2020; 107:104605. [PMID: 33421955 DOI: 10.1016/j.bioorg.2020.104605] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 12/12/2020] [Accepted: 12/25/2020] [Indexed: 12/29/2022]
Abstract
Early detection of cancer increases the chance of effective treatment and survival rates. The aim of this study is to develop a rapid and non-invasive nano-biosensing method to screen common lethal cancers in their early stages. In that regard, two circulating microRNA (miR-21, miR-155) biomarkers, which are upregulated in plasma in prevalent cancers, were targeted by a rapid and colorimetric nano-biosensor based on non-crosslinking Au-nanoprobes without amplification requirement. Multiple cancerous cell lines, including A549, MCF7, HT-29, A2780, AGS, MKN-45, and SW-1736 and the primary fibroblast were examined with naked eyes after the hybridization assay using exogenous biomarkers. The results were also confirmed by spectroscopy analysis. The upregulated miRNAs in cancerous cell lines caused a significant blue shift in the Au-nanoprobe absorbance spectrum while the samples isolated from normal cells remained intact red. The limit of detection (LOD) of the method was determined to be less than one ng/µL of total isolated miRNA using an instrument-free visual method. The developed geno-sensing method could serve as a simple, point-of-care platform for cancer prognosis and diagnosis, leading to operative nano-theranostics.
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Affiliation(s)
- Hamidreza Mollasalehi
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Velenjak, Tehran Postal Code: 1983969411, Iran.
| | - Elmira Shajari
- Protein Research Center (PRC), Shahid Beheshti University, Velenjak, Tehran, Iran
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30
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Saberinia A, Alinezhad A, Jafari F, Soltany S, Akhavan Sigari R. Oncogenic miRNAs and target therapies in colorectal cancer. Clin Chim Acta 2020; 508:77-91. [DOI: 10.1016/j.cca.2020.05.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 05/06/2020] [Accepted: 05/07/2020] [Indexed: 12/18/2022]
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31
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Sun Z, Zeng B, Liu D, Zhao Q, Wang J, Rosie Xing H. S100A8 transported by SEC23A inhibits metastatic colonization via autocrine activation of autophagy. Cell Death Dis 2020; 11:650. [PMID: 32811814 PMCID: PMC7435177 DOI: 10.1038/s41419-020-02835-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 07/28/2020] [Accepted: 07/29/2020] [Indexed: 12/19/2022]
Abstract
Metastasis is the main cause of failure of cancer treatment. Metastatic colonization is regarded the most rate-limiting step of metastasis and is subjected to regulation by a plethora of biological factors and processes. On one hand, regulation of metastatic colonization by autophagy appears to be stage- and context-dependent, whereas mechanistic characterization remains elusive. On the other hand, interactions between the tumor cells and their microenvironment in metastasis have long been appreciated, whether the secretome of tumor cells can effectively reshape the tumor microenvironment has not been elucidated mechanistically. In the present study, we have identified “SEC23A-S1008-BECLIN1-autophagy axis” in the autophagic regulation of metastatic colonization step, a mechanism that tumor cells can exploit autophagy to exert self-restrain for clonogenic proliferation before the favorable tumor microenvironment is established. Specifically, we employed a paired lung-derived oligometastatic cell line (OL) and the homologous polymetastatic cell line (POL) from human melanoma cell line M14 that differ in colonization efficiency. We show that S100A8 transported by SEC23A inhibits metastatic colonization via autocrine activation of autophagy. Furthermore, we verified the clinical relevance of our experimental findings by bioinformatics analysis of the expression of Sec23a and S100A8 and the clinical-pathological associations. We demonstrate that higher Sec23a and Atg5 expression levels appear to be protective factors and favorable diagnostic (TNM staging) and prognostic (overall survival) markers for skin cutaneous melanoma (SKCM) and colon adenocarcinoma (COAD) patients. And we confirm the bioinformatics analysis results with SKCM biopsy samples.
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Affiliation(s)
- Zhiwei Sun
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China.,Laboratory of Translational Cancer Stem Cell Research, Chongqing Medical University, Chongqing, China
| | - Bin Zeng
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China.,Laboratory of Translational Cancer Stem Cell Research, Chongqing Medical University, Chongqing, China
| | - Doudou Liu
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China.,Laboratory of Translational Cancer Stem Cell Research, Chongqing Medical University, Chongqing, China
| | - Qiting Zhao
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China.,Laboratory of Translational Cancer Stem Cell Research, Chongqing Medical University, Chongqing, China
| | - Jianyu Wang
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China. .,Laboratory of Translational Cancer Stem Cell Research, Chongqing Medical University, Chongqing, China.
| | - H Rosie Xing
- Laboratory of Translational Cancer Stem Cell Research, Chongqing Medical University, Chongqing, China. .,State Key Laboratory of Ultrasound Engineering in Medicine Co-Founded by Chongqing and the Ministry of Science and Technology, College of Biomedical Engineering, Chongqing Medical University, Chongqing, China.
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32
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Kundaktepe BP, Sozer V, Papila C, Durmus S, Kocael PC, Simsek G, Gelisgen R, Zengin K, Ulualp K, Uzun H. Associations Between miRNAs and Two Different Cancers: Breast and Colon. Cancer Manag Res 2020; 12:871-879. [PMID: 32104069 PMCID: PMC7012229 DOI: 10.2147/cmar.s227628] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Accepted: 01/22/2020] [Indexed: 12/23/2022] Open
Abstract
Objective Screening approaches using microRNAs (miRNAs) have been gaining increased attention owing to their potential applications in the diagnosis, prognosis, and monitoring of cancer, because aberrant miRNA expression plays a role in the development and advancement of malignancies. The objectives of this study were to characterize mir21, miR31, mir143, mir145, and control RNU43, which are differentially expressed in peripheral blood mononuclear cells (PBMCs) of breast and colorectal cancer patients, compared to that in controls and to establish whether this is specific to breast and colon cancer for use as tumor markers. Methods Thirty newly diagnosed patients with breast cancer and 30 patients with colorectal cancer were enrolled together with 30 healthy controls. PBMCs were isolated from venous blood samples of individuals. Next, miRNA expression analysis was performed by a two-step method of reverse transcription and qPCR. Results The expression levels of miR-143 and miR-31 were significantly decreased, whereas the expression levels of miR-145 and miR-21 were significantly increased in breast cancer patients compared to those in healthy subjects. Moreover, the expression levels of miR-143, miR-145, and miR-21 were significantly increased and, in contrast, the changes in the expression levels of miR-31 were not statistically significant in colon cancer compared to those in healthy subjects. miR-21 exhibited the highest increase in both breast and colon cancers. There was a weak positive correlation between miR-145 and CA-15.3 in patients with breast cancer (r = 0.451; p = 0.012). miR-143 was positively correlated with the TNM stage in colon cancer patients (r = 0.568; p = 0.001). Conclusion A biomarker panel composed of miR-21, miR-31, miR-143, and miR-145 in PBMC may provide a new diagnostic approach for the early detection of breast and colon cancer. As miR-21 expression was found to be the highest among all the miRNAs evaluated, it may represent a new tumor biomarker and a candidate therapeutic drug or gene target in colon and breast cancer.
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Affiliation(s)
- Berrin Papila Kundaktepe
- Department of General Surgery, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Volkan Sozer
- Department of Biochemistry, Yildiz Technical University, Istanbul, Turkey
| | - Cigdem Papila
- Department of Internal Medicine, Division of Oncology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Sinem Durmus
- Department of Medical Biochemistry, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Pinar Cigdem Kocael
- Department of General Surgery, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Gonul Simsek
- Department of Physiology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Remise Gelisgen
- Department of Medical Biochemistry, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Kagan Zengin
- Department of General Surgery, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Kenan Ulualp
- Department of General Surgery, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Hafize Uzun
- Department of Medical Biochemistry, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
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33
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Jing J, Wang B, Liu P. The Functional Role of SEC23 in Vesicle Transportation, Autophagy and Cancer. Int J Biol Sci 2019; 15:2419-2426. [PMID: 31595159 PMCID: PMC6775307 DOI: 10.7150/ijbs.37008] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Accepted: 08/01/2019] [Indexed: 02/06/2023] Open
Abstract
SEC23, the core component of the coat protein complex II (COPII), functions to transport newly synthesized proteins and lipids from the endoplasmic reticulum (ER) to the Golgi apparatus in cells for secretion. SEC23 protein has two isoforms (SEC23A and SEC23B) and their aberrant expression and mutations were reported to cause human diseases and oncogenesis, whereas SEC23A and SEC23B may have the opposite activity in human cancer, for a reason that remains unclear. This review summarizes recent research in SEC23, COPII-vesicle transportation, autophagy, and cancer.
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Affiliation(s)
- Jingchen Jing
- Center for Translational Medicine, The First Affiliated Hospital, Xi'an Jiaotong University.,The Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Bo Wang
- Center for Translational Medicine, The First Affiliated Hospital, Xi'an Jiaotong University.,The Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Peijun Liu
- Center for Translational Medicine, The First Affiliated Hospital, Xi'an Jiaotong University.,The Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
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Exosomes from Adipose-Derived Stem Cells (ADSCs) Overexpressing miR-21 Promote Vascularization of Endothelial Cells. Sci Rep 2019; 9:12861. [PMID: 31492946 PMCID: PMC6731308 DOI: 10.1038/s41598-019-49339-y] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 08/21/2019] [Indexed: 12/20/2022] Open
Abstract
In the past few years, exosomes released from adipose-derived stem cells (abbreviated as ADSCs) have shown promises to provide therapeutic benefits in the fields of regenerative medicine. miRNAs, existing in exosomes, are endogenous, small noncoding RNAs that play important roles in a variety of cellular functions and tumor development. Emerging evidences have indicated that miR-21 is one of the important miRNAs associated with tumor angiogenesis. In this study, we identified the role of exosomes from ADSCs overexpressing miR-21 in regulating/promoting vascularization of endothelial cells. Experimental data indicated an elevated miR-21 level in exosomes released by ADSCs overexpressing miR-21. In vitro matrigel angiogenesis assay showed that exosomes secreted by ADSCs overexpressing miR-21 significantly promoted the vascularization of HUVEC cells (an endothelial cell line). Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot (WB) revealed an upregulation of HIF-1α, VEGF, SDF-1, p-Akt, p-ERK1/2 and downregulation of PTEN in response to miR-21 overexpression, indicating that miR-21 enriched exosomes induced angiogenesis through Akt and ERK activation and also HIF-1α and SDF-1 expression. Our work suggests that exosomes from ADSCs that overexpressing miR-21 can potentially promote vascularization and therefore the transplantation of exosomes from their culture may be suitable for clinical effort in regenerative medicine.
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Zhang Y, Chen Z, Feng L, Jiang P, Li X, Wang X. Ionizing Radiation-inducible microRNA-21 Induces Angiogenesis by Directly Targeting PTEN. Asian Pac J Cancer Prev 2019; 20:1587-1593. [PMID: 31128066 PMCID: PMC6857897 DOI: 10.31557/apjcp.2019.20.5.1587] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Background: Previous experimental studies have established that MicroRNAs (miRNAs) can function as oncogenes or tumor suppressors in the regulation of tumor biology or pathology. However, the effects of ionizing radiation (IR) on the expression levels of cellular miRNAs and their further effects on the biological behavior of tumor cells require further investigation. Methods: We determined the proliferation, migration and tube formation of HUVEC cells after ionizing radiation (control, 0h and 24h), and the changes of miR-21, VEFG and HIF-1α levels after ionizing radiation were measured by Western blot (WB). The effects of miR-21 mimics and inhibitors on the protein and mRNA expression of PTEN were determined by RT-PCT and WB. Two independent luciferase reporter plasmids were constructed to detect changes in PTEN protein expression. Results: We found that both IR and miR-21 increase proliferation, migration and tube formation of HUVEC cells. Ionizing radiation directly targets the inhibition of PTEN expression by causing an increase in miR-21 expression, and induces the accumulation of VEGF and HIF-1α expression in cells by the PI3K / AKT signaling pathway. Simultaneous induction of ectopic expression of PTEN can rescue radiation-induced proliferation, migration and tube formation in tumor cells. Conclusion: miR-21 promotes tumor cell proliferation and migration by targeting inhibition of PTEN expression, which may become a potential target for tumor therapy in the future.
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Affiliation(s)
- Yongchun Zhang
- Department of Radiotherapy, Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Zhiying Chen
- Department of Radiotherapy, Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Lingxin Feng
- Department of Radiotherapy, Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Peng Jiang
- Department of Radiotherapy, Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Xiumei Li
- Department of Radiotherapy, Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Xiang Wang
- Department of Radiotherapy, Affiliated Hospital of Qingdao University, Qingdao, China.
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Tang XJ, Wang W, Hann SS. Interactions among lncRNAs, miRNAs and mRNA in colorectal cancer. Biochimie 2019; 163:58-72. [PMID: 31082429 DOI: 10.1016/j.biochi.2019.05.010] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 05/07/2019] [Indexed: 02/06/2023]
Abstract
Long non-coding RNAs (lncRNAs) are longer than 200 nts non-coding transcripts and have recently emerged as one of the largest and significantly diverse RNA families whereas microRNAs (miRNAs) are highly conserved short single-stranded ncRNAs (∼18-22 nucleotides). As families of small and long evolutionarily conserved ncRNAs, lncRNAs activate and repress genes via a variety of mechanisms at both transcriptional and translational levels, while miRNAs regulate protein-coding gene expression mainly through mRNA degradation or silencing, These ncRNAs have been proved to be involved in multiple biological functions, such as proliferation, differentiation, migration, angiogenesis and apoptosis. Today, while majority of studies have focused on defining the regulatory functions of lncRNAs and miRNAs, limited information have now available for the mutual regulations of lncRNAs, miRNAs and mRNA. Thus, the underlying molecular mechanisms, in particularly the interactions among lncRNAs, miRNAs and mRNA in development, growth, metastasis and therapeutic potential of cancer still remain obscure. Colorectal cancer (CRC) is known as the third most common and fourth leading cancer death worldwide. Increasing evidence showed the close correlations among aberrant expressions of lncRNAs, miRNAs and the occurrence, development of CRC. This review summarize the potential links among these RNAs in following three areas: 1, The biogenesis and roles of miRNAs in CRC; 2, The biogenesis and functions of lncRNAs in CRC; 3, The interactions among lncRNAs, miRNAs and mRNA in tumorigensis, growth, progression, EMT formation, chemoradiotherapy resistance, and therapeutic potential in CRC. We believe that identifying diverging lncRNAs, miRNAs and relevant genes, their interactions and complex molecular regulatory networks will provide important clues for understanding the mechanism and developing novel diagnostic and therapeutic strategies for CRC. Further efforts are warranted to bring the promise of regulating their activities into clinical utilities.
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Affiliation(s)
- Xiao Juan Tang
- Laboratory of Tumor Biology, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, 510120, China
| | - Wei Wang
- Department of Gastrointestinal Surgery, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, 510120, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, 510120, China.
| | - Swei Sunny Hann
- Laboratory of Tumor Biology, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, 510120, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, 510120, China.
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Guan C, Zhang L, Wang S, Long L, Zhou H, Qian S, Ma M, Bai F, Meng QH, Lyu J. Upregulation of MicroRNA-21 promotes tumorigenesis of prostate cancer cells by targeting KLF5. Cancer Biol Ther 2019; 20:1149-1161. [PMID: 31002531 DOI: 10.1080/15384047.2019.1599659] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Prostate cancer (PCa) is the second frequently newly diagnosed cancer in men. Androgen deprivation therapy has been widely used to inhibit PCa growth but eventually fails in many patients. Androgen receptor and its downstream molecules like microRNAs could be promising therapeutic targets. We aimed to investigate the involvement of miR-21 in PCa tumorigenesis. We found that miR-21 was an unfavorable factor and correlated positively with tumor grade in PCa patients from TCGA database. MiR-21 was more highly expressed in androgen-independent PCa cells than in androgen-dependent PCa cells. Overexpression of miR-21 promoted androgen-dependent and -independent PCa cell proliferation, migration, invasion, and resistance to apoptosis. Furthermore, increased miR-21 expression promoted mouse xenograft growth. We identified nine genes differentially expressed in PCa tumors and normal tissue which could be potential targets of miR-21 by bioinformatic analyses. We demonstrate that miR-21 directly targeted KLF5 and inhibited KLF5 mRNA and protein levels in PCa. STRING and functional enrichment analysis results suggest that GSK3B might be regulated by KLF5. Our findings demonstrate that miR-21 promotes the tumorigenesis of PCa cells by directly targeting KLF5. These biological effects are mediated through upregulation of GSK3B and activation of the AKT signaling pathway.
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Affiliation(s)
- Chen Guan
- a Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences , Wenzhou Medical University , Wenzhou , Zhejiang , China
| | - Lingling Zhang
- a Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences , Wenzhou Medical University , Wenzhou , Zhejiang , China
| | - Sixuan Wang
- a Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences , Wenzhou Medical University , Wenzhou , Zhejiang , China
| | - Luye Long
- a Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences , Wenzhou Medical University , Wenzhou , Zhejiang , China
| | - Huaibin Zhou
- a Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences , Wenzhou Medical University , Wenzhou , Zhejiang , China
| | - Shihan Qian
- a Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences , Wenzhou Medical University , Wenzhou , Zhejiang , China
| | - Mengni Ma
- a Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences , Wenzhou Medical University , Wenzhou , Zhejiang , China
| | - Fumao Bai
- a Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences , Wenzhou Medical University , Wenzhou , Zhejiang , China
| | - Qing H Meng
- b Department of Laboratory Medicine , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Jianxin Lyu
- a Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences , Wenzhou Medical University , Wenzhou , Zhejiang , China
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Chu Y, Hu X, Wang G, Wang Z, Wang Y. Downregulation of miR-136 promotes the progression of osteosarcoma and is associated with the prognosis of patients with osteosarcoma. Oncol Lett 2019; 17:5210-5218. [PMID: 31186737 DOI: 10.3892/ol.2019.10203] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 02/02/2019] [Indexed: 12/20/2022] Open
Abstract
Osteosarcoma (OS) is the most common bone tumor in children and young adults, and is an aggressive tumor with poor prognosis. MicroRNAs (miRNAs) are aberrantly expressed in various types of cancer, and contribute to cancer tumorigenesis and progression. In the present study, the potential prognostic value and biological function of miRNA-136 (miR-136) in OS was investigated. Reverse transcription-quantitative polymerase chain reaction analysis was used to evaluate the expression of miR-136 in OS tissues and cell lines. Kaplan-Meier survival analysis and Cox regression analysis were conducted to investigate the prognostic significance of miR-136. Various in vitro cell based assays were used to evaluate the effects of miR-136 on the biological behavior of OS cells. A luciferase assay was performed to determine the key miR-136 targets associated with OS. The expression of miR-136 was significantly downregulated in osteosarcoma tissues and cells compared with the normal controls (all P<0.05). Decreased miR-136 expression was significantly associated with Enneking staging (P=0.030) and distant metastasis (P=0.016). Decreased miR-136 expression in patients was associated with shorter overall survival compared with patients with increased expression levels (log-rank test; P<0.05). The expression of miR-136 was indicated as an independent prognostic factor for the patients (hazard ratio=0.496; 95% confidence interval=0.250-0.987; P=0.046). MTT, transwell and Matrigel assays demonstrated that upregulation of miR-136 decreased proliferation, migration and invasion of OS cells. Bioinformatics and luciferase assays demonstrated that migration and invasion enhancer 1 (MIEN1) is a direct target of miR-136. Together, the results suggested that miR-136 functions as a tumor suppressor gene to regulate proliferation, migration and invasion of OS cells. MIEN1 was a potential target of miR-136. Additionally, miR-136 may serve as a prognostic biomarker for OS.
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Affiliation(s)
- Yanchen Chu
- Department of Spinal Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Xiaoli Hu
- Department of Obstetrics and Gynecology, Women and Children's Hospital of Linyi City, Linyi, Shandong 276000, P.R. China
| | - Guangfeng Wang
- Department of Medical Administration, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Zhijie Wang
- Department of Spinal Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Yanjin Wang
- Department of Orthopedics, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
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Ding T, Cui P, Zhou Y, Chen C, Zhao J, Wang H, Guo M, He Z, Xu L. Antisense Oligonucleotides against miR-21 Inhibit the Growth and Metastasis of Colorectal Carcinoma via the DUSP8 Pathway. MOLECULAR THERAPY. NUCLEIC ACIDS 2018; 13:244-255. [PMID: 30317164 PMCID: PMC6187053 DOI: 10.1016/j.omtn.2018.09.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 09/06/2018] [Accepted: 09/06/2018] [Indexed: 01/02/2023]
Abstract
Accumulating research has documented that microRNA-21 (miR-21) plays an important role in the development of human colorectal carcinoma (CRC). Our recent work also showed that antisense oligonucleotides (ASOs) against miR-21 can impair the growth of CRC cells in vitro. However, the potential role of miR-21 in gene therapy against CRC remains to be fully elucidated. Here, we further observed the effect of ASOs against miR-21 on the growth and metastasis of CRC in vivo using a xenograft model of human CRC. We found that ASOs could effectively inhibit the growth and metastasis of CRC in vivo, accompanied by downregulated expression of miR-21 and reduced transduction of the AKT and ERK pathway. Mechanically, global gene expression analysis showed that the expression of DUSP8, a novel target of miR-21, was upregulated in tumor mass. Furthermore, overexpression of DUSP8 could remarkably suppress the proliferation and migration of CRC cells in vitro. Finally, downregulation of DUSP8 could abrogate the effects of ASOs against miR-21 on the proliferation and migration of CRC cells, as well as altered transduction of the AKT and ERK signaling pathway. Together, these data suggest that ASOs against miRNAs are an attractive and potential therapeutic for the treatment of human CRC and warrant further development.
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Affiliation(s)
- Tao Ding
- Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Guizhou 563000, China
| | - Panpan Cui
- Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Guizhou 563000, China
| | - Ya Zhou
- Department of Medical Physics, Zunyi Medical University, Guizhou 563000, China
| | - Chao Chen
- Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Guizhou 563000, China
| | - Juanjuan Zhao
- Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Guizhou 563000, China
| | - Hairong Wang
- Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Guizhou 563000, China
| | - Mengmeng Guo
- Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Guizhou 563000, China
| | - Zhixu He
- Stem Cell and Tissue Engineering Research Center, Guizhou Medical University, Guizhou 550004, China
| | - Lin Xu
- Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Guizhou 563000, China.
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miR-21 expression analysis in budding colon cancer cells by confocal slide scanning microscopy. Clin Exp Metastasis 2018; 35:819-830. [PMID: 30361805 PMCID: PMC6267652 DOI: 10.1007/s10585-018-9945-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 10/18/2018] [Indexed: 01/09/2023]
Abstract
MicroRNA-21 (miR-21) expression in stromal fibroblastic cells in colorectal cancer is well-documented, whereas miR-21 expression in tumor budding cells (TBCs) is poorly described. TBCs are locally invasive carcinoma cells with increased metastatic properties and characteristics of epithelial to mesenchymal transition. This study was conducted to better characterize the expression of miR-21 in TBCs. First, chromogenic miR-21 in situ hybridization (ISH) staining was performed in 58 colon adenocarcinomas with evident TBCs. Then, to obtain unambiguous identification of miR-21 in the TBCs, twenty cases were selected for an additional multiplex fluorescence analysis combining miR-21 ISH with cytokeratin and laminin-5γ2 immunofluorescence. Employing confocal slide scanning microscopy, comprehensive digital images of the invasive front (10–40 mm2) were obtained from 16 of the 20 cases, and miR-21 expression was evaluated in cytokeratin-positive TBCs. The high resolution of the confocal digital slide images allowed a detailed examination of the confocal stacks of the multiplex-stained tissue sections. The cases with the highest fraction of miR-21 positive TBCs were all stage III cancers defined by the presence of regional lymph node metastasis. Some of the miR-21 positive TBCs were also laminin-5γ2 positive. The confocal image stacks also revealed that some TBCs were actually directly connected to malignant glands. In conclusion, miR-21 expression was unambiguously identified in TBCs by evaluation of digital slides obtained by confocal slide scanning microscopy. In addition, the digital confocal slides provided a more detailed understanding of local cancer cell invasion by allowing evaluation of the cell structures in three dimensions.
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Sabry D, El-Deek SEM, Maher M, El-Baz MAH, El-Bader HM, Amer E, Hassan EA, Fathy W, El-Deek HEM. Role of miRNA-210, miRNA-21 and miRNA-126 as diagnostic biomarkers in colorectal carcinoma: impact of HIF-1α-VEGF signaling pathway. Mol Cell Biochem 2018; 454:177-189. [PMID: 30357530 DOI: 10.1007/s11010-018-3462-1] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 10/16/2018] [Indexed: 12/11/2022]
Abstract
Colorectal cancer (CRC) is a major cause of death worldwide. Novel non-invasive, high diagnostic value screening test is urgently needed to improve survival rate, treatment and prognosis. Stable, small, circulating microRNA (miRNA) offers unique opportunities for the early diagnosis of several diseases. It acts as tumor oncogenes or suppressors and involve in cell death, survival, and metastasis. Communication between miRNA and carcinogenesis is critical but it still not clear and needs further investigation. The aim of our study is to evaluate the role of miR-210, miR-21, miR-126, as non-invasive diagnostic biomarkers for screening, early detection of CRC, studying their correlation with prognostic variables, and clarifying the roles of miRNAs on HIF-1α-VEGF signaling pathway. The expression of miR-210, miR-21 and miR-126 was performed using qRT-PCR in adenocarcinoma (no = 35), adenomas (no = 51), and neoplasm free controls (no = 101). Serum levels of VEGF and HIF-1α was determined by ELISA Kit. The results show that the expression of miR-210, miR-21, VEGF, HIF-1α was significantly up-regulated while that miRNA-126 was down-regulated in both adenocarcinoma and adenomas compared with controls (p < 0.001 for each). No significant difference was noted comparing patients with adenocarcinoma and adenomas. The three miRNAs correlated with VEGF, HIF-α. The miR-210 and miR-21 associated with TNM classification and clinical staging of adenocarcinoma (p < 0.001) and they show high diagnostic value with sensitivity and specificity 88.6%, 90.1% and 91.4%, 95.0% respectively. Our study revealed that circulating miR-210, miR-21 were up-regulated while miR-126 was down-regulated in CRC and adenomas patients, they all correlated with TNM staging and they had high diagnostic value. HIF-1α VEGF signaling pathways regulated by miRNAs played a role in colon cancer initiation. To the best of our knowledge, this is the first study of this miRNAs panel in CRC in our community. These data suggested that these biomarkers could be a potential novel, non-invasive marker for early diagnosis, screening and predicting prognosis of CRC. Understanding the molecular functions by which miRNAs affect cancer and understanding its roles in modulating the signaling output of VEGF might be fruitful in reducing the incidence and slowing the progression of this dark malignancy.
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Affiliation(s)
- Dina Sabry
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt.
| | - Sahar E M El-Deek
- Medical Biochemistry Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Moataz Maher
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mona A H El-Baz
- Medical Biochemistry Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Hala M El-Bader
- Medical Biochemistry Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Eman Amer
- Biochemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt
| | - Elham A Hassan
- Tropical Medicine Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Wael Fathy
- Tropical Medicine Department, Faculty of Medicine, Beny Suef University, Beny Suef, Egypt
| | - Heba E M El-Deek
- Pathology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
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Bahreyni A, Rezaei M, Bahrami A, Khazaei M, Fiuji H, Ryzhikov M, Ferns GA, Avan A, Hassanian SM. Diagnostic, prognostic, and therapeutic potency of microRNA 21 in the pathogenesis of colon cancer, current status and prospective. J Cell Physiol 2018; 234:8075-8081. [DOI: 10.1002/jcp.27580] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 09/18/2018] [Indexed: 12/23/2022]
Affiliation(s)
- Amirhossein Bahreyni
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences Mashhad Iran
| | - Melika Rezaei
- Department of Biology Ferdowsi University of Mashhad Mashhad Iran
| | - Afsane Bahrami
- Cellular and Molecular Research Center, Birjand University of Medical Sciences Birjand Iran
| | - Majid Khazaei
- Department of Medical Physiology Faculty of Medicine, Mashhad University of Medical Sciences Mashhad Iran
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences Mashhad Iran
| | - Hamid Fiuji
- Department of Biochemistry Payame‐Noor University Mashhad Iran
| | - Mikhail Ryzhikov
- Division of Pulmonary and Critical Care Medicine Washington University, School of Medicine Saint Louis Missouri
| | - Gordon A. Ferns
- Division of Medical Education Brighton & Sussex Medical School Brighton Sussex UK
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences Mashhad Iran
- Department of Modern Sciences and Technologies School of Medicine, Mashhad University of Medical Sciences Mashhad Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences Mashhad Iran
- Department of Medical Biochemistry Faculty of Medicine, Mashhad University of Medical Sciences Mashhad Iran
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Sec23a mediates miR-200c augmented oligometastatic to polymetastatic progression. EBioMedicine 2018; 37:47-55. [PMID: 30301603 PMCID: PMC6284370 DOI: 10.1016/j.ebiom.2018.10.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 09/12/2018] [Accepted: 10/01/2018] [Indexed: 12/21/2022] Open
Abstract
Background Cancer treatment is based on tumor staging. Curative intent is only applied to localized tumors. Recent studies show that oligometastatic patients who have limited number of metastases may benefit from metastasis-directed local treatments to achieve long-term survival. However, mechanisms underlying oligometastatic to polymetastatic progression remains elusive. Methods The effects of miR-200c and Sec23a on tumor metastasis were verified both in vitro and in vivo. The secretome changes were detected by mass spectrometry. Findings We established a pair of homologous lung-metastasis derived oligometastatic and polymetastatic cell lines from human melanoma cancer cell line M14. Using the two cell lines, we have identified Sec23a, a gene target of miR-200c, suppresses miR-200c augmented oligometastatic to polymetastatic progression via its secretome. Firstly, miR-200c over-expression and Sec23a interference accelerated oligometastatic to polymetatic progression. Secondly, Sec23a functions downstream of miR-200c. Thirdly, mass spectrometric analysis of the secretory protein profile suggests that Sec23a-dependent secretome may impact metastatic colonization by modifying tumor microenvironment. Fourthly, the survival analysis using The Cancer Genome Atlas database shows Sec23a as a favorable prognostic marker for skin cutaneous melanoma, supporting the clinical relevance of our findings. Interpretation The finding that Sec23a is a suppressor of oligometastatic to polymetastatic progression has clinical implications. First, it provides a new theoretical framework for the development of treatments that prevent oligometastasis to polymetastasis. Second, Sec23a may be used as a favorable prognostic marker for the selection of patients with stable oligometastatic disease for oligometastasis-based local therapies of curative intent. Fund National Natural Science Foundations of China.
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Li G, Wang C, Wang Y, Xu B, Zhang W. LINC00312 represses proliferation and metastasis of colorectal cancer cells by regulation of miR-21. J Cell Mol Med 2018; 22:5565-5572. [PMID: 30134003 PMCID: PMC6201213 DOI: 10.1111/jcmm.13830] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Accepted: 07/09/2018] [Indexed: 12/14/2022] Open
Abstract
Long non‐coding RNAs (lncRNAs) have emerged as important regulators of cancer, including colorectal cancer (CRC). The exact expression pattern of long intergenic noncoding RNA 00312 (LINC00312) in CRC and its mechanisms of action have not been reported. Here, we found that LINC00312 is underexpressed in CRC tissues and cell lines. Functional experiments suggested that LINC00312 suppresses growth, migration and invasion of CRC cells in vitro and attenuates tumour proliferation and metastasis in vivo. Mechanistically, LINC00312 was found to regulate the malignancy of CRC cells by binding to miR‐21 and by functioning as a tumour suppressor targeting PTEN. Overexpression of miR‐21 or knockdown of PTEN attenuated the LINC00312‐mediated inhibition of CRC cell proliferation and invasion. Taken together, our results elucidate the role of the LINC00312–miR‐21–PTEN axis in CRC cell proliferation and tumour progression and may lead to new lncRNA‐based diagnostics or therapeutics for CRC.
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Affiliation(s)
- Gang Li
- Department of General Surgery, Shanghai Pudong New Area People Hospital affiliated to Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Changming Wang
- Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Yongbing Wang
- Department of General Surgery, Shanghai Pudong New Area People Hospital affiliated to Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Bin Xu
- Department of General Surgery, Shanghai Pudong New Area People Hospital affiliated to Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Wenzhong Zhang
- Department of General Surgery, Shanghai Pudong New Area People Hospital affiliated to Shanghai University of Medicine & Health Sciences, Shanghai, China
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He XP, Chen P, Yang K, Liu B, Zhang Y, Wang F, Guo Z, Liu XD, Lou JX, Chen HR. Overexpression of miR‑21 is involved in acute monocytic leukemia‑associated angiogenesis by targeting IL‑12. Mol Med Rep 2018; 18:4122-4128. [PMID: 30106099 DOI: 10.3892/mmr.2018.9357] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 06/06/2017] [Indexed: 11/06/2022] Open
Abstract
Angiogenesis is important in pathophysiological processes, including the pathogenesis of acute monocytic leukemia (AML). MicroRNA‑21 (miR‑21) is overexpressed and exhibits oncogenic activity in cancer. However, the biological mechanism underlying the effect of miR‑21 in AML remains to be fully elucidated. In the present study, the expression levels of miR‑21 and vascular endothelial growth factor (VEGF) were determined in 26 patients with AML and 28 healthy individuals. The secretion of VEGF was also measured following the transfection of THP‑1 cells with miR‑21 mimic or inhibitor. The supernatants of the THP‑1 cells, which were transfected with miR‑21 mimic, inhibitor or small interfering RNA (si)VEGF, respectively, were used to incubate human umbilical vein endothelial cells (HUVECs), following which tube formation of the HUVECs was measured. miR‑21 targets were predicted using a biological target prediction website and confirmed using a luciferase assay. The effects of interleukin (IL)‑12 were investigated by examining the tube formation of HUVECs and the secretion of VEGF following recombinant human (rh) IL‑12 pretreatment. The results revealed that miR‑21 and VEGF expression was significantly increased in the peripheral blood monocytes of the patients, compared with the healthy controls. There was negative correlation between the expression of IL‑12 and miR‑21 in the serum of patients with AML. Furthermore, supernatant VEGF levels from the miR‑21 mimic‑transfected THP‑1 cells were increased, whereas a decreasing trend was observed in the miR‑21 inhibitor group. The angiogenic ability of the HUVECs pretreated with supernatant from the THP‑1 cells transfected with miR‑21 mimic was higher, and was lower in THP‑1 cells co‑transfected with miR‑21 mimic and siVEGF, compared with the miR‑21 mimic only group. A luciferase assay demonstrated that IL‑12 was the direct target of miR‑21, and the level of IL‑12 in the supernatant of THP‑1 cells transfected with miR‑21 mimic was increased. IL‑12 pretreatment increased VEGF expression and angiogenic ability in HUVECs. The inactivation of miR‑21 or activation of its target gene may be a potential therapeutic strategy in human AML.
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Affiliation(s)
- Xue-Peng He
- Department of Hematology, Military General Hospital of Beijing PLA, Beijing 100700, P.R. China
| | - Peng Chen
- Department of Hematology, Military General Hospital of Beijing PLA, Beijing 100700, P.R. China
| | - Kai Yang
- Department of Hematology, Military General Hospital of Beijing PLA, Beijing 100700, P.R. China
| | - Bing Liu
- Department of Hematology, Military General Hospital of Beijing PLA, Beijing 100700, P.R. China
| | - Yuan Zhang
- Department of Hematology, Military General Hospital of Beijing PLA, Beijing 100700, P.R. China
| | - Fang Wang
- Department of Hematology, Military General Hospital of Beijing PLA, Beijing 100700, P.R. China
| | - Zhi Guo
- Department of Hematology, Military General Hospital of Beijing PLA, Beijing 100700, P.R. China
| | - Xiao-Dong Liu
- Department of Hematology, Military General Hospital of Beijing PLA, Beijing 100700, P.R. China
| | - Jin-Xing Lou
- Department of Hematology, Military General Hospital of Beijing PLA, Beijing 100700, P.R. China
| | - Hui-Ren Chen
- Department of Hematology, Military General Hospital of Beijing PLA, Beijing 100700, P.R. China
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Zhu C, Zhang M, Hu J, Li H, Liu S, Li T, Wu L, Han B. Prognostic effect of IL-6/JAK2/STAT3 signal-induced microRNA-21-5p expression on short term recurrence of hepatocellular carcinoma after hepatectomy. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:4169-4178. [PMID: 31949811 PMCID: PMC6962805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 06/29/2018] [Indexed: 06/10/2023]
Abstract
AIM To investigate the putative role of interleukin (IL)-6/Janus Kinase (JAK) 2/Signal transducers and activators of transcription (STAT) 3 signaling pathway in hepatocellular carcinoma (HCC) short term recurrence (STR), and whether the pathway promotes HCC progression through microRNA-21-5p (miRNA-21). METHODS Immunohistochemistry was performed to evaluate the protein expression of IL-6, JAK2 and STAT3. Real-time PCR was used to evaluate the miRNA-21 expression. We also analyzed the correlation of IL-6, JAK2 and STAT3 protein expression with miRNA-21. Clinicopathological variables, including prognosis, were compared between low and high-expressing groups of miRNA-21. RESULTS miRNA-21 expression was significantly increased in the HCC tumor tissue compared to the non-tumor tissue. IL-6 and STAT3 high expression was significantly correlated to high miRNA-21 expression in HCC tumor tissues. Patients with high miRNA-21 expression have more frequent early recurrence. The 6 month overall survival and disease-free survival rate of the miRNA-21 high groups were 72.1% and 30.8%, respectively. Moreover, high miRNA-21 expression was correlated with disease-free survival (DFS) (P < 0.05) and overall survival (OS) (P < 0.05). Multivariate analysis revealed that miRNA-21 and STAT3 high expression were independent prognostic factors of DFS and OS. The area under the ROC curve (AUC) of miRNA-21 and STR, DFS, OS was 0.951 (P < 0.001), 0.847 (P < 0.001), 0.844 (P < 0.001), respectively. CONCLUSIONS miRNA-21 expression, induced by IL-6/JAK2/STAT3 signaling pathway, was increased in the early recurrence of HCC patients and indicated poor prognosis. Expression analysis of miRNA-21 revealed that it may be a valuable prognostic biomarker for HCC.
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Affiliation(s)
- Chengzhan Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao UniversityQingdao, Shandong, P. R. China
| | - Mao Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao UniversityQingdao, Shandong, P. R. China
| | - Jie Hu
- The Third Xiangya Hospital of Central South UniversityChangsha, Hunan, P. R. China
| | - Haoran Li
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao UniversityQingdao, Shandong, P. R. China
| | - Shihai Liu
- Medical Animal Laboratory, The Affiliated Hospital of Qingdao UniversityQingdao, Shandong, P. R. China
| | - Tianxiang Li
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao UniversityQingdao, Shandong, P. R. China
| | - Liqun Wu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao UniversityQingdao, Shandong, P. R. China
| | - Bing Han
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao UniversityQingdao, Shandong, P. R. China
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Yu W, Zhu K, Wang Y, Yu H, Guo J. Overexpression of miR-21-5p promotes proliferation and invasion of colon adenocarcinoma cells through targeting CHL1. Mol Med 2018; 24:36. [PMID: 30134821 PMCID: PMC6048725 DOI: 10.1186/s10020-018-0034-5] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 06/11/2018] [Indexed: 12/19/2022] Open
Abstract
Background This study aims to investigate the effect of miR-21-5p on process of colon adenocarcinoma (COAD) cells and its connection with neural cell adhesion molecule L1 (CHL1). Methods Different expressions of mRNAs and miRNAs were calculated with microarray analysis. QRT-PCR and western blot were performed to quantify miR-21-5p and CHL1 expression. Flow Cytometry, MTT assay, colony formation assay, transwell assay and ELISA were performed to evaluate propagation and invasiveness of COAD cells. Dual luciferase reporter assay was employed to scrutinize the relationship between miR-21-5P and CHL1. We performed in vivo experiment to detect the impact of miR-21-5p and CHL1 on COAD tumor growth. Results Expression level of miR-21-5p increased in both COAD tissues and cells. MTT and Cell cycle assay showed that overexpression of miR-21-5p accelerated proliferation of COAD cells. Transwell assay indicated that miR-21-5p promoted cell invasion. The result of dual luciferase reporter assay indicated that miR-21-5p targeted CHL1 directly and inhibited its expression. The result of in vivo experiments showed that down-regulation of miR-21-5p decreased the volume and weight of tumor, while knockdown of CHLI stimulated tumor growth. Conclusions The overexpression of miR-21-5p can promote propagation and invasiveness of COAD cells through inhibiting the expression of CHL1.
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Affiliation(s)
- Weihua Yu
- Department of gastroenterology, the Second Hospital of Shandong University, No.247 Beiyuan Street, Jinan, 250000, Shandong, China
| | - Kongxi Zhu
- Department of gastroenterology, the Second Hospital of Shandong University, No.247 Beiyuan Street, Jinan, 250000, Shandong, China
| | - Yulong Wang
- Department of Pediatric Internal Medicine, the Second Hospital of Shandong University, Jinan, 250000, Shandong, China
| | - Hualong Yu
- Department of Anus and Intestine Surgery, the Second Hospital of Shandong University, Jinan, 250000, Shandong, China
| | - Jianqiang Guo
- Department of gastroenterology, the Second Hospital of Shandong University, No.247 Beiyuan Street, Jinan, 250000, Shandong, China.
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Semaan A, Uhl B, Branchi V, Lingohr P, Bootz F, Kristiansen G, Kalff JC, Matthaei H, Pantelis D, Dietrich D. Significance of PITX2 Promoter Methylation in Colorectal Carcinoma Prognosis. Clin Colorectal Cancer 2018; 17:e385-e393. [PMID: 29580650 DOI: 10.1016/j.clcc.2018.02.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 02/17/2018] [Accepted: 02/20/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND New treatment modalities and a growing understanding of the complex genetic tumor landscape have improved the outcome of colorectal cancer (CRC) patients. Nonetheless, more individualized treatment regimens, taking individual tumor characteristics into account, have been recently postulated and prognostic biomarkers are needed. We therefore evaluated the prognostic potential of paired-like homeodomain transcription factor 2 (PITX2) promoter methylation in CRC patients. MATERIALS AND METHODS Data of 2 independent cohorts were investigated. Tissue specimens of cohort A (n = 179) were analyzed for their methylation in the PITX2 promoter region using quantitative methylation-specific polymerase chain reaction and compared with publicly available data (PITX2 promoter methylation and PITX2 mRNA expression levels) from "The Cancer Genome Atlas Research Network" (cohort B, n = 443). Data were correlated with clinicopathological parameters and outcome. RESULTS Tumor samples of both cohorts showed a decreased PITX2 promoter methylation level (both P < .001) compared with nonmalignant tissue. Additionally, PITX2 promoter hypomethylation was prognostic in univariate and multivariate analysis (hazard ratio [HR], 1.97 [95% confidence interval (CI), 1.12-3.47], P = .018 and HR, 1.89 [95% CI, 1.09-3.29], P = .023), and Kaplan-Meier analysis (median overall survival, 53.2 vs. 70.4 months, P = .004). Subanalysis of high-risk vs. low-risk stage II CRC patients also showed a PITX2 hypomethylation of the promoter region in the high-risk group (P = .006). CONCLUSION Our results suggest a prognostic role of PITX2 promoter methylation in CRC as biomarker for risk stratification in stage II CRC patients although the results need to be independently validated.
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Affiliation(s)
- Alexander Semaan
- Department of General, Visceral, Thoracic, and Vascular Surgery, University Hospital Bonn, Bonn, Germany.
| | - Barbara Uhl
- Institute of Pathology, University Hospital Bonn, Bonn, Germany
| | - Vittorio Branchi
- Department of General, Visceral, Thoracic, and Vascular Surgery, University Hospital Bonn, Bonn, Germany
| | - Philipp Lingohr
- Department of General, Visceral, Thoracic, and Vascular Surgery, University Hospital Bonn, Bonn, Germany
| | - Friedrich Bootz
- Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany
| | | | - Jörg C Kalff
- Department of General, Visceral, Thoracic, and Vascular Surgery, University Hospital Bonn, Bonn, Germany
| | - Hanno Matthaei
- Department of General, Visceral, Thoracic, and Vascular Surgery, University Hospital Bonn, Bonn, Germany
| | - Dimitrios Pantelis
- Department of General, Visceral, Thoracic, and Vascular Surgery, University Hospital Bonn, Bonn, Germany
| | - Dimo Dietrich
- Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany
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Bai F, Zhou H, Ma M, Guan C, Lyu J, Meng QH. A novel RNA sequencing-based miRNA signature predicts with recurrence and outcome of hepatocellular carcinoma. Mol Oncol 2018; 12:1125-1137. [PMID: 29719937 PMCID: PMC6026871 DOI: 10.1002/1878-0261.12315] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 04/18/2018] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common type of cancer and the second leading cause of cancer-related deaths worldwide. Given that the rate of HCC recurrence 5 years after liver resection is as high as 70%, patient with HCC typically has a poor outcome. A biomarker or set of biomarkers that could predict disease recurrence would have a substantial clinical impact, allowing earlier detection of recurrence and more effective treatment. With the aim of identifying a new microRNA (miRNA) signature associated with HCC recurrence, we analyzed data on 306 patients with HCC for whom both miRNA expression profiles and complete clinical information were available from The Cancer Genome Atlas database. Through this analysis, we identified a six-miRNA signature that could effectively predict patients' recurrence risk; the high-risk and low-risk groups had significantly different recurrence-free survival rates. Time-dependent receiver operating characteristic analysis indicated that this signature had a good predictive performance. Multivariable Cox regression and stratified analyses demonstrated that the six-miRNA signature was independent of other clinical features. Functional enrichment analysis of the gene targets of the six prognostic miRNA indicated enrichment mainly in cancer-related pathways and important cell biological processes. Our results support use of this six-miRNA signature as an independent factor for predicting recurrence and outcome of patients with HCC.
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Affiliation(s)
- Fumao Bai
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, China
| | - Huaibin Zhou
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, China
| | - Mengni Ma
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, China
| | - Chen Guan
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, China
| | - Jianxin Lyu
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, China
| | - Qing H Meng
- Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Zeng YL, Zheng H, Chen QR, Yuan XH, Ren JH, Luo XF, Chen P, Lin ZY, Chen SZ, Wu XQ, Xiao M, Chen YQ, Chen ZZ, Hu JD, Yang T. Bone marrow-derived mesenchymal stem cells overexpressing MiR-21 efficiently repair myocardial damage in rats. Oncotarget 2018; 8:29161-29173. [PMID: 28418864 PMCID: PMC5438721 DOI: 10.18632/oncotarget.16254] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 02/08/2017] [Indexed: 01/08/2023] Open
Abstract
Objective We investigated the ability of bone marrow derived mesenchymal stem cells (BMSCs) overexpressing microRNA-21 (miR-21) to repair cardiac damage induced by anthracyclines in rats. Methods Sprague-Dawley (SD) rats of 2~3 weeks old were selected to isolate and culture BMSCs. A lentivirus harboring pLVX-miR-21 was generated and transfected into rat BMSCs. The rats were assigned into an untreated negative control group, and groups injected with adriamycin alone or with adriamycin followed by BMSCs, pLVX-BMSCs or pLVX-miR-21-BMSCs (n = 10 each). Proliferation and migration of cells were detected by cholecystokinin-8 (CCK- 8) and transwell. MiR-21 expression, mRNA expressions of B cell lymphoma 2 (Bcl2), BAX (BCL-2-associated X protein) and vascular endothelial growth factor (VEGF) were tested by qRT-PCR. Western blotting was applied to detect protein expressions of Bcl-2, Bax and VEGF. Results Using CCK- 8 and transwell assays, we found that pLVX-miR-21-BMSCs, which overexpressed miR-21, exhibited greater proliferation and migration than untransfected BMSCs or pLVX-BMSCs. Ultrasonic cardiograms and immunohistochemical analysis demonstrated that among the five groups, the pLVX-miR-21-BMSC group exhibited the most improved heart function and enhanced angiogenesis. Moreover, the pLVX-miR-21-BMSC group showed enhanced expression of Bcl-2, VEGF and Cx43 and reduced expression of Bax, BNP and troponin T. Conclusion These findings suggest miR-21 overexpression enhanced the proliferation, invasiveness and differentiation of BMSCs as well as expression of key factors (Bcl-2, VEGF and Bax) essential for repairing the cardiac damage induced by anthracyclines and restoring heart function.
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Affiliation(s)
- Yan-Ling Zeng
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China.,Department of Hematology, Affiliated Nanping First Hospital of Fujian Medical University, Nanping 353000, P. R. China
| | - Hao Zheng
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Qiu-Ru Chen
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Xiao-Hong Yuan
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Jin-Hua Ren
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Xiao-Feng Luo
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Ping Chen
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Zhe-Yao Lin
- Department of Hematology, Affiliated Nanping First Hospital of Fujian Medical University, Nanping 353000, P. R. China
| | - Shao-Zhen Chen
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Xue-Qiong Wu
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Min Xiao
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Yong-Quan Chen
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Zhi-Zhe Chen
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Jian-Da Hu
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
| | - Ting Yang
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China
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