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Dong H, Peng Z, Yu T, Xiong J. YB-1 Targeted by miR-509-3-5p Affects Migration and Invasion of Triple‑Negative Breast Cancer by Regulating Cellular Epithelial‑Mesenchymal Transition. Mol Biotechnol 2025; 67:1014-1026. [PMID: 38436906 DOI: 10.1007/s12033-024-01101-0] [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: 08/24/2023] [Accepted: 01/30/2024] [Indexed: 03/05/2024]
Abstract
The epithelial-mesenchymal transition (EMT) process is closely linked to metastasis of breast cancer. This article elucidates the role of Y-box binding protein-1 (YB-1) on the migration and invasion of triple-negative breast cancer (TNBC) cells by regulating EMT, and the related mechanism. The expression data of YB-1 and miR-509-3-5p in TNBC samples and normal samples were downloaded from the GEO database. The proliferation, migration, invasion, and EMT of TNBC cells were detected by CCK-8 assay, colony formation assay, wound-healing assay, transwell assay, and immunoblotting analyses. The targeted binding of YB-1 and miR-509-3-5p was validated by luciferase reporter experiment. A xenograft mouse model was constructed to investigate the influence of the miR-509-3-5p/YB-1 axis on TNBC tumor growth in vivo. YB-1 was overexpressed, while miR-509-3-5p was underexpressed in TNBC tumor tissues and various cell lines. Silencing YB-1 depressed cell viability, proliferation, motility, and EMT in vitro, and miR-509-3-5p upregulation exerted the same effects. YB-1 was targeted by miR-509-3-5p. The suppressive effects on the phenotypes of TNBC cells caused by overexpressed miR-509-3-5p were attenuated by YB-1 upregulation. In addition, miR-509-3-5p overexpression restrained TNBC tumor growth and downregulated the YB-1-mediated EMT process in vivo. YB-1 targeted by miR-509-3-5p affects motility of TNBC cells by regulating cellular EMT.
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Affiliation(s)
- Hanzhi Dong
- Department of Medical Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 Yongwai Zhengjie, Donghu District, Nanchang, 330029, China
| | - Zhiqiang Peng
- Department of Lymphohematology, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Nanchang, 330029, China
| | - Tenghua Yu
- Department of Breast Surgery, Jiangxi Clinical Research Center for Cancer, Jiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Nanchang, 330029, China
| | - Jianping Xiong
- Department of Medical Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 Yongwai Zhengjie, Donghu District, Nanchang, 330029, China.
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Yang J, Li C, Wang Z, Jiang K. Multi-omics analysis of the biological function of the VEGF family in colon adenocarcinoma. Funct Integr Genomics 2024; 24:210. [PMID: 39527375 PMCID: PMC11554882 DOI: 10.1007/s10142-024-01493-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 10/10/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024]
Abstract
The vascular endothelial growth factor (VEGF) family plays a crucial role in cancer progression, but the prognostic significance and biological functions of VEGF family members in colon adenocarcinoma (COAD) remain unclear. Using data from The Cancer Genome Atlas, Gene Expression Omnibus, Gene Set Cancer Analysis, cBioPortal, GeneMANIA, String, MethSurv and starBase database, we identified vascular endothelial growth factor B (VEGFB) as a key gene associated with COAD prognosis, with its abnormal expression linked to methylation dysregulation. In vitro experiments confirmed VEGFB expression was significantly higher in colon cancer tissues compared to normal tissues, as shown by Real-time quantitative PCR and immunohistochemistry. Cell Counting Kit-8 and colony formation assay showed that decreased VEGFB expression in SW480 cells resulted in decreased cell viability and proliferation ability. Scratch assay showed that VEGFB downregulation impaired SW480 cell migration. In addition, our research suggests that VEGFB not only promotes angiogenesis but is also involved in the tumor microenvironment and immune regulation. The SHNG17-miR-375-VEGFB regulatory axis provides a potential therapeutic target for COAD, highlighting VEGFB's role in immune activation during anti-angiogenic therapy and potential reversal of drug resistance.
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Affiliation(s)
- Jianqiao Yang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China
| | - Chen Li
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China
| | - Zhu Wang
- Department of Gastroenterological Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China
| | - Kewei Jiang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China.
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3
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Mafi A, Hedayati N, Milasi YE, Kahkesh S, Daviran M, Farahani N, Hashemi M, Nabavi N, Alimohammadi M, Rahimzadeh P, Taheriazam A. The function and mechanism of circRNAs in 5-fluorouracil resistance in tumors: Biological mechanisms and future potential. Pathol Res Pract 2024; 260:155457. [PMID: 39018926 DOI: 10.1016/j.prp.2024.155457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 07/04/2024] [Accepted: 07/05/2024] [Indexed: 07/19/2024]
Abstract
5-Fluorouracil (5-FU) is a well-known chemotherapy drug extensively used in the treatment of breast cancer. It works by inhibiting cancer cell proliferation and inducing cell death through direct incorporation into DNA and RNA via thymidylate synthase (TS). Circular RNAs (circRNAs), a novel family of endogenous non-coding RNAs (ncRNAs) with limited protein-coding potential, contribute to 5-FU resistance. Their identification and targeting are crucial for enhancing chemosensitivity. CircRNAs can regulate tumor formation and invasion by adhering to microRNAs (miRNAs) and interacting with RNA-binding proteins, regulating transcription and translation. MiRNAs can influence enzymes responsible for 5-FU metabolism in cancer cells, affecting their sensitivity or resistance to the drug. In the context of 5-FU resistance, circRNAs can target miRNAs and regulate biological processes such as cell proliferation, cell death, glucose metabolism, hypoxia, epithelial-to-mesenchymal transition (EMT), and drug efflux. This review focuses on the function of circRNAs in 5-FU resistance, discussing the underlying molecular pathways and biological mechanisms. It also presents recent circRNA/miRNA-targeted cancer therapeutic strategies for future clinical application.
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Affiliation(s)
- Alireza Mafi
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran; Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Neda Hedayati
- School of Medicine, Iran University of Medical Science, Tehran, Iran
| | - Yaser Eshaghi Milasi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Samaneh Kahkesh
- Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Minoo Daviran
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Najma Farahani
- Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia V8V 1P7, Canada
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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4
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Al-Noshokaty TM, Elballal MS, Helal GK, Abulsoud AI, Elshaer SS, El-Husseiny AA, Fathi D, Abdelmaksoud NM, Abdel Mageed SS, Midan HM, Zaki MB, Abd-Elmawla MA, Rizk NI, Elrebehy MA, Zewail MB, Mohammed OA, Doghish AS. miRNAs driving diagnosis, prognosis and progression in Merkel cell carcinoma. Pathol Res Pract 2023; 249:154763. [PMID: 37595447 DOI: 10.1016/j.prp.2023.154763] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 08/09/2023] [Accepted: 08/12/2023] [Indexed: 08/20/2023]
Abstract
Merkel cell carcinoma (MCC) is a rare, aggressive form of skin malignancy with a high recurrence commonly within two to three years of initial diagnosis. The incidence of MCC has nearly doubled in the past few decades. Options for diagnosing, assessing, and treating MCC are limited. MicroRNAs (miRNAs) are a class of small, non-coding RNA molecules that play an important role in controlling many different aspects of cell biology. Many miRNAs are aberrantly expressed in distinct types of cancer, with some serving as tumor suppressors and others as oncomiRs. Therefore, the future holds great promise for the utilization of miRNAs in enhancing diagnostic, prognostic, and therapeutic approaches for MCC. Accordingly, the goal of this article is to compile, summarize, and discuss the latest research on miRNAs in MCC, highlighting their potential clinical utility as diagnostic and prognostic biomarkers.
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Affiliation(s)
- Tohada M Al-Noshokaty
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Gouda Kamel Helal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo 11231, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Ahmed I Abulsoud
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
| | - Shereen Saeid Elshaer
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Department of Biochemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo 11823, Egypt
| | - Ahmed A El-Husseiny
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt; Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City 11829 Cairo, Egypt
| | - Doaa Fathi
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | | | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Heba M Midan
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mohamed Bakr Zaki
- Biochemistry, Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt
| | - Mai A Abd-Elmawla
- Biochemistry, Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Nehal I Rizk
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Moataz B Zewail
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Osama A Mohammed
- Department of Clinical Pharmacology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
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Bhadresha K, Mirza S, Penny C, Mughal MJ. Targeting AXL in Mesothelioma: from functional characterization to clinical implication. Crit Rev Oncol Hematol 2023:104043. [PMID: 37268175 DOI: 10.1016/j.critrevonc.2023.104043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 05/24/2023] [Accepted: 05/30/2023] [Indexed: 06/04/2023] Open
Abstract
Malignant pleural mesothelioma (MM) is a highly aggressive and lethal cancer with a poor survival rate. Current treatment approaches primarily rely on chemotherapy and radiation, but their effectiveness is limited. Consequently, there is an urgent need for alternative treatment strategies, a comprehensive understanding of the molecular mechanisms underlying MM, and the identification of potential therapeutic targets. Extensive studies over the past decade have emphasized the role of Axl in driving tumor development and metastasis, while high levels of Axl expression have been associated with immune evasion, drug resistance, and reduced patient survival in various cancer types. Ongoing clinical trials are investigating the efficacy of Axl inhibitors for different cancers. However, the precise role of Axl in MM progression, development, and metastasis, as well as its regulatory mechanisms within MM, remain inadequately understood. This review aims to comprehensively investigate the involvement of Axl in MM. We discuss Axl role in MM progression, development, and metastasis, along with its specific regulatory mechanisms. Additionally, we examined the Axl associated signaling pathways, the relationship between Axl and immune evasion, and the clinical implications of Axl for MM treatment. Furthermore, we discussed the potential utility of liquid biopsy as a non-invasive diagnostic technique for early detection of Axl in MM. Lastly, we evaluated the potential of a microRNA signature that targets Axl. By consolidating existing knowledge and identifying research gaps, this review contributes to a better understanding of Axl's role in MM and sets the stage for future investigations and the development of effective therapeutic interventions.
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Affiliation(s)
- Kinjal Bhadresha
- Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Sheefa Mirza
- Department of Internal Medicine, Common Epithelial Cancer Research Center, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Clement Penny
- Department of Internal Medicine, Common Epithelial Cancer Research Center, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Muhammed Jameel Mughal
- Department of Biochemistry and Molecular Medicine, School of Medicine and Health Science, The George Washington University, Washington DC, United States of America.
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6
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Wu Z, Fang ZX, Hou YY, Wu BX, Deng Y, Wu HT, Liu J. Exosomes in metastasis of colorectal cancers: Friends or foes? World J Gastrointest Oncol 2023; 15:731-756. [PMID: 37275444 PMCID: PMC10237026 DOI: 10.4251/wjgo.v15.i5.731] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 03/07/2023] [Accepted: 04/04/2023] [Indexed: 05/12/2023] Open
Abstract
Colorectal cancer (CRC), the third most common type of cancer worldwide, threaten human health and quality of life. With multidisciplinary, including surgery, chemotherapy and/or radiotherapy, patients with an early diagnosis of CRC can have a good prognosis. However, metastasis in CRC patients is the main risk factor causing cancer-related death. To elucidate the underlying molecular mechanisms of CRC metastasis is the difficult and research focus on the investigation of the CRC mechanism. On the other hand, the tumor microenvironment (TME) has been confirmed as having an essential role in the tumorigenesis and metastasis of malignancies, including CRCs. Among the different factors in the TME, exosomes as extracellular vesicles, function as bridges in the communication between cancer cells and different components of the TME to promote the progression and metastasis of CRC. MicroRNAs packaged in exosomes can be derived from different sources and transported into the TME to perform oncogenic or tumor-suppressor roles accordingly. This article focuses on CRC exosomes and illustrates their role in regulating the metastasis of CRC, especially through the packaging of miRNAs, to evoke exosomes as novel biomarkers for their impact on the metastasis of CRC progression.
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Affiliation(s)
- Zheng Wu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Ze-Xuan Fang
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yan-Yu Hou
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Bing-Xuan Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu Deng
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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7
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Safe S. Specificity Proteins (Sp) and Cancer. Int J Mol Sci 2023; 24:5164. [PMID: 36982239 PMCID: PMC10048989 DOI: 10.3390/ijms24065164] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/01/2023] [Accepted: 03/03/2023] [Indexed: 03/10/2023] Open
Abstract
The specificity protein (Sp) transcription factors (TFs) Sp1, Sp2, Sp3 and Sp4 exhibit structural and functional similarities in cancer cells and extensive studies of Sp1 show that it is a negative prognostic factor for patients with multiple tumor types. In this review, the role of Sp1, Sp3 and Sp4 in the development of cancer and their regulation of pro-oncogenic factors and pathways is reviewed. In addition, interactions with non-coding RNAs and the development of agents that target Sp transcription factors are also discussed. Studies on normal cell transformation into cancer cell lines show that this transformation process is accompanied by increased levels of Sp1 in most cell models, and in the transformation of muscle cells into rhabdomyosarcoma, both Sp1 and Sp3, but not Sp4, are increased. The pro-oncogenic functions of Sp1, Sp3 and Sp4 in cancer cell lines were studied in knockdown studies where silencing of each individual Sp TF decreased cancer growth, invasion and induced apoptosis. Silencing of an individual Sp TF was not compensated for by the other two and it was concluded that Sp1, Sp3 and Sp4 are examples of non-oncogene addicted genes. This conclusion was strengthened by the results of Sp TF interactions with non-coding microRNAs and long non-coding RNAs where Sp1 contributed to pro-oncogenic functions of Sp/non-coding RNAs. There are now many examples of anticancer agents and pharmaceuticals that induce downregulation/degradation of Sp1, Sp3 and Sp4, yet clinical applications of drugs specifically targeting Sp TFs are not being used. The application of agents targeting Sp TFs in combination therapies should be considered for their potential to enhance treatment efficacy and decrease toxic side effects.
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Affiliation(s)
- Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA
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Xu J, Sang N, Zhao J, He W, Zhang N, Li X. Knockdown of circ_0067934 inhibits gastric cancer cell proliferation, migration and invasion via the miR‑1301‑3p/KIF23 axis. Mol Med Rep 2022; 25:202. [PMID: 35475447 PMCID: PMC9073844 DOI: 10.3892/mmr.2022.12718] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 07/28/2021] [Indexed: 11/24/2022] Open
Abstract
In recent years, circular RNAs (circRNAs/circs) have attracted significant attention due to their potentially important functions in a variety of human cancer types. circ_0067934 is a newly identified circRNA, the role of which in gastric cancer (GC) has yet to be reported, to the best of our knowledge. In the present study, the expression levels of circ_0067934, microRNA (miR)‑1301‑3p and kinesin family member 23 (KIF23) in GC cells were detected via reverse transcription‑quantitative PCR. Cell proliferation was measured using Cell Counting Kit‑8 assays and EdU staining. Wound healing and Transwell assays were performed to assess cell migration and invasion, respectively. Western blotting was performed to measure the protein expression levels of Ki67, proliferating cell nuclear antigen, MMP2, MMP9 and KIF23. The starBase database and luciferase reporter assays were used to predict and verify the binding between circ_0067934 and miR‑1301‑3p, as well as KIF23, in GC cells. The results demonstrated that circ_0067934 expression was upregulated in GC cells, and circ_0067934 silencing significantly inhibited GC cell proliferation, migration and invasion. In addition, miR‑1301‑3p was regulated by circ_0067934, and miR‑1301‑3p overexpression suppressed GC cell migration, invasion and proliferation. miR‑1301‑3p was found to target KIF23, and KIF23 overexpression reversed the effects of circ_0067934 silencing and miR‑1301‑3p overexpression on cell proliferation, migration and invasion. In conclusion, circ_0067934 may regulate the proliferation, invasion and migration of GC cells via the miR‑1301‑3p/KIF23 signaling axis, which may represent a novel therapeutic target for GC metastasis.
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Affiliation(s)
- Jin Xu
- Department of Gastroenterology, Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu 210024, P.R. China
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Nan Sang
- Department of Gastroenterology, Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu 210024, P.R. China
| | - Junning Zhao
- Department of Gastroenterology, Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu 210024, P.R. China
| | - Wei He
- Department of Gastroenterology, Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu 210024, P.R. China
| | - Nannan Zhang
- Department of Gastroenterology, Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu 210024, P.R. China
| | - Xueliang Li
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
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Zhang T, Huo S, Wei S, Cui S. miR-21, miR-125b, and let-7b contribute to the involution of atretic follicles and corpus lutea in Tibetan sheep ovaries. Anim Sci J 2022; 93:e13756. [PMID: 35822516 DOI: 10.1111/asj.13756] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 05/18/2022] [Accepted: 06/09/2022] [Indexed: 11/30/2022]
Abstract
Follicular granulosa cells (FGCs) are crucial for ovarian follicle functions, and miRNAs are differentially expressed at various stages of follicular developments. In this study, we confirmed that miR-21, miR-125b, and let-7b were located in FGCs/luteal cells by in situ hybridization experiments. Moreover, miR-21 and miR-125b expressions were upregulated in late corpus lutea (CL) and atretic follicles (AF); let-7b expression was increased in early AF. After transfected with inhibitor or mimic of miRNAs in FGCs, we found that FGCs apoptosis was decreased in the miR-21-mi group but increased in the miR-125b-mi group using flow cytometry. mRNA and protein expression levels were determined for apoptosis-related factors (e.g., Bcl-2 and Bax), the potential target genes of miRNAs (e.g., SMAD7, SP1, and STAT3), hormone receptors (e.g., FSHR and LHR), and genes related to hormone secretion (e.g., CYP19, CYP11, and 3βHSD). The protein levels of SMAD7 were decreased in the miR-21-mi group but opposite to SP1 and FSHR. In the let-7b-mi group, Bcl-2, SMAD7, and FSHR were suppressed but not Bax, CYP11, and 3βHSD. However, hormone secretion was not changed in the supernatant of transfected FGCs. This study provides information about ovarian miRNAs to improve the fertility in Tibetan sheep.
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Affiliation(s)
- Taojie Zhang
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, China.,Life Science and Engineering College, Northwest Minzu University, Lanzhou, Gansu, China.,State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Shengdong Huo
- Life Science and Engineering College, Northwest Minzu University, Lanzhou, Gansu, China
| | - Suocheng Wei
- Life Science and Engineering College, Northwest Minzu University, Lanzhou, Gansu, China
| | - Sheng Cui
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, China.,State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
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Pang P, Fang H, Wu H, Wang S, Liu M, Jin S, Qi Z, Li Z, Liu F, Sun C. Specificity protein 1/microRNA-92b forms a feedback loop promoting the migration and invasion of head and neck squamous cell carcinoma. Bioengineered 2021; 12:11397-11409. [PMID: 34905435 PMCID: PMC8810166 DOI: 10.1080/21655979.2021.2008698] [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: 09/15/2021] [Revised: 11/11/2021] [Accepted: 11/16/2021] [Indexed: 11/09/2022] Open
Abstract
In this study we report a novel specificity protein 1 (SP1)/microRNA-92b (miR-92b) feedback loop regulating the migration and invasion of head and neck squamous cell carcinoma (HNSCC). Microarray and real-time Polymerase Chain Reaction (PCR) were used to detect gene expression in HNSCC tissues and cell lines. Transwell migration, invasion, wound healing and cell counting kit - 8 (CCK-8) cell assays were used to compare cell migration, invasion and proliferation abilities. Chromatin Immunoprecipitation (ChIP) assays were used to detect SP1 binding to the miR-92b promoter. Western blot was used to detect protein levels. An in vivo tumorigenesis experiment was used to evaluate the effect of SP1 knockdown on tumor growth and protein levels were evaluated by immunohistochemistry. We found that the miR-92b expression level was elevated in HNSCC primary focus tissue compared with adjacent normal tissue, and a higher level of miR-92b was related to a higher clinical stage and worse prognosis of HNSCC patients. MiR-92b and SP1 mutually promoted each expression and cooperatively facilitated the migration, invasion and proliferation of HNSCC cells. A decreased level of SP1/miR-92b resulted in a restraint of in vivo tumor growth. In conclusion, our results suggest that the SP1/miR-92b feedback loop generally promotes HNSCC invasion and metastasis, thus presenting a possible therapeutic target in the treatment of HNSCC patients.
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Affiliation(s)
- Pai Pang
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No.117, Nanjing Bei Street, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Hui Fang
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No.117, Nanjing Bei Street, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Hong Wu
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No.117, Nanjing Bei Street, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Song Wang
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No.117, Nanjing Bei Street, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Minda Liu
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No.117, Nanjing Bei Street, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Shan Jin
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No.117, Nanjing Bei Street, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Zhongzheng Qi
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No.117, Nanjing Bei Street, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Zhenning Li
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No.117, Nanjing Bei Street, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Fayu Liu
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No.117, Nanjing Bei Street, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
| | - Changfu Sun
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No.117, Nanjing Bei Street, Heping District, Shenyang, Liaoning, 110002, People's Republic of China
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11
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Qiu K, Song Y, Rao Y, Liu Q, Cheng D, Pang W, Ren J, Zhao Y. Diagnostic and Prognostic Value of MicroRNAs in Metastasis and Recurrence of Head and Neck Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis. Front Oncol 2021; 11:711171. [PMID: 34646767 PMCID: PMC8503605 DOI: 10.3389/fonc.2021.711171] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 09/01/2021] [Indexed: 02/05/2023] Open
Abstract
MicroRNAs have been proven to make remarkable differences in the clinical behaviors of head and neck squamous cell carcinoma (HNSCC). This study aims to systematically analyze whether differential expression levels of microRNAs are related to recurrence or metastasis in patients with HNSCC. A comprehensive search of the PubMed, EMBASE, and CENTRAL was conducted up to July 24th, 2021. Data were collected and combined from studies reporting recurrence-free survival (RFS) of HNSCC patients with high microRNA expression compared to those with low expression. Besides, studies providing necessary data for evaluating the diagnostic value of microRNAs for detecting recurrence and metastasis based on their expression levels were also included and combined. The pooled hazard ratio (HR) value for the outcomes of RFS in 1,093 HNSCC samples from 10 studies was 2.51 (95%CI: 2.13–2.96). A sensitivity of 0.79 (95% CI: 0.72–0.85) and specificity of 0.77 (95%CI: 0.68–0.83) were observed in three studies, of which 93 patients with recurrence and 82 nonrecurrence controls were included, and the area under the curve (AUC) was 0.85 (95% CI: 0.81–0.88). Additionally, high diagnostic accuracy of microRNAs in detecting lymph node metastasis (LNM) was also reported. In conclusion, two panels of microRNAs showed the potential to predict recurrence or diagnose recurrence in HNSCC patients, respectively, which could facilitate prognosis prediction and diagnosis of clinical behaviors in HNSCC patients.
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Affiliation(s)
- Ke Qiu
- Department of Oto-Rhino-Laryngology, West China Hospital, Sichuan University, Chengdu, China
| | - Yao Song
- Department of Oto-Rhino-Laryngology, West China Hospital, Sichuan University, Chengdu, China
| | - Yufang Rao
- Department of Oto-Rhino-Laryngology, West China Hospital, Sichuan University, Chengdu, China
| | - Qiurui Liu
- Department of Oto-Rhino-Laryngology, West China Hospital, Sichuan University, Chengdu, China
| | - Danni Cheng
- Department of Oto-Rhino-Laryngology, West China Hospital, Sichuan University, Chengdu, China
| | - Wendu Pang
- Department of Oto-Rhino-Laryngology, West China Hospital, Sichuan University, Chengdu, China
| | - Jianjun Ren
- Department of Oto-Rhino-Laryngology, West China Hospital, Sichuan University, Chengdu, China.,West China Biomedical Big Data Center, West China Hospital/West China School of Medicine, Sichuan University, Chengdu, China.,Medical Big Data Center, Sichuan University, Chengdu, China
| | - Yu Zhao
- Department of Oto-Rhino-Laryngology, West China Hospital, Sichuan University, Chengdu, China
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12
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MicroRNA-375: potential cancer suppressor and therapeutic drug. Biosci Rep 2021; 41:229736. [PMID: 34494089 PMCID: PMC8458691 DOI: 10.1042/bsr20211494] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 08/31/2021] [Accepted: 09/06/2021] [Indexed: 02/06/2023] Open
Abstract
MiR-375 is a conserved noncoding RNA that is known to be involved in tumor cell proliferation, migration, and drug resistance. Previous studies have shown that miR-375 affects the epithelial-mesenchymal transition (EMT) of human tumor cells via some key transcription factors, such as Yes-associated protein 1 (YAP1), Specificity protein 1 (SP1) and signaling pathways (Wnt signaling pathway, nuclear factor κB (NF-κB) pathway and transforming growth factor β (TGF-β) signaling pathway) and is vital for the development of cancer. Additionally, recent studies have identified microRNA (miRNA) delivery system carriers for improved in vivo transportation of miR-375 to specific sites. Here, we discussed the role of miR-375 in different types of cancers, as well as molecular mechanisms, and analyzed the potential of miR-375 as a molecular biomarker and therapeutic target to improve the efficiency of clinical diagnosis of cancer.
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13
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Liu Y, Wang Q, Wen J, Wu Y, Man C. MiR-375: A novel multifunctional regulator. Life Sci 2021; 275:119323. [PMID: 33744323 DOI: 10.1016/j.lfs.2021.119323] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 02/20/2021] [Accepted: 02/27/2021] [Indexed: 01/23/2023]
Abstract
MiR-375, a primitively described beta cell-specific miRNA, is confirmed to function as multi-functional regulator in diverse typical cellular pathways according to the follow-up researches. Based on the existing studies, miR-375 can regulate many functional genes and ectopic expressions of miR-375 are usually associated with pathological changes, and its expression regulation mechanism is mainly related to promoter methylation or circRNA. In this review, the regulatory functions of miR-375 in immunity, such as its relevance with macrophages, T helper cells and autoimmune diseases were briefly discussed. Also, the functions of miR-375 involved in inflammation, development and virus replication were reviewed. Finally, the mechanisms and application prospects of miR-375 in cancers were analyzed. Studies show that the application of miR-375 as therapeutic target and biomarker has a broad developing space in future. We hope this paper can provide reference for its further study.
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Affiliation(s)
- Yang Liu
- College of Life Science and Technology, Harbin Normal University, Harbin 150001, PR China
| | - Qiuyuan Wang
- College of Life Science and Technology, Harbin Normal University, Harbin 150001, PR China
| | - Jie Wen
- College of Life Science and Technology, Harbin Normal University, Harbin 150001, PR China
| | - Yiru Wu
- College of Life Science and Technology, Harbin Normal University, Harbin 150001, PR China
| | - Chaolai Man
- College of Life Science and Technology, Harbin Normal University, Harbin 150001, PR China.
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14
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CircPPP1R12A promotes the progression of colon cancer through regulating CTNNB1 via sponging miR-375. Anticancer Drugs 2021; 32:635-646. [PMID: 33595945 DOI: 10.1097/cad.0000000000001037] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Circular RNAs (circRNAs) have been identified as potential biomarkers for many cancer, including colon cancer (CC). However, the function and mechanism of circPPP1R12A in CC have not been fully elucidated. Quantitative real-time PCR was employed to assess the expression of circPPP1R12A, microRNA (miR)-375 and catenin beta-1 (CTNNB1). The proliferation, apoptosis, migration and invasion of cells were determined using colony formation assay, flow cytometry, wound healing assay and transwell assay. The protein levels of cell cyclin-related markers and CTNNB1 were detected by western blot analysis. The interaction between miR-375 and circPPP1R12A or CTNNB1 was verified by dual-luciferase reporter assay. Xenograft models were built to evaluate the effect of circPPP1R12A silencing and CTNNB1 overexpression on CC tumor growth in vivo. Our results showed that circPPP1R12A was a highly expressed circRNA in CC tissues and cells. Silenced circPPP1R12A suppressed the proliferation, promoted the apoptosis, and inhibited the migration and invasion of CC cells. MiR-375 could be sponged by circPPP1R12A, and its inhibitor could reverse the inhibition of circPPP1R12A silencing on CC progression. Furthermore, CTNNB1 was a target of miR-375, and its overexpression also abolished the suppression of miR-375 on CC progression. Moreover, circPPP1R12A indirectly regulated CTNNB1 expression by sponging miR-375. Importantly, circPPP1R12A knockdown reduced the tumor growth of CC in vivo, and this effect also could be reversed by overexpressing CTNNB1. Our study proposed that circPPP1R12A might play an oncogenic role in CC, which could act as a potential therapeutic target for CC.
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15
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Wang C, Luo J, Chen Z, Ye M, Hong Y, Liu J, Nie J, Zhao Q, Chang Y. MiR-375 Impairs the Invasive Capabilities of Hepatoma Cells by Targeting HIF1α Under Hypoxia. Dig Dis Sci 2021; 66:493-502. [PMID: 32215815 DOI: 10.1007/s10620-020-06202-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 03/10/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIMS Hypoxia represents one of the most pervasive microenvironmental stresses in HCC due to the overwhelming growth and inadequate blood supply. HIF1α as an important transcription factor participates in the regulation of various biological behaviors of HCC cells under hypoxia. Our previous study indicated that miR-375 is a hypoxia-associated miRNA. However, the interaction between miR-375 and HIF1α remains unclear. METHODS Bioinformatic analysis was performed for miRNA screening. qRT-PCR, western blotting, and immunohistochemical staining were used to detect the expression of related molecules. Bioinformatic analysis and dual luciferase assay were used to predict and further confirm the target association. Transwell chamber assay and flow cytometry were, respectively, used to detect migration, invasion and apoptosis of hepatoma cells. RESULTS MiR-375 presented an obviously differential expression in human HCCs versus background livers (BLs) and HCCs versus normal liver tissues (NLTs). In rat models, miR-375 was gradually declined during hepatocarcinogenesis. HIF1α was remarkably upregulated at protein level rather than at mRNA level in human HCCs versus BLs, HCCs versus NLTs, BLs versus NLTs, and in rat fibrotic livers versus NLTs. HIF1α was determined to be a target of miR-375. MiR-375 inhibitor induced the migration and invasive capabilities and attenuated apoptosis of hepatoma cells under hypoxia. Depriving HIF1α by siRNA could partially reverse the function of miR-375 inhibitor under hypoxia. CONCLUSIONS MiR-375 impairs the invasive capabilities of HCC cells by targeting HIF1α under hypoxia.
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Affiliation(s)
- Chun Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Jie Luo
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Zhihang Chen
- Department of Coloproctological Surgery, The First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Mingliang Ye
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Yinghui Hong
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Jialiang Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Jiayan Nie
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
| | - Ying Chang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China. .,Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China.
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16
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Exosome-mediated delivery of functionally active miRNA-375-3p mimic regulate epithelial mesenchymal transition (EMT) of colon cancer cells. Life Sci 2021; 269:119035. [PMID: 33450254 DOI: 10.1016/j.lfs.2021.119035] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/20/2020] [Accepted: 01/03/2021] [Indexed: 12/12/2022]
Abstract
AIMS EMT is the process by which a polarized epithelial cell undergoes several changes leading to highly invasive and fibroblast-like morphology. It has been described that miR-375 is inversely associated with EMT in cancerous patients and can effectively inhibit invasion and migration of tumor cells. Here, we investigate whether miR-375 mimic delivered by tumor-derived exosomes could reverse EMT process. MAIN METHODS The exosomes were isolated from HT-29 and SW480. Subsequently, exosomes were loaded with miR-375-3p mimic applying modified calcium chloride method. Quantitative real-time PCR was used for evaluation of the loading efficiency of miR-375 mimic in the exosomes. The effects of miR-375 loaded tumor exosomes (TEXomiR) on EMT process investigated using flow cytometry, cell morphology, and invasion and migration assay. KEY FINDINGS The in vitro results showed that the tumor derived exosomes can efficiently deliver miR-375 mimic to reduce the expression of β-catenin, vimentin, ZEB1, and snail. In contrast, TEXomiR significantly increased the expression of E- cadherin in EMT process. Furthermore, the migration and invasion abilities of HT-29 and SW480 cells were inhibited by TEXomiR. The expression of CD44 and CD133 are increased in EMT process. Flow cytometry evaluation demonstrated that treatment with TEXomiR significantly decreased the expression of CD44 and CD133 in SW480 cell line. SIGNIFICANCE Our results imply that colon cancer cells-derived exosomes could be used as an effective nonvehicle to deliver miR-375-3p mimic. Moreover, TEXomiR may be a potent therapeutic agent for the treatment of metastatic colorectal cancer.
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17
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Wang L, Jiang J, Sun G, Zhang P, Li Y. Effects of lncRNA TUSC7 on the malignant biological behavior of osteosarcoma cells via regulation of miR-375. Oncol Lett 2020; 20:133. [PMID: 32934702 PMCID: PMC7471645 DOI: 10.3892/ol.2020.11994] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 07/06/2020] [Indexed: 12/23/2022] Open
Abstract
The present study aimed at investigating how long-chain non-coding RNA (lncRNA) tumor suppressor candidate 7 (TUSC7) regulates the malignant biological behavior of osteosarcoma cells. Tumor tissues and adjacent tissues of 30 patients with osteosarcoma were collected, and the expression levels of lncRNA TUSC7 and miR-375 were detected by RT-qPCR. lncRNA TUSC7 mimic and miR-375 mimic transfection models were established in MG63 osteosarcoma cells, and Transwell assays were used to detect the migration ability of MG63 cells. An MTT assay was used to assess the proliferation ability of MG63 cells. lncRNA TUSC7 in osteosarcoma tissue was significantly lower than that of adjacent tissues, while miR-375 levels were significantly higher than that of adjacent tissues; the two levels have a negative correlation. lncRNA TUSC7 mimic inhibited MG63 proliferation and migration abilities. miR-375 mimic promoted MG63 proliferation and migration abilities. The lncRNA TUSC7 mimic and miR-375 mimic co-transfection system could partially rescue the inhibition of lncRNA TUSC7 mimic on MG63 cells. In conclusion, lncRNA TUSC7 inhibited the proliferation and migration of MG63 osteosarcoma cells by regulating miR-375.
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Affiliation(s)
- Lulu Wang
- Department of Spinal Surgery, ShengLi Oilfield Central Hospital, Dongying, Shandong 257000, P.R. China
| | - Jiankui Jiang
- Department of Hand and Foot Surgery, ShengLi Oilfield Central Hospital, Dongying, Shandong 257000, P.R. China
| | - Guisen Sun
- Department of Spinal Surgery, ShengLi Oilfield Central Hospital, Dongying, Shandong 257000, P.R. China
| | - Panpan Zhang
- Department of Spinal Surgery, ShengLi Oilfield Central Hospital, Dongying, Shandong 257000, P.R. China
| | - Ya Li
- Department of Spinal Surgery, ShengLi Oilfield Central Hospital, Dongying, Shandong 257000, P.R. China
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18
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Non-coding RNAS and colorectal cancer liver metastasis. Mol Cell Biochem 2020; 475:151-159. [PMID: 32767228 DOI: 10.1007/s11010-020-03867-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 07/31/2020] [Indexed: 02/08/2023]
Abstract
More than 50% of colorectal cancer (CRC) deaths are attributed to metastasis, and the liver is the most common distant metastatic site of CRC. The molecular mechanisms underlying CRC liver metastasis are very complicated and remain largely unknown. Accumulated evidence has shown that non-coding RNAs (NcRNAs) play critical roles in tumor development and progression. Here we reviewed the roles and underlying mechanisms of NcRNAs in CRC liver metastasis.
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19
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Zhang KF, Wang J, Guo J, Huang YY, Huang TR. Metformin enhances radiosensitivity in hepatocellular carcinoma by inhibition of specificity protein 1 and epithelial-to-mesenchymal transition. J Cancer Res Ther 2020; 15:1603-1610. [PMID: 31939444 DOI: 10.4103/jcrt.jcrt_297_19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Objective Radiotherapy becomes more and more important in hepatocellular carcinoma (HCC) due to the development of technology, especially in unresectable cases. Metformin has a synergistic benefit with radiotherapy in some cancers, but remains unclear in HCC. This study aims to investigate the effect of metformin on radiosensitivity of HCC cells and the roles of specificity protein 1 (Sp1) as a target of metformin. Methods The SMMC-7721 cell line was exposed to various doses of γ-ray irradiation (0, 2, 4, 6, and 8 Gy) and with or without different concentrations of metformin (0, 1, 5, 10, and 20 mM) to measure the radiosensitivity using MTT assay. Flow cytometry was used to determine cell cycle by propidium iodide (PI) staining and apoptosis by Hoechst 33342/PI staining and Annexin V-FITC/PI staining. Real-time polymerase chain reaction and Western blotting were performed to analyze the Sp1 mRNA and protein expressions of Sp1 and epithelial-to-mesenchymal transition (EMT) marker E-cadherin and Vimentin. The invasion capability was measured by the Boyden chamber assay. Results In SMMC-7721 cells exposed to irradiation, metformin reduced proliferation and survival cells at various concentrations (0, 1, 5, 10, and 20 mM) and induced cell cycle arrest, apoptosis, and inhibited invasion. In SMMC-7721 cells with irradiation, the mRNA and protein expressions of Sp1 were significantly decreased by metformin as well as a selective Sp1 inhibitor. Metformin attenuated transforming growth factor-β1 induced decrease of E-cadherin and increase of Vimentin proteins. Conclusion Metformin demonstrated enhanced radiosensitivity and inhibition of EMT in HCC cells. Sp1 might be a target of metformin in radiosensitization.
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Affiliation(s)
- Ke-Fen Zhang
- Research Department, Affifiliated Cancer Hospital of Guangxi Medical University, Guangxi; Department of Pathology, Taishan Sanatorium, Taian, P.R. China
| | - Jun Wang
- Research Department, Affifiliated Cancer Hospital of Guangxi Medical University, Guangxi; Department of Oncology, The Central Hospital of Taian, Taian, Shandong, P.R. China
| | - Jiao Guo
- Research Department, Affifiliated Cancer Hospital of Guangxi Medical University, Guangxi, P.R. China
| | - Yue-Ying Huang
- Research Department, Affifiliated Cancer Hospital of Guangxi Medical University, Guangxi, P.R. China
| | - Tian-Ren Huang
- Research Department, Affifiliated Cancer Hospital of Guangxi Medical University, Guangxi, P.R. China
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20
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Chen H, Pei L, Xie P, Guo G. Circ-PRKDC Contributes to 5-Fluorouracil Resistance of Colorectal Cancer Cells by Regulating miR-375/FOXM1 Axis and Wnt/β-Catenin Pathway. Onco Targets Ther 2020; 13:5939-5953. [PMID: 32606803 PMCID: PMC7320885 DOI: 10.2147/ott.s253468] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 05/31/2020] [Indexed: 12/15/2022] Open
Abstract
Purpose Diverse circular RNAs (circRNAs) participate in the regulation of drug resistance in human cancers. However, the role of circRNAs in drug resistance in colorectal cancer (CRC) is dismal. In this study, we aimed to explore the effect of circ-PRKDC on 5-fluorouracil (5-FU) resistance in CRC. Materials and Methods The levels of circ-PRKDC, microRNA-375 (miR-375) and forkhead box protein M1 (FOXM1) mRNA were determined by quantitative real-time polymerase chain reaction (qRT-PCR). IC50 of 5-FU, cell colony formation ability and invasion were assessed by Cell Counting Kit-8 (CCK-8) assay, colony formation assay and transwell assay, respectively. The protein levels of P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), FOXM1, β-catenin and c-Myc were measured via Western blot assay. The targeting relationship between miR-375 and circ-PRKDC or FOXM1 was investigated by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. The effect of circ-PRKDC in vivo was explored by murine xenograft model assay. Results Circ-PRKDC was upregulated in 5-FU-resistant CRC tissues and cells. Circ-PRKDC silencing repressed 5-FU resistance, cell colony formation and invasion in 5-FU-resistant CRC cells in vitro and inhibited 5-FU resistance in vivo. MiR-375 was a target of circ-PRKDC and miR-375 inhibition reversed the effects of circ-PRKDC silencing on 5-FU resistance, cell colony formation and invasion. FOXM1 was a direct target gene of miR-375. MiR-375 suppressed 5-FU resistance by targeting FOXM1. Moreover, circ-PRKDC knockdown decreased FOXM1 expression by targeting miR-375. Additionally, circ-PRKDC knockdown impeded wnt/β-catenin pathway by regulating miR-375 and FOXM1. Conclusion Circ-PRKDC enhanced 5-FU resistance in CRC by regulating FOXM1/miR-375 axis and wnt/β-catenin pathway.
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Affiliation(s)
- Hao Chen
- Department of Emergency Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Lingyu Pei
- Department of Digestive System, Yongcheng People's Hospital, Shangqiu, Henan, People's Republic of China
| | - Peng Xie
- Department of Emergency Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Guancheng Guo
- Department of Emergency Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
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21
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Huang G, Wei B, Chen Z, Wang J, Zhao L, Peng X, Liu K, Lai Y, Ni L. Identification of a four-microRNA panel in serum as promising biomarker for colorectal carcinoma detection. Biomark Med 2020; 14:749-760. [PMID: 32672054 DOI: 10.2217/bmm-2019-0605] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 04/09/2020] [Indexed: 02/06/2023] Open
Abstract
Background: Screening for colorectal carcinoma (CRC) lacks an efficient, inexpensive and noninvasive approach. The stable presence of serum miRNA is expected to become a new diagnostic marker. Materials & methods: Based on 135 CRC patients and 135 normal controls, this study was conducted in three phases to identify suitable serum miRNA for CRC diagnosis by using quantitative reverse transcription PCR. Bioinformatic assays were used for target genes prediction and functional annotation. Results: Serum expression level of seven miRNAs were significantly different between CRC patients and the normal controls. The final diagnostic panel (area under the curve = 0.893; sensitivity = 81.25%, specificity = 73.33%) consists of miR-203a-3p, miR-145-5p, miR-375-3p and miR-200c-3p. Conclusion: The four-miRNA panel may serve as a novel, noninvasive biomarker for CRC diagnosis and screening.
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Affiliation(s)
- Guocheng Huang
- Guangdong & Shenzhen Key Laboratory of Male Reproductive Medicine & Genetics, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, China
- Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Benlin Wei
- Guangdong & Shenzhen Key Laboratory of Male Reproductive Medicine & Genetics, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, China
| | - Zebo Chen
- Guangdong & Shenzhen Key Laboratory of Male Reproductive Medicine & Genetics, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, China
| | - Jingyao Wang
- Guangdong & Shenzhen Key Laboratory of Male Reproductive Medicine & Genetics, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, China
| | - Liwen Zhao
- Guangdong & Shenzhen Key Laboratory of Male Reproductive Medicine & Genetics, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, China
- Anhui Medical University, Hefei, Anhui 230032, China
| | - Xiqi Peng
- Guangdong & Shenzhen Key Laboratory of Male Reproductive Medicine & Genetics, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, China
- Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Kaihao Liu
- Guangdong & Shenzhen Key Laboratory of Male Reproductive Medicine & Genetics, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, China
- Anhui Medical University, Hefei, Anhui 230032, China
| | - Yongqing Lai
- Guangdong & Shenzhen Key Laboratory of Male Reproductive Medicine & Genetics, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, China
- Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Liangchao Ni
- Guangdong & Shenzhen Key Laboratory of Male Reproductive Medicine & Genetics, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, China
- Shantou University Medical College, Shantou, Guangdong 515041, China
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22
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Li J, Peng W, Yang P, Chen R, Gu Q, Qian W, Ji D, Wang Q, Zhang Z, Tang J, Sun Y. MicroRNA-1224-5p Inhibits Metastasis and Epithelial-Mesenchymal Transition in Colorectal Cancer by Targeting SP1-Mediated NF-κB Signaling Pathways. Front Oncol 2020; 10:294. [PMID: 32231999 PMCID: PMC7083241 DOI: 10.3389/fonc.2020.00294] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Accepted: 02/19/2020] [Indexed: 01/12/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that play pivotal roles in cancer initiation and progression. However, the roles and molecular mechanisms of miRNAs in colorectal cancer (CRC) progression remain unclear. Here, we show that downregulation of miR-1224-5p in CRC is negatively correlated with SP1 expression and metastasis in patients and xenografted mouse models. Gain- and loss-of-function assays reveal that miR-1224-5p suppresses the migration, invasion, and epithelial–mesenchymal transition (EMT) of CRC cells in vitro and in vivo by directly targeting SP1. Moreover, SP1 promotes the phosphorylation of p65, which results in EMT progress in CRC cells. Clinical analysis reveals that miR-1224-5p and SP1 expression are remarkably associated with advanced clinical features and unfavorable prognosis of patients with CRC. Further study confirms that hypoxia accounts for the depletion of miR-1224-5p in CRC. The enhancement of hypoxia during epithelial–mesenchymal transition and metastasis of CRC cells is abolished by miR-1224-5p. Our findings provide the first evidence that miR-1224-5p is a potential therapeutic target and prognostic biomarker for patients with CRC.
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Affiliation(s)
- Jie Li
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China.,Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wen Peng
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China.,Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Peng Yang
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China.,Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ranran Chen
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China.,Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qiou Gu
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China.,Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wenwei Qian
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China.,Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dongjian Ji
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China.,Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qingyuan Wang
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China.,Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhiyuan Zhang
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China.,Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Junwei Tang
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China.,Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yueming Sun
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China.,Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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23
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Cai LJ, Tu L, Li T, Yang XL, Ren YP, Gu R, Zhang Q, Yao H, Qu X, Wang Q, Tian JY. Up-regulation of microRNA-375 ameliorates the damage of dopaminergic neurons, reduces oxidative stress and inflammation in Parkinson's disease by inhibiting SP1. Aging (Albany NY) 2020; 12:672-689. [PMID: 31927536 PMCID: PMC6977707 DOI: 10.18632/aging.102649] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 12/24/2019] [Indexed: 01/18/2023]
Abstract
Background: This study is conducted to investigate the protective role of elevated microRNA-375 (miR-375) in dopaminergic neurons in Parkinson’s disease through down-regulating transcription factor specificity protein 1 (SP1). Results: The successfully modeled rats with Parkinson’s disease showed aggregated neurobehavioral change, increased neuroinflammatory response and oxidative stress, and lowered dopamine content. Parkinson’s disease rats treated with overexpressed miR-375 displayed improved neurobehavioral change, ameliorated neuroinflammatory response and oxidative stress, heightened dopamine content and abated neuronal apoptosis by down-regulating SP1. Up-regulation of SP1 reversed the protective effect of upregulated miR-375 on Parkinson’s disease. Conclusion: Up-regulation of miR-375 ameliorated the damage of dopaminergic neurons, reduced oxidative stress and inflammation in Parkinson’s disease by inhibiting SP1. Methods: Parkinson’s disease rat model was established by targeted injection of 6-hydroxydopamine to damage the substantia nigra striatum. The successfully modeled Parkinson’s disease rats were intracerebroventricularly injected with miR-375 mimics or pcDNA3.1-SP1. The functions of miR-375 and SP1 in neurobehavioral change, neuroinflammatory response, oxidative stress, dopamine content and expression of apoptosis-related proteins in the substantia nigra of Parkinson’s disease rats were evaluated. The target relation of miR-375 and SP1 was confirmed by bioinformatics analysis and dual luciferase reporter gene assay.
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Affiliation(s)
- Li-Jun Cai
- Department of Neurology, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, PR. China
| | - Li Tu
- Department of General Medical, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, PR. China
| | - Tian Li
- Zunyi Medical University, Zunyi 563000, PR. China.,Department of Emergency, Guizhou Provincial People's Hospital, Guiyang 550004, PR. China
| | - Xiu-Lin Yang
- Department of Emergency, Guizhou Provincial People's Hospital, Guiyang 550004, PR. China
| | - Yi-Pin Ren
- Department of Emergency, Guizhou Provincial People's Hospital, Guiyang 550004, PR. China
| | - Ran Gu
- Department of Neurology, Guizhou Provincial People's Hospital, Guiyang 550004, PR. China
| | - Qian Zhang
- Department of Emergency, Guizhou Provincial People's Hospital, Guiyang 550004, PR. China
| | - Huan Yao
- Department of Emergency, Guizhou Provincial People's Hospital, Guiyang 550004, PR. China
| | - Xiang Qu
- Department of Emergency, Guizhou Provincial People's Hospital, Guiyang 550004, PR. China
| | - Qian Wang
- Department of Neurology, Guizhou Provincial People's Hospital, Guiyang 550004, PR. China
| | - Jin-Yong Tian
- Department of Emergency, Guizhou Provincial People's Hospital, Guiyang 550004, PR. China
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24
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Xu X, Chen X, Xu M, Liu X, Pan B, Qin J, Xu T, Zeng K, Pan Y, He B, Sun H, Sun L, Wang S. miR-375-3p suppresses tumorigenesis and partially reverses chemoresistance by targeting YAP1 and SP1 in colorectal cancer cells. Aging (Albany NY) 2019; 11:7357-7385. [PMID: 31543507 PMCID: PMC6781994 DOI: 10.18632/aging.102214] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Accepted: 08/13/2019] [Indexed: 02/07/2023]
Abstract
Clinically, one of the principal factors in the failure of advanced colorectal cancer (CRC) treatment is chemoresistance to 5-fluorouracil (5FU)-based chemotherapy. Although microRNA-375-3p (miR-375) is considered a tumor suppressor in multiple cancers, the mechanism of miR-375 in the regulation of drug resistance in CRC remains unclear. In this study, we investigated the chemosensitivity of miR-375 to 5FU in CRC from biological and clinical aspects. We found that miR-375 was significantly downregulated in CRC tissues and cell lines, and low miR-375 expression was strongly correlated with poor overall survival in CRC patients. Overexpression of miR-375 sensitized CRC cells to a broad spectrum of chemotherapeutic drugs in vitro and in vivo. Further mechanistic analysis demonstrated that miR-375 enhanced CRC cell sensitivity to 5FU by directly targeting YAP1 and SP1. MiR-375 downregulated YAP1, resulting in reduced expression of the Hippo-YAP1 pathway downstream genes CTGF, cyclin D1 and BIRC5 (also known as survivin). Overall, miR-375 was confirmed as a prospective molecular biomarker in the chemoresistance and prognosis of CRC patients, and the synergy between miR-375 and chemotherapeutic drugs could be a promising therapeutic strategy for CRC patients, especially with chemoresistance.
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Affiliation(s)
- Xueni Xu
- School of Medicine, Southeast University, Nanjing 210009, China
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Xiaoxiang Chen
- School of Medicine, Southeast University, Nanjing 210009, China
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Mu Xu
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Xiangxiang Liu
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Bei Pan
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Jian Qin
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Tao Xu
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Kaixuan Zeng
- School of Medicine, Southeast University, Nanjing 210009, China
| | - Yuqin Pan
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Bangshun He
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Huiling Sun
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Li Sun
- Department of Laboratory Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China
| | - Shukui Wang
- School of Medicine, Southeast University, Nanjing 210009, China
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
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25
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Feng Y, Zhang Y, Zhou D, Chen G, Li N. MicroRNAs, intestinal inflammatory and tumor. Bioorg Med Chem Lett 2019; 29:2051-2058. [PMID: 31213403 DOI: 10.1016/j.bmcl.2019.06.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 06/10/2019] [Accepted: 06/11/2019] [Indexed: 01/06/2023]
Abstract
Colorectal cancer (CRC) is the third most malignant tumor. Inflammatory bowel disease (IBD) can increase the risk of colorectal cancer. And colitis-associated cancer (CAC) is a CRC subtype, representing the inflammation-related colorectal cancer. For the past decades, we have known that ectopic microRNA (miRNA) expression was involved in the pathogenesis of IBD and CRC, playing a pivotal role in the progression of inflammation to colorectal cancer. Thus, this review provides the recent advances in altered human tissue-specific miRNAs that contribute to IBD, CRC and CAC pathogenesis, diagnosis and treatment. Meanwhile, the potential utilization of miRNAs as novel therapeutic targets for the prevention of CRC was also discussed.
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Affiliation(s)
- Yuan Feng
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Wenhua Road 103, Shenyang 110016, China
| | - Yuan Zhang
- Tianjin Vocational College of Bioengineering, Tianjin 300462, China
| | - Di Zhou
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Wenhua Road 103, Shenyang 110016, China
| | - Gang Chen
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Wenhua Road 103, Shenyang 110016, China.
| | - Ning Li
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Wenhua Road 103, Shenyang 110016, China.
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26
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MiR-218-5p targets LHFPL3 to regulate proliferation, migration, and epithelial-mesenchymal transitions of human glioma cells. Biosci Rep 2019; 39:BSR20180879. [PMID: 30314994 PMCID: PMC6395304 DOI: 10.1042/bsr20180879] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 07/27/2018] [Accepted: 08/20/2018] [Indexed: 01/01/2023] Open
Abstract
Glioblastoma (GBM) is a main subtype of high-grade gliomas with features in progressive brain tumor. Lipoma HMGIC fusion partner-like 3 (LHFPL3) is reported to be highly expressed in malignant glioma, but the relationship and mechanism between LHFPL3 and tumor is inexplicit. The present study aimed to screen the miRNAs targeting LHFPL3 and verify the pathogenesis and development of gliomas. Bioinformatics software predicted that miR-218-5p and miR-138-5p can specifically bind to LHFPL3 mRNA. And the expression of miR-218-5p and miR-138-5p was down-regulated in glioma cell lines and glioma tissues from the patients compared with the normal cells. While dual luciferase activity experiment confirmed, only miR-218-5p can directly bind to LHFPL3. After miR-218-5p transfection of U251 and U87 cells, cytological examinations found a reduction in cell activity, proliferation and invasive ability. Further study showed that miR-218-5p transfection could inhibit epithelial–mesenchymal transitions (EMT). Therefore, miR-218-5p targeting LHFPL3 mRNA plays significant roles in preventing the invasiveness of glioma cells. The present study also revealed a novel mechanism for miRNA–LHFPL3 interaction in glioma cells, which may be potential targets for developing therapies in treating glioma.
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27
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Wang P, Xu L, Li L, Ren S, Tang J, Zhang M, Xu M. The microRNA-375 as a potentially promising biomarker to predict the prognosis of patients with head and neck or esophageal squamous cell carcinoma: a meta-analysis. Eur Arch Otorhinolaryngol 2019; 276:957-968. [PMID: 30747316 DOI: 10.1007/s00405-019-05325-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Accepted: 01/31/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND The prognostic value of microRNA-375 (miR-375) expression in squamous cell carcinoma (SCC) had been reported in the previous studies; however, the results remain inconsistent. This study was performed to investigate the prognostic significance of miR-375 expression in SCC based on all eligible evidences. METHODS Relevant studies were identified by searching PubMed, Embace, Medline, Cochrane Library, and China Biology Medicine disk. Survival outcome including overall survival (OS) and other survival outcomes were used as the primary endpoint to evaluate the prognostic outcome of patients with SCC. All statistical analyses were performed in RevMan software version 5.3 and STATA software version 14.1. Furthermore, the quality of included studies was assessed by The Newcastle-Ottawa Scale. RESULTS In total, 13 studies, including 1340 patients, met the inclusion criteria for our meta-analysis. The pooled analysis results indicated that downregulation of miR-375 significantly predicted poor OS (HR 1.58, 95% CI 1.34-1.88, P < 0.001). Downregulated miR-375 was also correlated with the other survival outcomes. Subgroup analysis based on tumor type found that lower expression of miR-375 was significantly related with poor OS in patients with esophageal squamous cell carcinoma (ESCC) (HR 1.58, 95% CI 1.29-1.94, P < 0.001) and head and neck squamous cell carcinoma (HNSCC) (HR 1.59, 95% CI 1.16-2.18, P = 0.004). CONCLUSIONS This meta-analysis demonstrated that the downexpression of miR-375 was significantly correlated with poor OS in patients with SCCs and indicated the potential clinical use of miR-375 as a molecular biomarker, particularly in assessing prognosis for patients with ESCC and HNSCC.
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Affiliation(s)
- Peng Wang
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - LiangLiang Xu
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Lian Li
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - ShengSheng Ren
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - JianWei Tang
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Ming Zhang
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. .,Department of General Surgery, Mianzhu Hospital of West China Hospital, Sichuan University, Mianzhu, Sichuan, China.
| | - MingQing Xu
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
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28
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Liang Y, Zhang C, Ma MH, Dai DQ. Identification and prediction of novel non-coding and coding RNA-associated competing endogenous RNA networks in colorectal cancer. World J Gastroenterol 2018; 24:5259-5270. [PMID: 30581274 PMCID: PMC6295837 DOI: 10.3748/wjg.v24.i46.5259] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Revised: 10/18/2018] [Accepted: 11/09/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To identify and predict the competing endogenous RNA (ceRNA) networks in colorectal cancer (CRC) by bioinformatics analysis.
METHODS In the present study, we obtained CRC tissue and normal tissue gene expression profiles from The Cancer Genome Atlas project. Differentially expressed (DE) genes (DEGs) were identified. Then, upregulated and downregulated miRNA-centered ceRNA networks were constructed by analyzing the DEGs using multiple bioinformatics approaches. DEmRNAs in the ceRNA networks were identified in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways using KEGG Orthology Based Annotation System 3.0. The interactions between proteins were analyzed using the STRING database. Kaplan-Meier survival analysis was conducted for DEGs and real time quantitative polymerase chain reaction (RT-qPCR) was also performed to validate the prognosis-associated lncRNAs in CRC cell lines.
RESULTS Eighty-one DElncRNAs, 20 DEmiRNAs, and 54 DEmRNAs were identified to construct the ceRNA networks of CRC. The KEGG pathway analysis indicated that nine out of top ten pathways were related with cancer and the most significant pathway was “colorectal cancer”. Kaplan-Meier survival analysis showed that the overall survival was positively associated with five DEGs (IGF2-AS, POU6F2-AS2, hsa-miR-32, hsa-miR-141, and SERPINE1) and it was negatively related to three DEGs (LINC00488, hsa-miR-375, and PHLPP2). Based on the STRING protein database, it was found that SERPINE1 and PHLPP2 interact with AKT1. Besides, SERPINE1 can interact with VEGFA, VTN, TGFB1, PLAU, PLAUR, PLG, and PLAT. PHLPP2 can interact with AKT2 and AKT3. RT-qPCR revealed that the expression of IGF2-AS, POU6F2-AS2, and LINC00488 in CRC cell lines was consistent with the in silico results.
CONCLUSION CeRNA networks play an important role in CRC. Multiple DEGs are related with clinical prognosis, suggesting that they may be potential targets in tumor diagnosis and treatment.
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Affiliation(s)
- Yu Liang
- Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
| | - Cheng Zhang
- Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
| | - Ming-Hui Ma
- Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
| | - Dong-Qiu Dai
- Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
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29
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The Impact of miRNA in Colorectal Cancer Progression and Its Liver Metastases. Int J Mol Sci 2018; 19:ijms19123711. [PMID: 30469518 PMCID: PMC6321452 DOI: 10.3390/ijms19123711] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 11/19/2018] [Accepted: 11/20/2018] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies with a high incidence and mortality rate. An essential challenge in colorectal cancer management is to identify new prognostic factors that could better estimate the evolution and treatment responses of this disease. Considering their role in cancer development, progression and metastasis, miRNAs have become an important class of molecules suitable for cancer biomarkers discovery. We performed a systematic search of studies investigating the role of miRNAs in colorectal progression and liver metastasis published until October 2018. In this review, we present up-to-date information regarding the specific microRNAs involved in CRC development, considering their roles in alteration of Wnt/βcatenin, EGFR, TGFβ and TP53 signaling pathways. We also emphasize the role of miRNAs in controlling the epithelial⁻mesenchymal transition of CRC cells, a process responsible for liver metastasis in a circulating tumor cell-dependent manner. Furthermore, we discuss the role of miRNAs transported by CRC-derived exosomes in mediating liver metastases, by preparing the secondary pre-metastatic niche and in inducing liver carcinogenesis in a Dicer-dependent manner.
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30
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Salem SM, Hamed AR, Fayez AG, Nour Eldeen G. Non-target Genes Regulate miRNAs-Mediated Migration Steering of Colorectal Carcinoma. Pathol Oncol Res 2018; 25:559-566. [PMID: 30361904 DOI: 10.1007/s12253-018-0502-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Accepted: 10/15/2018] [Indexed: 12/14/2022]
Abstract
MicroRNAs (miRNAs) trigger a two-layer regulatory network directly or through transcription factors and their co-regulators. Unlike miR-375, the role of miR-145 and miR-224 in inhibiting or driving cancer cell migration is controversial. This study is a step towards addressing the potential of miR-375, miR-145 and miR-224 expression modulation to inhibit colorectal carcinoma (CRC) cells migration in vitro through regulation of non-target genes VEGFA, TGFβ1, IGF1, CD105 and CD44. Transwell migration assay results revealed a significant subdue of migration ability of cells transfected with miR-375 and miR-145 mimics and miR-224 inhibitor. Real time PCR data showed that expression of VEGFA, TGFβ1, IGF1, CD105 and CD44 was downregulated as a consequence of exogenous re-expression of miR-375 and inhibition of miR-224. On the other hand, ectopic expression of miR-145 did not affect VEGFA, TGFβ1 and CD44 expression, while it elevated CD105 and suppressed IGF1 expression. MAP4K4, a predicted target of miR-145, was validated as a target that could play a role in miR-145-mediated regulation of migration. At mRNA level, no change was observed in expression of MAP4K4 in cells with restored expression of miR-145, while western blotting analysis revealed a 25% reduction of protein level. By applying luciferase reporter assay, a significant decrease in luciferase activity was observed, supporting that miR-145 directly target 3' UTR of MAP4K4. The study highlighted the involvement of non-target genes VEGFA, TGFβ1, IGF1, CD105 and CD44 in mediating anti- and pro-migratory effect of miR-375 and miR-224, respectively, and validated MAP4K4 as a direct target of anti-migratory miR-145.
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Affiliation(s)
- Sohair M Salem
- Molecular Genetics and Enzymology Department, National Research Centre, 33 El-Buhouth St., Dokki, Giza, 12622, Egypt.
| | - Ahmed R Hamed
- Phytochemistry Department, National Research Centre, 33 El-Buhouth St., Dokki, Giza, 12622, Egypt.,Biology Unit - Central Laboratory of Pharmaceutical and Drug Industries Research Division, National Research Centre, 33 El-Buhouth St., Dokki, Giza, 12622, Egypt
| | - Alaaeldin G Fayez
- Molecular Genetics and Enzymology Department, National Research Centre, 33 El-Buhouth St., Dokki, Giza, 12622, Egypt
| | - Ghada Nour Eldeen
- Molecular Genetics and Enzymology Department, National Research Centre, 33 El-Buhouth St., Dokki, Giza, 12622, Egypt.,Stem Cell Research Unit, National Research Centre, 33 El-Buhouth St., Dokki, Giza, 12622, Egypt
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31
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Kwon YJ, Ye DJ, Baek HS, Chun YJ. 7,12-Dimethylbenz[α]anthracene increases cell proliferation and invasion through induction of Wnt/β-catenin signaling and EMT process. ENVIRONMENTAL TOXICOLOGY 2018; 33:729-742. [PMID: 29663660 DOI: 10.1002/tox.22560] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 03/14/2018] [Accepted: 03/25/2018] [Indexed: 06/08/2023]
Abstract
7,12-Dimethylbenz[α]anthracene (DMBA) is a hazardous component present in polluted environments. DMBA has been used as an experimental tool for in vivo tumor formation owing to its carcinogenic effects, but the detailed molecular mechanism of DMBA has not been fully established. To comprehend the carcinogenic mechanism of DMBA, we explored its effects in the breast cancer cell lines, MCF-7 and MDA-MB-231, and the cervical cancer cell line, HeLa. Cell viability assay and measurement of a proliferation marker showed that DMBA markedly increased cancer cell proliferation. Furthermore, morphological observations and wound healing assays in nontumorigenic MCF-10A cells and trans-well invasion assays in cancer cells following DMBA treatment revealed that DMBA induced cell migration and invasion. To reveal the molecular mechanism of DMBA, we investigated the effects of DMBA on the epithelial-mesenchymal transition (EMT) process and Wnt/β-catenin signaling, a critical pathway for cell proliferation that was reported to correlate with the EMT process, by using quantitative RT-PCR (qPCR), western blot analysis, and confocal microscopy. Consequently, we found that DMBA increased cancer cell proliferation and invasion through the promotion of EMT-inducing factors and β-catenin. Especially, it was revealed in promoter activity assay using mutated luciferase vectors on transcription factor-binding sites that TWIST1 is promoted by DMBA through induction of STAT3-mediated promoter activation. To further elucidate the detailed mechanism of DMBA, we aimed to identify the key regulator of its carcinogenic action. DMBA was shown to significantly upregulate the expression of specificity protein 1 (Sp1), a transcription factor, and the carcinogenic effects of DMBA were blocked via the suppression or interruption of Sp1 activity. In conclusion, our data suggested that DMBA induced carcinogenic effects through activation of Wnt/β-catenin signaling and the EMT process by upregulating Sp1 activity.
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Affiliation(s)
- Yeo-Jung Kwon
- College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul, 06974, Republic of Korea
| | - Dong-Jin Ye
- College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul, 06974, Republic of Korea
| | - Hyoung-Seok Baek
- College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul, 06974, Republic of Korea
| | - Young-Jin Chun
- College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul, 06974, Republic of Korea
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32
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MicroRNAs as Potential Biomarkers in Merkel Cell Carcinoma. Int J Mol Sci 2018; 19:ijms19071873. [PMID: 29949882 PMCID: PMC6073391 DOI: 10.3390/ijms19071873] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 06/18/2018] [Accepted: 06/22/2018] [Indexed: 12/27/2022] Open
Abstract
Merkel cell carcinoma (MCC) is a rare and aggressive type of skin cancer associated with a poor prognosis. This carcinoma was named after its presumed cell of origin, the Merkel cell, which is a mechanoreceptor cell located in the basal epidermal layer of the skin. Merkel cell polyomavirus seems to be the major causal factor for MCC because approximately 80% of all MCCs are positive for viral DNAs. UV exposure is the predominant etiological factor for virus-negative MCCs. Intracellular microRNA analysis between virus-positive and virus-negative MCC cell lines and tumor samples have identified differentially expressed microRNAs. Comparative microRNA profiling has also been performed between MCCs and other non-MCC tumors, but not between normal Merkel cells and malignant Merkel cells. Finally, Merkel cell polyomavirus encodes one microRNA, but its expression in virus-positive MCCs is low, or non-detectable or absent, jeopardizing its biological relevance in tumorigenesis. Here, we review the results of microRNA studies in MCCs and discuss the potential application of microRNAs as biomarkers for the diagnosis, progression and prognosis, and treatment of MCC.
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Zhao J, Xu J, Zhang R. MicroRNA-539 inhibits colorectal cancer progression by directly targeting SOX4. Oncol Lett 2018; 16:2693-2700. [PMID: 30013665 DOI: 10.3892/ol.2018.8892] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 10/26/2017] [Indexed: 12/22/2022] Open
Abstract
Colorectal cancer (CRC) is the third most prevalent cancer and the fourth most common cause of cancer-associated mortality in males and females globally. Aberrant expression of microRNA-539 (miR-539) has been reported in multiple types of cancer. However, miR-539 expression, function and underlying mechanisms have not been clearly elucidated in CRC. In the present study, miR-539 expression was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in CRC tissues and cell lines. The effects of miR-539 on CRC cells were further examined in in vitro studies. In addition, the direct targets of miR-539 in CRC were investigated using bioinformatics, luciferase reporter assays, RT-qPCR and western blotting. miR-539 was revealed to be significantly downregulated in CRC cell lines and tissues. Decreased miR-539 expression was associated with lymph node metastasis and tumor-node-metastasis stage in patients with CRC. Functional assays revealed that the rescue of miR-539 expression attenuated CRC cell proliferation and invasion in vitro. Additionally, SRY-box 4 (SOX4) was validated as a direct target gene of miR-539 in CRC. Furthermore, SOX4 was revealed to be upregulated in CRC tissues at the mRNA and protein level. A significant negative correlation between miR-539 and SOX4 mRNA expression levels was observed in CRC tissues. Furthermore, upregulation of SOX4 partially restored the tumor suppressive effects of miR-539 on CRC cell proliferation and invasion. Taken together, this suggests that miR-539 may serve tumor-suppressive functions in CRC during the process of malignant transformation, by directly targeting SOX4. miR-539/SOX4-based targeted therapy may represent a potential novel treatment for patients with CRC.
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Affiliation(s)
- Jian Zhao
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, P.R. China
| | - Jian Xu
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, P.R. China
| | - Rui Zhang
- Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, P.R. China
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Chu PC, Lin PC, Wu HY, Lin KT, Wu C, Bekaii-Saab T, Lin YJ, Lee CT, Lee JC, Chen CS. Mutant KRAS promotes liver metastasis of colorectal cancer, in part, by upregulating the MEK-Sp1-DNMT1-miR-137-YB-1-IGF-IR signaling pathway. Oncogene 2018; 37:3440-3455. [PMID: 29559746 DOI: 10.1038/s41388-018-0222-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 11/20/2017] [Accepted: 02/25/2018] [Indexed: 02/07/2023]
Abstract
Although the role of insulin-like growth factor-I receptor (IGF-IR) in promoting colorectal liver metastasis is known, the mechanism by which IGF-IR is upregulated in colorectal cancer (CRC) is not defined. In this study, we obtained evidence that mutant KRAS transcriptionally activates IGF-IR gene expression through Y-box-binding protein (YB)-1 upregulation via a novel MEK-Sp1-DNMT1-miR-137 pathway in CRC cells. The mechanistic link between the tumor suppressive miR-137 and the translational regulation of YB-1 is intriguing because epigenetic silencing of miR-137 represents an early event in colorectal carcinogenesis due to promoter hypermethylation. This proposed signaling axis was further verified by the immunohistochemical evaluations of liver metastases from a cohort of 46 KRAS mutant CRC patients, which showed a significant correlation in the expression levels among Sp1, miR-137, YB-1, and IGF-1R. Moreover, suppression of the expression of YB-1 and IGF-IR via genetic knockdown or the pharmacological inhibition of MEK hampers KRAS-driven colorectal liver metastasis in our animal model studies. From a translational perspective, the identification of this KRAS-driven pathway might provide a mechanistic rationale for the use of a MEK inhibitor as an adjuvant, in combination with standard of care, to prevent the recurrence of colorectal liver metastasis in KRAS mutant CRC patients after receiving liver resection, which warrants further investigation.
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Affiliation(s)
- Po-Chen Chu
- Institute of Biological Chemistry, Academia Sinica, 11529, Taipei, Taiwan
- Institute of New Drug Development, College of Biopharmaceutical and Food Sciences, China Medical University, 40402, Taichung, Taiwan
| | - Peng-Chan Lin
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 70403, Tainan, Taiwan
| | - Hsing-Yu Wu
- Institute of Biological Chemistry, Academia Sinica, 11529, Taipei, Taiwan
- Institute of Biochemical Sciences, College of Life Science, National Taiwan University, 10617, Taipei, Taiwan
| | - Kuen-Tyng Lin
- Institute of Biological Chemistry, Academia Sinica, 11529, Taipei, Taiwan
| | - Christina Wu
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA
| | - Tanios Bekaii-Saab
- Mayo Clinic College of Medicine and Science, Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, AZ, 85054, USA
| | - Yih-Jyh Lin
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 70403, Tainan, Taiwan
| | - Chung-Ta Lee
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 70403, Tainan, Taiwan
| | - Jeng-Chang Lee
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 70403, Tainan, Taiwan
| | - Ching-Shih Chen
- Institute of Biological Chemistry, Academia Sinica, 11529, Taipei, Taiwan.
- Institute of New Drug Development, College of Biopharmaceutical and Food Sciences, China Medical University, 40402, Taichung, Taiwan.
- Institute of Biochemical Sciences, College of Life Science, National Taiwan University, 10617, Taipei, Taiwan.
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High Vimentin Expression Predicts a Poor Prognosis and Progression in Colorectal Cancer: A Study with Meta-Analysis and TCGA Database. BIOMED RESEARCH INTERNATIONAL 2018; 2018:6387810. [PMID: 29955607 PMCID: PMC6000861 DOI: 10.1155/2018/6387810] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Revised: 04/10/2018] [Accepted: 04/29/2018] [Indexed: 12/17/2022]
Abstract
The aim of this study was to evaluate the role of vimentin expression in the prognosis and progression of CRC. Meta-analysis was conducted to investigate the correlations between vimentin and prognosis and clinicopathological features in CRC. Literatures were searched by PubMed, Embase, ClinicalKey, CNKI, VIP, and WanFang databases. The Cancer Genome Atlas (TCGA) database was used to assess the association of vimentin expression with survival rate in CRC. Eleven reports with 1969 cases were included in the meta-analysis. The results showed that positive vimentin expression predicted a poor overall survival (OS) in the univariate analysis (HR: 2.087, 95%CI: 1.660-2.625) and multivariate analysis (HR: 1.633, 95%CI: 1.223-2.181). Vimentin overexpression also conferred worse disease-free survival (DFS) in the univariate analysis (HR: 2.069, 95%CI: 1.024-4.179) and multivariate analysis (HR: 2.802, 95%CI: 1.421-5.527). Moreover, upregulated vimentin is related to lymph node metastasis (OR: 2.288, 95%CI: 1.159-4.517), TNM stages (OR: 1.957, 95%CI: 1.333-2.873), and N stage (OR: 2.316, 95%CI: 1.482-3.620). Analysis of TCGA database indicated that elevated vimentin predicated a shorter OS (p=0.033). Our findings reveal that upregulated vimentin contributes to the progression and poor prognosis of CRC. Vimentin may be a prognostic biomarker and therapeutic target in patients with CRC.
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Costantini A, Julie C, Dumenil C, Hélias-Rodzewicz Z, Tisserand J, Dumoulin J, Giraud V, Labrune S, Chinet T, Emile JF, Giroux Leprieur E. Predictive role of plasmatic biomarkers in advanced non-small cell lung cancer treated by nivolumab. Oncoimmunology 2018; 7:e1452581. [PMID: 30221046 PMCID: PMC6136870 DOI: 10.1080/2162402x.2018.1452581] [Citation(s) in RCA: 111] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 03/07/2018] [Accepted: 03/09/2018] [Indexed: 12/17/2022] Open
Abstract
Immune checkpoint inhibitors, as nivolumab, are used in advanced non-small cell lung cancer (NSCLC). However, no associated biomarker is validated in clinical practice with this drug. We investigated herein immune-related blood markers in patients with advanced NSCLC treated with nivolumab. Plasma of 43 consecutive patients were prospectively collected at time of the diagnosis of cancer, at the initiation of nivolumab and at the first tumour evaluation (2 months). Concentrations of PD-L1 (sPD-L1), soluble PD-L2 (sPD-L2), Interleukine-2 (sIl-2), Interferon-gamma (sIFN-γ), and Granzyme B (sGranB) were quantified by ELISA. Cell free RNA was quantified by Reverse Transcriptase -PCR), and plasmatic microRNAs (miRNAs) were evaluated by targeted sequencing. Expression of PD-L1 on tumour biopsies was performed by immunohistochemistry using E13LN. High sPD-L1 at 2 months and increase of sPD-L1 concentrations were associated with poor response and absence of clinical benefit (nivolumab treatment less than 6 months). The variation of sPD-L1 concentrations were confirmed by RNA quantification. sPD-L1 concentrations were not correlated with PD-L1 expression on corresponding tumour samples. Low sGranB at nivolumab initiation was also associated with poor response. High sPD-L1 and low sGranB were associated with poor progression-free survival (PFS) and overall survival (OS). Low sPD-L2, low sIl-2 and high sIFN-γ were associated with grade 3-4 toxicities. Finally, miRNA screening showed that patients with clinical benefit (n = 9) had down-expression of miRNA-320b and -375 compared to patients with early progression at 2 months (n = 9). In conclusion, our results highlight the interest of circulating biomarkers in patients treated with nivolumab.
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Affiliation(s)
- Adrien Costantini
- EA4340, UVSQ, Paris-Saclay University, Boulogne-Billancourt, France
- Department of Respiratory Diseases and Thoracic Oncology, APHP – Ambroise Pare Hospital, Boulogne-Billancourt, France
| | - Catherine Julie
- EA4340, UVSQ, Paris-Saclay University, Boulogne-Billancourt, France
- Department of Pathology, APHP – Ambroise Pare Hospital, Boulogne-Billancourt, France
| | - Coraline Dumenil
- EA4340, UVSQ, Paris-Saclay University, Boulogne-Billancourt, France
- Department of Respiratory Diseases and Thoracic Oncology, APHP – Ambroise Pare Hospital, Boulogne-Billancourt, France
| | - Zofia Hélias-Rodzewicz
- EA4340, UVSQ, Paris-Saclay University, Boulogne-Billancourt, France
- Department of Pathology, APHP – Ambroise Pare Hospital, Boulogne-Billancourt, France
| | - Julie Tisserand
- EA4340, UVSQ, Paris-Saclay University, Boulogne-Billancourt, France
- Department of Pathology, APHP – Ambroise Pare Hospital, Boulogne-Billancourt, France
| | - Jennifer Dumoulin
- EA4340, UVSQ, Paris-Saclay University, Boulogne-Billancourt, France
- Department of Respiratory Diseases and Thoracic Oncology, APHP – Ambroise Pare Hospital, Boulogne-Billancourt, France
| | - Violaine Giraud
- EA4340, UVSQ, Paris-Saclay University, Boulogne-Billancourt, France
- Department of Respiratory Diseases and Thoracic Oncology, APHP – Ambroise Pare Hospital, Boulogne-Billancourt, France
| | - Sylvie Labrune
- EA4340, UVSQ, Paris-Saclay University, Boulogne-Billancourt, France
- Department of Respiratory Diseases and Thoracic Oncology, APHP – Ambroise Pare Hospital, Boulogne-Billancourt, France
| | - Thierry Chinet
- EA4340, UVSQ, Paris-Saclay University, Boulogne-Billancourt, France
- Department of Respiratory Diseases and Thoracic Oncology, APHP – Ambroise Pare Hospital, Boulogne-Billancourt, France
| | - Jean-François Emile
- EA4340, UVSQ, Paris-Saclay University, Boulogne-Billancourt, France
- Department of Pathology, APHP – Ambroise Pare Hospital, Boulogne-Billancourt, France
| | - Etienne Giroux Leprieur
- EA4340, UVSQ, Paris-Saclay University, Boulogne-Billancourt, France
- Department of Respiratory Diseases and Thoracic Oncology, APHP – Ambroise Pare Hospital, Boulogne-Billancourt, France
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Xia SS, Zhang GJ, Liu ZL, Tian HP, He Y, Meng CY, Li LF, Wang ZW, Zhou T. MicroRNA-22 suppresses the growth, migration and invasion of colorectal cancer cells through a Sp1 negative feedback loop. Oncotarget 2018; 8:36266-36278. [PMID: 28422727 PMCID: PMC5482653 DOI: 10.18632/oncotarget.16742] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 03/21/2017] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs have recently emerged as regulators of many biological processes including cell proliferation, development and differentiation. This study identified that miR-22 was statistically decreased in colorectal cancer clinical specimens and highly metastatic cell lines. Moreover, low miR-22 expression was associated with tumor metastasis, advanced clinical stage and relapse. Consistent with clinical observations, miR-22 significantly suppressed the ability of colorectal cancer cells to growth and metastasize in vitro and in vivo. Sp1 was validated as a target of miR-22, and ectopic expression of Sp1 compromised the inhibitory effects of miR-22. In addition, Sp1 repressed miR-22 transcription by binding to the miR-22 promoter, hence forming a negative feedback loop. Further study has shown that miR-22 suppresses the activity of PTEN/AKT pathway by Sp1. Our present results implicate the newly indentified miR-22/Sp1/PTEN/AKT axis might represent a potential therapeutic target for colorectal cancer.
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Affiliation(s)
- Shu-Sen Xia
- The Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Guang-Jun Zhang
- The Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China.,Institute of Hepatobiliary, Pancreatic and Intestinal Disease, North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
| | - Zuo-Liang Liu
- The Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China.,Institute of Hepatobiliary, Pancreatic and Intestinal Disease, North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
| | - Hong-Peng Tian
- The Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China.,Institute of Hepatobiliary, Pancreatic and Intestinal Disease, North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
| | - Yi He
- The Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China.,Institute of Hepatobiliary, Pancreatic and Intestinal Disease, North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
| | - Chang-Yuan Meng
- The Department of Pathology, North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
| | - Li-Fa Li
- The Department of Medical Microbiology and Parasitology, North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
| | - Zi-Wei Wang
- The Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Tong Zhou
- The Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China.,Institute of Hepatobiliary, Pancreatic and Intestinal Disease, North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
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38
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Vu T, Datta PK. Regulation of EMT in Colorectal Cancer: A Culprit in Metastasis. Cancers (Basel) 2017; 9:cancers9120171. [PMID: 29258163 PMCID: PMC5742819 DOI: 10.3390/cancers9120171] [Citation(s) in RCA: 374] [Impact Index Per Article: 46.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 12/05/2017] [Accepted: 12/05/2017] [Indexed: 12/12/2022] Open
Abstract
Epithelial to mesenchymal transition (EMT) is a process during which cells lose their epithelial characteristics, for instance cell polarity and cell-cell contact, and gain mesenchymal properties, such as increased motility. In colorectal cancer (CRC), EMT is associated with an invasive or metastatic phenotype. In this review, we discuss recent studies exploring novel regulation mechanisms of EMT in CRC, including the identification of new CRC EMT regulators. Upregulation of inducers can promote EMT, leading to increased invasiveness and metastasis in CRC. These inducers can downregulate E-cadherin and upregulate N-cadherin and vimentin (VIM) through modulating EMT-related signaling pathways, for instance WNT/β-catenin and TGF-β, and EMT transcription factors, such as zinc finger E-box binding homeobox 1 (ZEB1) and ZEB2. In addition, several microRNAs (miRNAs), including members of the miR-34 and miR-200 families, are found to target mRNAs of EMT-transcription factors, for example ZEB1, ZEB2, or SNAIL. Downregulation of these miRNAs is associated with distant metastasis and advanced stage tumors. Furthermore, the role of EMT in circulating tumor cells (CTCs) is also discussed. Mesenchymal markers on the surface of EMT CTCs were found to be associated with metastasis and could serve as potential biomarkers for metastasis. Altogether, these studies indicate that EMT is orchestrated by a complicated network, involving regulators of different signaling pathways. Further studies are required to understand the mechanisms underlying EMT in CRC.
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Affiliation(s)
- Trung Vu
- Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
| | - Pran K Datta
- Division of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
- Birmingham Veterans Affairs Medical Center, Birmingham, AL 35233, USA.
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Targeting epithelial-mesenchymal plasticity in cancer: clinical and preclinical advances in therapy and monitoring. Biochem J 2017; 474:3269-3306. [PMID: 28931648 DOI: 10.1042/bcj20160782] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 08/01/2017] [Accepted: 08/07/2017] [Indexed: 02/07/2023]
Abstract
The concept of epithelial-mesenchymal plasticity (EMP), which describes the dynamic flux within the spectrum of phenotypic states that invasive carcinoma cells may reside, is being increasingly recognised for its role in cancer progression and therapy resistance. The myriad of events that are able to induce EMP, as well as the more recently characterised control loops, results in dynamic transitions of cancerous epithelial cells to more mesenchymal-like phenotypes through an epithelial-mesenchymal transition (EMT), as well as the reverse transition from mesenchymal phenotypes to an epithelial one. The significance of EMP, in its ability to drive local invasion, generate cancer stem cells and facilitate metastasis by the dissemination of circulating tumour cells (CTCs), highlights its importance as a targetable programme to combat cancer morbidity and mortality. The focus of this review is to consolidate the existing knowledge on the strategies currently in development to combat cancer progression via inhibition of specific facets of EMP. The prevalence of relapse due to therapy resistance and metastatic propensity that EMP endows should be considered when designing therapy regimes, and such therapies should synergise with existing chemotherapeutics to benefit efficacy. To further improve upon EMP-targeted therapies, it is imperative to devise monitoring strategies to assess the impact of such treatments on EMP-related phenomenon such as CTC burden, chemosensitivity/-resistance and micrometastasis in patients.
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Lv QL, Du H, Liu YL, Huang YT, Wang GH, Zhang X, Chen SH, Zhou HH. Low expression of microRNA-320b correlates with tumorigenesis and unfavorable prognosis in glioma. Oncol Rep 2017; 38:959-966. [PMID: 28656255 DOI: 10.3892/or.2017.5762] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Accepted: 03/13/2017] [Indexed: 11/05/2022] Open
Abstract
Accumulating evidence demonstrates that dysregulated microRNAs (miRNAs) play a critical role in tumorigenesis and progression of various cancers. miR-320b, a member of miR‑320 family, was revealed downregulated in numerous human cancers, including nasopharyngeal carcinoma and colorectal cancer. However, the function of miR‑320b in human glioma remained poorly defined. In this study, we report that miR‑320b was lowly expressed in glioma tissues and cell lines in contrast with controls, being closely correlated with histological malignancy of glioma. Furthermore, patients with low expression of miR‑320b were associated with poor prognostic outcomes. In vitro functional assays indicated that overexpression of miR‑320b could markedly enhance cell apoptosis rate and suppress cell proliferation, migration and invasion. miR-320b mimic impaired cell cycle and metastasis through inhibiting the expression of G1/S transition key regulator Cyclin D1 as well as decreasing the expression level of MMP2 and MMP9. Additionally, upregulation of miR‑320b could markedly promote apoptosis by increasing the level of Bax and reducing Bcl-2 expression in glioma. Taken together, our data suggested that miR‑320b might serve as a novel prognostic marker and potential therapeutic target for glioma.
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Affiliation(s)
- Qiao-Li Lv
- Department of Science and Education, Jiangxi Key Laboratory of Translational Cancer Research, Jiangxi Cancer Hospital, Nanchang, Jiangxi 330029, P.R. China
| | - Hong Du
- Department of Pharmacy, Qingdao Mental Health Center, Qingdao, Shandong 266034, P.R. China
| | - Yan-Ling Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Yuang-Tao Huang
- Department of Neurology, The Brain Hospital of Hunan Province, Changsha, Hunan 410008, P.R. China
| | - Gui-Hua Wang
- Department of Oncology, Changsha Central Hospital, Changsha, Hunan 410008, P.R. China
| | - Xue Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Shu-Hui Chen
- Department of Radiation Oncology, Jiangxi Cancer Hospital, Nanchang, Jiangxi 330029, P.R. China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
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Elshafei A, Shaker O, Abd El-Motaal O, Salman T. The expression profiling of serum miR-92a, miR-375, and miR-760 in colorectal cancer: An Egyptian study. Tumour Biol 2017; 39:1010428317705765. [PMID: 28618945 DOI: 10.1177/1010428317705765] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Dysregulation in microRNA expression is a common feature in colorectal cancer. Due to the inconsistent results regarding serum miR-92a expression pattern and the insufficient studies on serum miR-375 and miR-760, we aimed in this study to investigate their expression profile and diagnostic and prognostic power in Egyptian colorectal cancer patients. The expression profile of miR-92a, miR-375, and miR-760 was determined in the sera of 64 colorectal cancer patients using quantitative real-time reverse transcription polymerase chain reaction in comparison to 27 healthy control subjects. The expression fold change of the studied microRNAs was correlated with patients' clinicopathological features. Receiver operating characteristic curve analysis was done to determine the role of these microRNAs in colorectal cancer diagnosis and follow-up according to the yielded area under the curve. The expression pattern of miR-92a was significantly upregulated (3.38 ± 2.52, p < 0.0001), while both of miR-375 and 760 were significantly downregulated (-1.250 ± 1.80, p< 0.0001; -1.710 ± 1.88, p < 0.0001, respectively) in colorectal cancer than the control. MiR-92a was positively correlated ( r = 0.671, p = 0.0001), while miR-375 and miR-760 were inversely correlated ( r = -0.414, p = 0.001; r = -0.644, p = 0.0001) with advanced colorectal cancer stages. Receiver operating characteristic curve analysis disclosed the highest diagnostic potential for miR-760 to discriminate colorectal cancer patients and early-stage colorectal cancer from the control (area under the curve = 0.922 and 0.875, respectively), while the highest prognostic potential for discrimination between colorectal cancer stages was for miR-92a. In conclusion, serum level of miR-92a, miR-375, and miR-760 may serve as biomarkers of colorectal cancer in Egyptian patients with high diagnostic power for miR-760 and high prognostic power for miR-92a.
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Affiliation(s)
- Ahmed Elshafei
- 1 Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Olfat Shaker
- 2 Department of Medical Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ossama Abd El-Motaal
- 1 Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Tarek Salman
- 1 Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
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Bajpai R, Nagaraju GP. Specificity protein 1: Its role in colorectal cancer progression and metastasis. Crit Rev Oncol Hematol 2017; 113:1-7. [PMID: 28427500 DOI: 10.1016/j.critrevonc.2017.02.024] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Indexed: 01/20/2023] Open
Abstract
Specificity protein 1 (Sp1) is a widely expressed transcription factor that plays an important role in the promotion of oncogenes required for tumor survival, progression and metastasis. Sp1 is highly expressed in several cancers including colorectal cancer (CRC) and is related to poor prognosis. Therefore, targeting Sp1 is a rational for CRC therapy. In this review, we will recapitulate the current understanding of Sp1 signaling, its molecular mechanisms, and its potential involvement in CRC growth, progression and metastasis. We will also discuss the current therapeutic drugs for CRC and their mechanism of action via Sp1.
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Affiliation(s)
- Richa Bajpai
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, 30322, USA
| | - Ganji Purnachandra Nagaraju
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, 30322, USA.
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Guo L, Yuan J, Xie N, Wu H, Chen W, Song S, Wang X. miRNA-411 acts as a potential tumor suppressor miRNA via the downregulation of specificity protein 1 in breast cancer. Mol Med Rep 2016; 14:2975-82. [PMID: 27572271 PMCID: PMC5042781 DOI: 10.3892/mmr.2016.5645] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2015] [Accepted: 07/13/2016] [Indexed: 01/02/2023] Open
Abstract
The expression and functions of microRNA (miR)-411 have been investigated in several types of cancer. However, until now, miR-411 in human breast cancer has not been examined. The present study investigated the expression, biological functions and molecular mechanisms of miR‑411 in human breast cancer, discussing whether it offers potential as a therapeutic biomarker for breast cancer in the future. The expression levels of miR‑411 in human breast cancer tissues and cells were measured using reverse transcription‑quantitative polymerase chain reaction analysis. Following transfection with miR‑411 mimics, an MTT assay, cell migration and invasion assay, western blot analysis and luciferase assay were performed in human breast cancer cell lines. According to the results, it was found that miR‑411 was significantly downregulated in breast cancer, and associated with lymph node metastasis and histological grade. Additionally, it was observed that miR‑411 suppressed cell growth, migration and invasion in the breast cancer cells. The present study also provided the first evidence, to the best of our knowledge, that miR‑411 was likely to directly target specificity protein 1 in breast cancer. These findings indicated that miR‑411 may be used a therapeutic biomarker for the treatment of breast cancer in the future.
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Affiliation(s)
- Liangfeng Guo
- Department of Surgery, Clinical Medicine, The Affiliated Clinical College Second People's Hospital of Shenzhen, Anhui Medical University, Hefei, Anhui 230032
- Department of Breast Surgery, The Second People's Hospital of Shenzhen, Shenzhen, Guangdong 518035
| | - Jianhui Yuan
- Toxicology Research Laboratory, The Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong 518055, P.R. China
| | - Ni Xie
- Department of Breast Surgery, The Second People's Hospital of Shenzhen, Shenzhen, Guangdong 518035
| | - Huisheng Wu
- Department of Breast Surgery, The Second People's Hospital of Shenzhen, Shenzhen, Guangdong 518035
| | - Weicai Chen
- Department of Breast Surgery, The Second People's Hospital of Shenzhen, Shenzhen, Guangdong 518035
| | - Shufen Song
- Department of Breast Surgery, The Second People's Hospital of Shenzhen, Shenzhen, Guangdong 518035
| | - Xianming Wang
- Department of Surgery, Clinical Medicine, The Affiliated Clinical College Second People's Hospital of Shenzhen, Anhui Medical University, Hefei, Anhui 230032
- Department of Breast Surgery, The Second People's Hospital of Shenzhen, Shenzhen, Guangdong 518035
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Sun L, Liang J, Wang Q, Li Z, Du Y, Xu X. MicroRNA-137 suppresses tongue squamous carcinoma cell proliferation, migration and invasion. Cell Prolif 2016; 49:628-35. [PMID: 27571935 DOI: 10.1111/cpr.12287] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 07/14/2016] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES Tongue squamous cell carcinoma (TSCC) is the most frequent type of oral malignancy. Increasing evidence has shown that miRNAs play key roles in many biological processes such as cell development, invasion, proliferation, differentiation, metabolism, apoptosis and migration. MATERIALS AND METHODS qRT-PCR analysis was performed to measure miR-137 expression. CCK-8 analysis, cell colony formation, wound-healing analysis and invasion were performed to detect resultant cell functions. The direct target of miR-137 was labelled and measured by luciferase assay and Western blotting. RESULTS We demonstrated that expression of miR-137 was downregulated in TSCC tissues compared to matched normal ones. miR-137 expression was downregulated in TSCC lines (SCC4, SCC1, UM1 and Cal27) compared to the immortalized NOK16B cell line and normal oral keratinocytes in culture (NHOK). In addition, we have shown that miR-137 expression was epigenetically regulated in TSCCs. Overexpression of miR-137 suppressed TSCC proliferation and colony formation. Ectopic expression of miR-137 promoted expression of the epithelial biomarker, E-cadherin, and inhibited the mesenchymal biomarker, N-cadherin, as well as vimentin and Snail expression, indicating that miR-137 suppressed TSCC epithelial-mesenchymal transition (EMT). We also showed that ectopic expression of miR-137 inhibited TSCC invasion and migration. In addition, we identified SP1 as a direct target gene of miR-137 in SCC1 cells. SP1 overexpression rescued inhibitory effects exerted by miR-137 on cell proliferation and EMT. CONCLUSIONS These results indicate that miR-137 acted as a tumour suppressor in TSCC by targeting SP1.
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Affiliation(s)
- Lanying Sun
- School of Stomatology, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong University, Jinan, 250012, China.,Oral Implantology Center, Stomatology Hospital of Jinan, Jinan, 250001, China
| | - Jin Liang
- School of Stomatology, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong University, Jinan, 250012, China
| | - Qibao Wang
- Department of Endodontics, Stomatology Hospital of Jinan, Jinan, 250001, China
| | - Zhaoyuan Li
- Oral Implantology Center, Stomatology Hospital of Jinan, Jinan, 250001, China
| | - Yi Du
- Department of Endodontics, Stomatology Hospital of Jinan, Jinan, 250001, China
| | - Xin Xu
- School of Stomatology, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong University, Jinan, 250012, China.
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