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Saadh MJ, Hussain QM, Alazzawi TS, Fahdil AA, Athab ZH, Yarmukhamedov B, Al-Nuaimi AMA, Alsaikhan F, Farhood B. MicroRNA as Key Players in Hepatocellular Carcinoma: Insights into Their Role in Metastasis. Biochem Genet 2025; 63:1014-1062. [PMID: 39103713 DOI: 10.1007/s10528-024-10897-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 07/29/2024] [Indexed: 08/07/2024]
Abstract
Liver cancer or hepatocellular carcinoma (HCC) remains the most common cancer in global epidemiology. Both the frequency and fatality of this malignancy have shown an upward trend over recent decades. Liver cancer is a significant concern due to its propensity for both intrahepatic and extrahepatic metastasis. Liver cancer metastasis is a multifaceted process characterized by cell detachment from the bulk tumor, modulation of cellular motility and invasiveness, enhanced proliferation, avoidance of the immune system, and spread either via lymphatic or blood vessels. MicroRNAs (miRNAs) are small non-coding ribonucleic acids (RNAs) playing a crucial function in the intricate mechanisms of tumor metastasis. A number of miRNAs can either increase or reduce metastasis via several mechanisms, such as control of motility, proliferation, attack by the immune system, cancer stem cell properties, altering the microenvironment, and the epithelial-mesenchymal transition (EMT). Besides, two other types of non-coding RNAs, such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) can competitively bind to endogenous miRNAs. This competition results in the impaired ability of the miRNAs to inhibit the expression of the specific messenger RNAs (mRNAs) that are targeted. Increasing evidence has shown that the regulatory axis comprising circRNA/lncRNA-miRNA-mRNA is correlated with the regulation of HCC metastasis. This review seeks to present a thorough summary of recent research on miRNAs in HCC, and their roles in the cellular processes of EMT, invasion and migration, as well as the metastasis of malignant cells. Finally, we discuss the function of the lncRNA/circRNA-miRNA-mRNA network as a crucial modulator of carcinogenesis and the regulation of signaling pathways or genes that are relevant to the metastasis of HCC. These findings have the potential to offer valuable insight into the discovery of novel therapeutic approaches for management of liver cancer metastasis.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan
| | | | - Tuqa S Alazzawi
- College of Dentist, National University of Science and Technology, Nasiriyah, Dhi Qar, Iraq
| | - Ali A Fahdil
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Zainab H Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
| | - Bekhzod Yarmukhamedov
- Department of Public Health and Healthcare management, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan
| | | | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia.
- School of Pharmacy, Ibn Sina National College for Medical Studies, Jeddah, Saudi Arabia.
| | - Bagher Farhood
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Tolentino-Molina BX, Loaeza-Loaeza J, Ortega-Soto A, Castro-Coronel Y, Fernández-Tilapa G, Hernández-Sotelo D. Hsa_circ_0009910 knockdown in HeLa cells increases miR‑198 expression levels and decreases c‑Met expression levels and cell viability. Oncol Lett 2025; 29:74. [PMID: 39650233 PMCID: PMC11622005 DOI: 10.3892/ol.2024.14820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 09/09/2024] [Indexed: 12/11/2024] Open
Abstract
Cervical cancer (CC) is considered a public health problem. Circular RNAs (circRNAs) serve important roles in different types of cancer, including CC. However, the mechanisms used by circRNAs to facilitate CC progression are currently unclear. The present study analyzed the effects of hsa_circ_0009910 knockdown on microRNA (miRNA/miR)-198 and mesenchymal-epithelial transition factor (c-Met) expression levels and its impact on apoptosis and the viability of HeLa cells. Differentially expressed circRNAs in CC were identified using analysis of circRNA microarray data. Bioinformatics analysis was performed to predict circRNA-microRNA (miRNA) and miRNA-mRNA interactions. The knockdown of hsa_circ_0009910 in HeLa cells was performed using small interfering RNA and the expression levels of hsa_circ_0009910, miR-198 and c-Met were assessed using reverse transcription-quantitative PCR. The viability and apoptosis of HeLa cells were evaluated using MTT, neutral red uptake and ApoLive-Glo™ multiplex assays. Hsa_circ_0009910 was significantly upregulated in HeLa cells and the knockdown of hsa_circ_0009910 increased miRNA-198 expression levels, reduced c-Met expression levels and decreased cellular viability, but not apoptosis, in HeLa cells. Overall, these results indicated that hsa_circ_0009910 could act as a molecular sponge of miRNA-198 and contribute to the upregulation of c-Met expression levels. The hsa_circ_0009910/miRNA-198/c-Met interaction network affects the viability, but not apoptosis, of HeLa cells. Based on this mechanism, the present study suggests that hsa_circ_0009910 may be a promising biomarker for CC.
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Affiliation(s)
- Bernardo Xavier Tolentino-Molina
- Laboratory of Cancer Epigenetics, School of Chemical and Biological Sciences, Autonomous University of Guerrero, Chilpancingo, Guerrero 39070, Mexico
| | - Jaqueline Loaeza-Loaeza
- Laboratory of Neurotoxicology, Department of Toxicology, Center for Research and Advanced Studies of the National Polytechnic Institute, Mexico City 07300, Mexico
| | - Arturo Ortega-Soto
- Laboratory of Neurotoxicology, Department of Toxicology, Center for Research and Advanced Studies of the National Polytechnic Institute, Mexico City 07300, Mexico
| | - Yaneth Castro-Coronel
- Laboratory of Cytopathology and Histochemistry, School of Chemical and Biological Sciences, Autonomous University of Guerrero, Chilpancingo, Guerrero 39070, Mexico
| | - Gloria Fernández-Tilapa
- Clinical Research Laboratory, School of Chemical and Biological Sciences, Autonomous University of Guerrero, Chilpancingo, Guerrero 39070, Mexico
| | - Daniel Hernández-Sotelo
- Laboratory of Cancer Epigenetics, School of Chemical and Biological Sciences, Autonomous University of Guerrero, Chilpancingo, Guerrero 39070, Mexico
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Guo L, Wang M, Zhao W, Guo M, Qian T, Peng F, Cao G, Yu S, Liu D. CircATXN7 regulates the proliferation and invasion of esophageal cancer cells through miR-4319/NLRC5. Cell Signal 2024; 122:111341. [PMID: 39121974 DOI: 10.1016/j.cellsig.2024.111341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 07/26/2024] [Accepted: 08/05/2024] [Indexed: 08/12/2024]
Abstract
BACKGROUND This study aimed to explore the molecular mechanism through which circular RNA of ataxin 7 (circATXN7) regulates the proliferation and invasion of esophageal cancer (EC) cells via microRNA (miR)-4319/NLR family CARD domain containing 5 (NLRC5). METHODS The localization of circATXN7 in EC cells was determined by RNA fluorescent in situ hybridization (RNA-FISH). The mRNA levels of circATXN7, miR-4319, and NLRC5 were quantified by reverse transcription-polymerase chain reactions. The binding activity of circATXN7 to miR-4319 was assessed using RNA-binding protein immunoprecipitation. Whether circATXN7 regulates the proliferation of EC cells via miR-4319 was explored using dual-luciferase reporter gene colony formation assays. Protein levels were quantified by western blot. The effect of NLRC5 on the proliferation and invasion of EC cells was examined using colony formation and Transwell assays. A subcutaneous transplanted tumor nude mouse model was established to observe the effect of circATXN7 on the proliferation of EC cells in vivo. RESULTS circATXN7 localized mainly to the cytoplasm. Overexpression or inhibition of miR-4319 significantly regulated the proliferation of EC cells, while circATXN7 competitively inhibited miR-4319 expression. Overexpression of miR-4319 significantly inhibited NLRC5 expression, indicating NLRC5 is a downstream regulatory target of miR-4319. circATXN7 influenced NLRC5 expression via miR-4319. In vivo tumor formation experiments in nude mice revealed that knocking down circATXN7 regulated NLRC5 expression via miR-4319 and significantly inhibited the proliferation of EC cells. CONCLUSIONS In vitro cell and in vivo animal experiments showed that circATXN7 regulates the proliferation, invasion, and migration of EC cells through the miR-4319/NLRC5 signaling pathway.
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Affiliation(s)
- Luni Guo
- Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Min Wang
- Department of the Pain Rehabilitation Clinic, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research &The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Wenhui Zhao
- Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Mengya Guo
- Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Ting Qian
- Department of Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Fanyu Peng
- Department of Radiotherapy, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Guochun Cao
- Department of Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Shaorong Yu
- Department of Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Delin Liu
- Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China.
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Alzahrani MS, Almutairy B, Althobaiti YS, Alsaab HO. Recent Advances in RNA Interference-Based Therapy for Hepatocellular Carcinoma: Emphasis on siRNA. Cell Biochem Biophys 2024; 82:1947-1964. [PMID: 38987439 DOI: 10.1007/s12013-024-01395-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/30/2024] [Indexed: 07/12/2024]
Abstract
Even though RNA treatments were first proposed as a way to change aberrant signaling in cancer, research in this field is currently ongoing. The term "RNAi" refers to the use of several RNAi technologies, including ribozymes, riboswitches, Aptamers, small interfering RNA (siRNA), antisense oligonucleotides (ASOs), and CRISPR/Cas9 technology. The siRNA therapy has already achieved a remarkable feat by revolutionizing the treatment arena of cancers. Unlike small molecules and antibodies, which need administration every three months or even every two years, RNAi may be given every quarter to attain therapeutic results. In order to overcome complex challenges, delivering siRNAs to the targeted tissues and cells effectively and safely and improving the effectiveness of siRNAs in terms of their action, stability, specificity, and potential adverse consequences are required. In this context, the three primary techniques of siRNA therapies for hepatocellular carcinoma (HCC) are accomplished for inhibiting angiogenesis, decreasing cell proliferation, and promoting apoptosis, are discussed in this review. We also deliberate targeting issues, immunogenic reactions to siRNA therapy, and the difficulties with their intrinsic chemistry and transportation.
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Affiliation(s)
- Mohammad S Alzahrani
- Department of Clinical Pharmacy, College of Pharmacy, Taif University, P.O. Box 11099, Taif21944, Saudi Arabia
| | - Bandar Almutairy
- Department of Pharmacology, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia
| | - Yusuf S Althobaiti
- Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif21944, Saudi Arabia
- Addiction and Neuroscience Research Unit, Taif University, P.O. Box 11099, Taif21944, Saudi Arabia
| | - Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, P.O. Box 11099, Taif21944, Saudi Arabia.
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Wang Q, Feng J, Tang L. Non-Coding RNA Related to MAPK Signaling Pathway in Liver Cancer. Int J Mol Sci 2022; 23:11908. [PMID: 36233210 PMCID: PMC9570382 DOI: 10.3390/ijms231911908] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 10/03/2022] [Accepted: 10/04/2022] [Indexed: 11/16/2022] Open
Abstract
The advancement in high-throughput sequencing analysis and the evaluation of chromatin state maps have revealed that eukaryotic cells produce many non-coding transcripts/RNAs. Further, a strong association was observed between some non-coding RNAs and cancer development. The mitogen-activated protein kinases (MAPK) belong to the serine-threonine kinase family and are the primary signaling pathways involved in cell proliferation from the cell surface to the nucleus. They play an important role in various human diseases. A few non-coding RNAs associated with the MAPK signaling pathway play a significant role in the development of several malignancies, including liver cancer. In this review, we summarize the molecular mechanisms and interactions of microRNA, lncRNA, and other non-coding RNAs in the development of liver cancer that are associated with the MAPK signaling pathway. Further, we briefly discuss the therapeutic strategies for liver cancer related to ncRNA and the MAPK signaling pathway.
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Affiliation(s)
- Qiuxia Wang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Jianguo Feng
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
- Laboratory of Anesthesiology, Southwest Medical University, Luzhou 646000, China
| | - Liling Tang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
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Yu X, Eischeid-Scholz H, Meder L, Kondylis V, Büttner R, Odenthal M. SQSTM1/p62 promotes miR-198 loading into extracellular vesicles and its autophagy-related secretion. Hum Cell 2022; 35:1766-1784. [PMID: 36050615 PMCID: PMC9515045 DOI: 10.1007/s13577-022-00765-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/31/2022] [Indexed: 11/30/2022]
Abstract
MicroRNA dysregulation is a hallmark of hepatocellular carcinoma (HCC), leading to tumor growth and metastasis. Previous screening on patient specimens identified miR-198 as the most downregulated miRNA in HCC. Here, we show that miR-198 compensation leads to self-release into extracellular vesicles (EVs). Importantly, the vesicular secretion is mediated by autophagy-related pathway, initiated by sequestration of p62/miR-198 complexes in autophagosome-associated vesicle fractions. miR-198 is selectively recognized and loaded by p62 into autophagosomal fractions, whereas mutated miR-198 forms neither induce autophagy and nor interact with p62. Gain and loss of function experiments, using a CRIPR/Cas knockout (KO) and transgenic site-specific p62 mutants, identified p62 as an essential repressor of cellular miR-198 abundancy. Notably, EVs, harboring miR-198/p62 protein complexes, can be uptaken by cells in the close vicinity, leading to change of gene expression in recipient cells. In conclusion, miR-198 enhances autophagy; conversely autophagic protein p62 reduces the miR-198 levels by sorting into extracellular space.
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Affiliation(s)
- Xiaojie Yu
- Faculty of Medicine, Institute for Pathology and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany. .,Faculty of Medicine, Center for Molecular Medicine Cologne (CMMC), and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany.
| | - Hannah Eischeid-Scholz
- Faculty of Medicine, Institute for Pathology and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany
| | - Lydia Meder
- Faculty of Medicine, Center for Molecular Medicine Cologne (CMMC), and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany.,Faculty of Medicine Department I of Internal Medicine, University Hospital Cologne, University of Cologne, 50931, Cologne, Germany
| | - Vangelis Kondylis
- Faculty of Medicine, Institute for Pathology and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany.,Cologne Excellence Cluster On Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany
| | - Reinhard Büttner
- Faculty of Medicine, Institute for Pathology and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany.,Faculty of Medicine, Center for Molecular Medicine Cologne (CMMC), and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany.,Faculty of Medicine, Center of Integrative Oncology and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany
| | - Margarete Odenthal
- Faculty of Medicine, Institute for Pathology and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany. .,Faculty of Medicine, Center for Molecular Medicine Cologne (CMMC), and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany. .,Faculty of Medicine, Center of Integrative Oncology and University Hospital Cologne, University of Cologne, 50924, Cologne, Germany.
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7
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Sartorius K, Antwi SO, Chuturgoon A, Roberts LR, Kramvis A. RNA Therapeutic Options to Manage Aberrant Signaling Pathways in Hepatocellular Carcinoma: Dream or Reality? Front Oncol 2022; 12:891812. [PMID: 35600358 PMCID: PMC9115561 DOI: 10.3389/fonc.2022.891812] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 04/04/2022] [Indexed: 11/24/2022] Open
Abstract
Despite the early promise of RNA therapeutics as a magic bullet to modulate aberrant signaling in cancer, this field remains a work-in-progress. Nevertheless, RNA therapeutics is now a reality for the treatment of viral diseases (COVID-19) and offers great promise for cancer. This review paper specifically investigates RNAi as a therapeutic option for HCC and discusses a range of RNAi technology including anti-sense oligonucleotides (ASOs), Aptamers, small interfering RNA (siRNA), ribozymes, riboswitches and CRISPR/Cas9 technology. The use of these RNAi based interventions is specifically outlined in three primary strategies, namely, repressing angiogenesis, the suppression of cell proliferation and the promotion of apoptosis. We also discuss some of the inherent chemical and delivery problems, as well as targeting issues and immunogenic reaction to RNAi interventions.
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Affiliation(s)
- Kurt Sartorius
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
- The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL, United States
- Department of Surgery, KZN Kwazulu-Natal (UKZN) Gastrointestinal Cancer Research Centre, Durban, South Africa
| | - Samuel O. Antwi
- The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL, United States
- Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, United States
| | - Anil Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, Durban, South Africa
| | - Lewis R. Roberts
- The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL, United States
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
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Salah RA, Nasr MA, El-Derby AM, Abd Elkodous M, Mohamed RH, El-Ekiaby N, Osama A, Elshenawy SE, Hamad MHM, Magdeldin S, Gabr MM, Abdelaziz AI, El-Badri NS. Hepatocellular carcinoma cell line-microenvironment induced cancer-associated phenotype, genotype and functionality in mesenchymal stem cells. Life Sci 2022; 288:120168. [PMID: 34826437 DOI: 10.1016/j.lfs.2021.120168] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 11/08/2021] [Accepted: 11/18/2021] [Indexed: 12/21/2022]
Abstract
Mesenchymal stromal cells (MSCs) have shown promise in liver cancer treatment. However, when MSCs are recruited to hepatic site of injury, they acquire cancerous promoting phenotype. AIMS To assess the influence of Hepatocellular carcinoma (HCC) microenvironment on human adipose MSCs (hA-MSCs) and predict hA-MSCs intracellular miRNAs role. MATERIALS AND METHODS After indirect co-culturing with Huh-7 cells, hA-MSCs were characterized via cell cycle profile, proliferation and migration potentials by MTT and scratch assays respectively. Functional enrichment analysis of deregulated proteins and miRNA targets was also analyzed. KEY FINDINGS Co-cultured hA-MSCs could acquire a cancer-associated phenotype as shown by upregulation of CAF, cancer markers, and downregulation of differentiation markers. Migration of these cancer-associated cells was increased concomitantly with upregulation of adhesion molecules, but not epithelial to mesenchymal transition markers. Co-cultured cells showed increased proliferation confirmed by downregulation in cell percentage in G0/G1, G2/M and upregulation in S phases of cell cycle. Upregulation of miR-17-5p and 615-5p in co-cultured hA-MSCs was also observed. Functional enrichment analysis of dysregulated proteins in co-cultured hA-MSCs, including our selected miRNAs targets, showed their involvement in development of cancer-associated characteristics. SIGNIFICANCE This study suggests an interaction between tumor cells and surrounding stromal components to generate cancer associated phenotype of some CAF-like characteristics, known to favor cancer progression. This sheds the light on the use of hA-MSCs in HCC therapy. hA-MSCs modulation may be partially achieved via dysregulation of intracellular miR17-5P and 615-5p expression, suggesting an important role for miRNAs in HCC pathogenesis, and as a possible therapeutic candidate.
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Affiliation(s)
- Radwa Ayman Salah
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Egypt
| | - Mohamed A Nasr
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Egypt
| | - Azza M El-Derby
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Egypt
| | - M Abd Elkodous
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Egypt
| | - Rania Hassan Mohamed
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Nada El-Ekiaby
- School of Medicine NewGiza University (NGU), Cairo, Egypt
| | - Aya Osama
- Proteomics and metabolomics Research Program, Basic Research Department, Children Cancer Hospital Egypt, 57357 Cairo, Egypt
| | - Shimaa E Elshenawy
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Egypt
| | | | - Sameh Magdeldin
- Proteomics and metabolomics Research Program, Basic Research Department, Children Cancer Hospital Egypt, 57357 Cairo, Egypt; Department of Physiology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
| | - Mahmoud M Gabr
- Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
| | | | - Nagwa S El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Egypt.
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Kaushik P, Kumar A. Emerging role and function of miR-198 in human health and diseases. Pathol Res Pract 2021; 229:153741. [PMID: 34952425 DOI: 10.1016/j.prp.2021.153741] [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: 08/13/2021] [Revised: 12/09/2021] [Accepted: 12/16/2021] [Indexed: 01/10/2023]
Abstract
Ever since their discovery, microRNAs (miRNAs/miRs) have astonished us by the plethora of processes they regulate, and thus adding another dimension to the gene regulation. They have been implicated in several diseases affecting cardiovascular, neurodegenerative, hepatic, autoimmune and inflammatory functions. A primate specific exonic miRNA, miR-198 has been vastly studied during the past decade, and shown to have a critical role in wound healing. The aberrant expression of miR-198 was first reported in schizophrenia, linking it to neural development. Later, its dysregulation and tumor suppressive role was reported in hepatocellular carcinoma. However, this was just a beginning, and after which there was an explosion of reports linking miR-198 deregulation to cancers and other ailments. The first target to be identified for miR-198 was Cyclin T1 in monocytes affecting HIV1 replication. Depending on the type of cancer, miR-198 has been shown to function either as a tumor suppressor or an oncomir. Interestingly, miR-198 is not only known to regulate multiple targets and pathways, but also is itself regulated by several circular RNAs and long-non-coding RNAs, highlighting a complex regulatory network. This review highlights the currently understood mechanism and regulation of miR-198 in different diseases, and its possible diagnostic and therapeutic potential.
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Affiliation(s)
- Pankhuri Kaushik
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India
| | - Arun Kumar
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India.
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10
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Fu Z, Wang L, Li S, Chen F, Au-Yeung KKW, Shi C. MicroRNA as an Important Target for Anticancer Drug Development. Front Pharmacol 2021; 12:736323. [PMID: 34512363 PMCID: PMC8425594 DOI: 10.3389/fphar.2021.736323] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/10/2021] [Indexed: 12/15/2022] Open
Abstract
Cancer has become the second greatest cause of death worldwide. Although there are several different classes of anticancer drugs that are available in clinic, some tough issues like side-effects and low efficacy still need to dissolve. Therefore, there remains an urgent need to discover and develop more effective anticancer drugs. MicroRNAs (miRNAs) are a class of small endogenous non-coding RNAs that regulate gene expression by inhibiting mRNA translation or reducing the stability of mRNA. An abnormal miRNA expression profile was found to exist widely in cancer cell, which induces limitless replicative potential and evading apoptosis. MiRNAs function as oncogenes (oncomiRs) or tumor suppressors during tumor development and progression. It was shown that regulation of specific miRNA alterations using miRNA mimics or antagomirs can normalize the gene regulatory network and signaling pathways, and reverse the phenotypes in cancer cells. The miRNA hence provides an attractive target for anticancer drug development. In this review, we will summarize the latest publications on the role of miRNA in anticancer therapeutics and briefly describe the relationship between abnormal miRNAs and tumorigenesis. The potential of miRNA-based therapeutics for anticancer treatment has been critically discussed. And the current strategies in designing miRNA targeting therapeutics are described in detail. Finally, the current challenges and future perspectives of miRNA-based therapy are conferred.
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Affiliation(s)
- Zhiwen Fu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Liu Wang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Shijun Li
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Fen Chen
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | | | - Chen Shi
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
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11
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Yuan C, Su Z, Liao S, Li D, Zhou Z, Wang Y, Quan M, Zeng L, Lv C, Shen C, Gong W, Wu J, Chen X, Hu W, Lv X, Si W, Yu X. miR-198 inhibits the progression of renal cell carcinoma by targeting BIRC5. Cancer Cell Int 2021; 21:390. [PMID: 34289837 PMCID: PMC8296723 DOI: 10.1186/s12935-021-02092-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 07/14/2021] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND miR-198 is involved in the formation, migration, invasion, and metastasis of various malignant cancers. However, the function and mechanism of action of miR-198 in the tumorigenesis of renal cell carcinoma (RCC) remain elusive. Here, we aimed to explore the role of miR198 in RCC. METHODS Immunohistochemistry was performed to estimate the level of survivin in RCC sections. Quantitative real-time polymerase chain reaction was performed to determine the expression level of miR-198 in fresh RCC tissues. Furthermore, the target relationship between miR-198 and BIRC5 was predicted using the TargetScanHuman 7.2 database and verified via dual-luciferase reporter assay and western blotting. The effects of miR-198 on the viability, apoptosis, invasion, and migration of A498 and ACHN cells were studied using Cell Counting Kit-8, flow cytometry, transwell migration assay, and wound healing assay, respectively. Additionally, a xenograft nude mouse model was established to evaluate the effect of miR-198 on RCC tumorigenesis. RESULTS The expression levels of BIRC5 and miR-198 were respectively higher and lower in RCC tissues than those in normal adjacent tissues. Furthermore, miR-198 could inhibit luciferase activity and reduce the protein level of survivin without affecting the BIRC5 mRNA levels. miR-198 inhibited cell viability, migration, and invasion and promoted cell apoptosis; co-transfection with BIRC5 could rescue these effects. Moreover, miR-198 could repress tumor growth in the xenograft nude mouse model of RCC. CONCLUSIONS Our study demonstrates that miR-198 suppresses RCC progression by targeting BIRC5.
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Affiliation(s)
- Chao Yuan
- Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University School of Medicine, Xialu District guilin north, road no. 16, Huangshi, 435003, Hubei, China
| | - Zhenhong Su
- Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University School of Medicine, Xialu District guilin north, road no. 16, Huangshi, 435003, Hubei, China
| | - Shengjie Liao
- Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University School of Medicine, Xialu District guilin north, road no. 16, Huangshi, 435003, Hubei, China
| | - Duanzhuo Li
- Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University School of Medicine, Xialu District guilin north, road no. 16, Huangshi, 435003, Hubei, China
| | - Zhiwen Zhou
- Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University School of Medicine, Xialu District guilin north, road no. 16, Huangshi, 435003, Hubei, China
| | - Yawen Wang
- Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University School of Medicine, Xialu District guilin north, road no. 16, Huangshi, 435003, Hubei, China
| | - Mingchun Quan
- Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University School of Medicine, Xialu District guilin north, road no. 16, Huangshi, 435003, Hubei, China
| | - Lingling Zeng
- Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University School of Medicine, Xialu District guilin north, road no. 16, Huangshi, 435003, Hubei, China
| | - Cai Lv
- Department of Urology, Haikou Municipal Hospital, Haikou, 570208, Hainan, China
| | - Chenyi Shen
- Yixing Cancer Hospital, Dongshan Dong Lu No. 45, Yixing, 214200, Jiangsu, China
| | - Weida Gong
- Yixing Cancer Hospital, Dongshan Dong Lu No. 45, Yixing, 214200, Jiangsu, China
| | - Jianfeng Wu
- Yixing Cancer Hospital, Dongshan Dong Lu No. 45, Yixing, 214200, Jiangsu, China
| | - Xiaogang Chen
- Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Huangshi, 435000, Hubei, China
| | - Wenbing Hu
- Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Huangshi, 435000, Hubei, China
| | - Xu Lv
- Yixing Cancer Hospital, Dongshan Dong Lu No. 45, Yixing, 214200, Jiangsu, China.
| | - Wenxia Si
- Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University School of Medicine, Xialu District guilin north, road no. 16, Huangshi, 435003, Hubei, China.
| | - Xin Yu
- Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University School of Medicine, Xialu District guilin north, road no. 16, Huangshi, 435003, Hubei, China.
- Zhaoqing Medical College, Zhaoqing, 526020, Guangdong, China.
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12
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Meng W, Chen T. Association between the HGF/c‑MET signaling pathway and tumorigenesis, progression and prognosis of hepatocellular carcinoma (Review). Oncol Rep 2021; 46:191. [PMID: 34278495 DOI: 10.3892/or.2021.8142] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 06/10/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most aggressive and lethal malignancies with a rising incidence, and is characterized by rapid progression, frequent metastasis, late diagnosis, high postoperative recurrence and poor prognosis. Therefore, novel treatment strategies for HCC, particularly advanced HCC, are urgently required. The hepatocyte growth factor (HGF)/c‑mesenchymal‑epithelial transition receptor (c‑MET) axis is a key signaling pathway in HCC and is strongly associated with its highly malignant features. Available treatments based on HGF/c‑MET inhibition may prolong the lifespan of patients with HCC; however, they do not achieve the desired therapeutic effects. The aim of the present article was to review the basic knowledge regarding the role of the HGF/c‑MET signaling pathway in HCC, and examine the association between the HGF/c‑MET signaling pathway and the tumorigenesis, progression and prognosis of HCC.
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Affiliation(s)
- Wei Meng
- School of Medicine, China Three Gorges University, Yichang, Hubei 443002, P.R. China
| | - Tao Chen
- School of Medicine, China Three Gorges University, Yichang, Hubei 443002, P.R. China
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13
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Kang Y, Zhang Y, Sun Y. MicroRNA‑198 suppresses tumour growth and metastasis in oral squamous cell carcinoma by targeting CDK4. Int J Oncol 2021; 59:39. [PMID: 33982769 PMCID: PMC8121097 DOI: 10.3892/ijo.2021.5219] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 04/14/2021] [Indexed: 12/20/2022] Open
Abstract
MicroRNAs (miRNAs/miR) often contribute to the progression of oral squamous cell carcinoma (OSCC) via the regulation of mRNA. The present study aimed to investigate the role of miR‑198 in OSCC pathogenesis and explore the underlying mechanism. Reverse transcription‑quantitative (RT‑q)PCR was performed to determine miR‑198 expression in OSCC tissues and cell lines, and univariate and multivariate analyses were applied to evaluate the survival of patients with OSCC. The effects of miR‑198 on OSCC cell lines were studied in vitro and in vivo. A set of epithelial‑mesenchymal transition (EMT) markers were detected to determine whether miR‑198 was involved in EMT. Lastly, using luciferase assays, a novel target of miR‑198 was identified and the effect of the new target gene of miR‑198 on cell proliferation and invasion was also studied. It was identified that miR‑198 expression was decreased in OSCC tissues and cell lines, and low expression of miR‑198 was associated with poor overall survival and disease‑free survival. Overexpression of miR‑198 appeared to significantly inhibit the proliferation, invasion and EMT of OSCC cells. Moreover, the luciferase assay results showed that miR‑198 interacted with cyclin‑dependent kinase 4 (CDK4) by directly targeting the miRNA‑binding site in the CDK4 sequence, and RT‑qPCR results showed that CDK4 expression was increased in OSCC tissues and cell lines. In addition, transfection of small interfering RNA against CDK4 in OSCC cells showed similar inhibitory effects on cell proliferation, invasion and EMT, whereas CDK4 overexpression in OSCC cells partially reversed the inhibitory effects of the miR‑198 mimic. The present results indicated that miR‑198 suppressed OSCC tumour growth and metastasis by directly targeting CDK4 expression. Thus, miR‑198 may be a potential therapeutic target in the treatment of OSCC.
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Affiliation(s)
- Yuanyuan Kang
- Department of Emergency and Oral Medicine, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, Liaoning 110002, P.R. China
| | - Ying Zhang
- Department of Emergency and Oral Medicine, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, Liaoning 110002, P.R. China
| | - Yan Sun
- Department of Emergency and Oral Medicine, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, Liaoning 110002, P.R. China
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14
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Wang T, Zhang Q, Wang N, Liu Z, Zhang B, Zhao Y. Research Progresses of Targeted Therapy and Immunotherapy for Hepatocellular Carcinoma. Curr Med Chem 2021; 28:3107-3146. [PMID: 33050856 DOI: 10.2174/0929867327666201013162144] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 08/25/2020] [Accepted: 09/01/2020] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, with nearly one million new cases and deaths every year. Owing to the complex pathogenesis, hidden early symptoms, rapidly developing processes, and poor prognosis, the morbidity and mortality of HCC are increasing yearly. With the progress being made in modern medicine, the treatment of HCC is no longer limited to traditional methods. Targeted therapy and immunotherapy have emerged to treat advanced and metastatic HCC in recent years. Since Sorafenib is the first molecular targeting drug against angiogenesis, targeted drugs for HCC are continually emerging. Moreover, immunotherapy plays a vital role in clinical trials. In particular, the application of immune checkpoint inhibitors, which have received increasing attention in the field of cancer treatment, is a possible research path. Interestingly, these two therapies generally complement each other at some stages of HCC, bringing new hope for patients with advanced HCC. In this paper, we discuss the research progress of targeted therapy and immunotherapy for HCC in recent years, which will provide a reference for the further development of drugs for HCC.
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Affiliation(s)
- Tao Wang
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Qiting Zhang
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Ning Wang
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Ziqi Liu
- Department of Pharmacy, the PLA Rocket Force Characteristic Medical Center, Beijing 100088, China
| | - Bin Zhang
- Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Research Center, Department of Marine Pharmacy, College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Yufen Zhao
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, China
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15
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Shi T, Kobara H, Oura K, Masaki T. Mechanisms Underlying Hepatocellular Carcinoma Progression in Patients with Type 2 Diabetes. J Hepatocell Carcinoma 2021; 8:45-55. [PMID: 33604315 PMCID: PMC7886236 DOI: 10.2147/jhc.s274933] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) ranks third in cancer-related deaths from solid tumors worldwide. The incidence of type 2 diabetes mellitus (T2DM) has increased worldwide in conjunction with the expansion of the Western lifestyle. Furthermore, patients with T2DM have been documented to have an increased risk of HCC, as well as bile tract cancer. Growing evidence shows that T2DM is a strong additive metabolic risk factor for HCC, but how diabetes affects the incidence of HCC requires additional investigation. In this review, we discuss the underlying mechanisms of HCC in patients with T2DM. Topics covered include abnormal glucose and lipid metabolism, hyperinsulinemia, and insulin resistance; the effect of activated platelets; hub gene expression associated with HCC; inflammation and signaling pathways; miRNAs; altered gut microbiota and immunomodulation. The evidence suggests that reducing obesity, diabetes, and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis through efficient measures of prevention may lead to decreased rates of T2DM-related HCC.
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Affiliation(s)
- Tingting Shi
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa, 761-0793, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa, 761-0793, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa, 761-0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa, 761-0793, Japan
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16
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Wang Q, Liu S, Han Z. miR-339-3p regulated acute pancreatitis induced by caerulein through targeting TNF receptor-associated factor 3 in AR42J cells. Open Life Sci 2020; 15:912-922. [PMID: 33817278 PMCID: PMC7874543 DOI: 10.1515/biol-2020-0084] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 07/13/2020] [Accepted: 07/14/2020] [Indexed: 12/17/2022] Open
Abstract
Acute pancreatitis (AP) is an inflammatory disease with high morbidity and mortality. The regulation mechanism of miRNA is involved in the production and development of various diseases, but the regulation mechanism of miRNA in AP is still not fully elucidated. The expression of miR-339-3p was detected using quantitative real-time PCR. The levels of TNF-α, IL-1β, and IL-6 were detected using enzyme-linked immunosorbent assay. Cell apoptosis was measured using flow cytometry. The protein expressions of TNF receptor-associated factor 3 (TRAF3), Bcl-2, C-caspase 3, Bax, p-p38, and p38 were measured using western blot. Luciferase reporter assay and RNA immunoprecipitation assay were applied to ensure that miR-399-3p targeted TRAF3. Caerulein promoted the expression of TNF-α, IL-1β, and IL-6, enhanced the expression of C-caspase 3 and Bax while inhibited Bcl-2 protein expression. Meanwhile, caerulein also reduced the expression of miR-339-3p and induced the expression of TRAF3 in rat pancreatic acinar cells. miR-399-3p transfection inhibited the levels of TNF-α, IL-1β, and IL-6 and C-caspase 3 and Bax protein expression as well as suppressed cell apoptosis, while increased Bcl-2 protein expression in caerulein-induced AP. TRAF3 has been verified as a target of miR-339-3p. Interestingly, the reduction of miR-399-3p inhibited the p38 pathway, which was impaired by the upregulation of TRAF3. In addition, the suppression effects of miR-339-3p on cell inflammation and apoptosis in caerulein-induced AP were reversed by enhancing TRAF3 expression. In this study, in vitro model of AP was characterized by strong inflammation and cell apoptosis. We have first demonstrated the regulatory network of miR-339-3p and TRAF3. Overexpression of miR-339-3p inhibited cell inflammation and cell apoptosis in caerulein-induced AP through modulating TRAF3 expression via the p38 pathway, providing a new therapeutic target in the treatment of AP.
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Affiliation(s)
- Qi Wang
- Department of Gastroenterology, The Yijishan Hospital of Wannan Medical College, Room 505, Unit 3, Building 1, Yiyuan Community, No. 109, Tuanjie West Rd, 241001, Wuhu, Anhui, China
| | - Shaofeng Liu
- Department of Gastroenterology, The Yijishan Hospital of Wannan Medical College, Room 505, Unit 3, Building 1, Yiyuan Community, No. 109, Tuanjie West Rd, 241001, Wuhu, Anhui, China
| | - Zhen Han
- Department of Gastroenterology, The Yijishan Hospital of Wannan Medical College, Room 505, Unit 3, Building 1, Yiyuan Community, No. 109, Tuanjie West Rd, 241001, Wuhu, Anhui, China
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17
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Petkovic M, Sørensen AE, Leal EC, Carvalho E, Dalgaard LT. Mechanistic Actions of microRNAs in Diabetic Wound Healing. Cells 2020; 9:E2228. [PMID: 33023156 PMCID: PMC7601058 DOI: 10.3390/cells9102228] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 09/25/2020] [Accepted: 09/30/2020] [Indexed: 02/06/2023] Open
Abstract
Wound healing is a complex biological process that is impaired under diabetes conditions. Chronic non-healing wounds in diabetes are some of the most expensive healthcare expenditures worldwide. Early diagnosis and efficacious treatment strategies are needed. microRNAs (miRNAs), a class of 18-25 nucleotide long RNAs, are important regulatory molecules involved in gene expression regulation and in the repression of translation, controlling protein expression in health and disease. Recently, miRNAs have emerged as critical players in impaired wound healing and could be targets for potential therapies for non-healing wounds. Here, we review and discuss the mechanistic background of miRNA actions in chronic wounds that can shed the light on their utilization as specific wound healing biomarkers.
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Affiliation(s)
- Marija Petkovic
- Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark; (A.E.S.); (L.T.D.)
- Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; (E.C.L.); (E.C.)
- Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
| | - Anja Elaine Sørensen
- Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark; (A.E.S.); (L.T.D.)
| | - Ermelindo Carreira Leal
- Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; (E.C.L.); (E.C.)
- Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
| | - Eugenia Carvalho
- Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; (E.C.L.); (E.C.)
- Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
- Department of Geriatrics, University of Arkansas for Medical Sciences, and Arkansas Children’s Research Institute, Little Rock, AR 72205, USA
| | - Louise Torp Dalgaard
- Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark; (A.E.S.); (L.T.D.)
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18
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Shi Y, Fang N, Li Y, Guo Z, Jiang W, He Y, Ma Z, Chen Y. Circular RNA LPAR3 sponges microRNA-198 to facilitate esophageal cancer migration, invasion, and metastasis. Cancer Sci 2020; 111:2824-2836. [PMID: 32495982 PMCID: PMC7419039 DOI: 10.1111/cas.14511] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 05/06/2020] [Accepted: 05/28/2020] [Indexed: 12/19/2022] Open
Abstract
In this study, we explored expression and functions of circular RNA LPAR3 (circLPAR3) in esophageal squamous cell carcinoma (ESCC). The differential expression of circular RNAs (circRNAs) in 10 ESCC and corresponding paracarcinoma tissues was analyzed through circRNA microarray, then the candidate circRNAs were detected and verified through quantitative RT-PCR, and a novel circRNA was screened, which was circLPAR3. Circular RNA LPAR3 showed apparently high expression in ESCC tissues and cells, which was closely correlated with the clinical stage and lymph node metastasis of ESCC patients. Circular RNA LPAR3 was mainly located in the cytoplasm of ESCC cells, which was more stable than the baseline gene. Circular RNA LPAR3 upregulated MET gene expression through sponge adsorption of microRNA (miR)-198, activated the RAS/MAPK and the PI3K/Akt pathways, and promoted ESCC cell migration, invasion, and metastasis in vivo and in vitro. However, it had no effect on ESCC cell proliferation. Circular RNA LPAR3 can regulate the miR-198-MET signal axis to promote the migration, invasion, and metastasis of esophageal cancer cells, which can thereby serve as a potential diagnostic and therapeutic target of esophageal cancer.
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Affiliation(s)
- Yijun Shi
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Na Fang
- Department of Molecular Cell Biology and Toxicology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yadong Li
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zizhang Guo
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Jiang
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yaozhou He
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zijian Ma
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yijiang Chen
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Li S, Yang J, Liu X, Guo R, Zhang R. circITGA7 Functions as an Oncogene by Sponging miR-198 and Upregulating FGFR1 Expression in Thyroid Cancer. BIOMED RESEARCH INTERNATIONAL 2020; 2020:8084028. [PMID: 32685526 PMCID: PMC7327604 DOI: 10.1155/2020/8084028] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Accepted: 04/21/2020] [Indexed: 01/22/2023]
Abstract
BACKGROUND Emerging evidence has indicated that circular RNAs (circRNAs), recognized as functional noncoding transcripts in eukaryotic cells, may be involved in regulating many physiological or pathological processes. However, the regulation and function of circular RNA circITGA7 in thyroid cancer (TC) remains unknown. METHODS In this study, we found that circITGA7 is upregulated in TC cell lines. We then performed functional analyses in the cell lines to support clinical findings. Mechanistically, we demonstrated that circITGA7 can directly bind to miR-198 and reduce the inhibition effect of miR-198 on target FGFR1 expression. RESULTS We reported an upregulation of circITGA7 in patients with TC. Silencing of circITGA7 inhibits metastasis and proliferation of TC cell lines in vitro. In addition, in the TC cell lines, the knockdown of circITGA7 or overexpression of miR-198 significantly suppressed FGFR1 levels. Mechanistically, we found that circITGA7 acts as miR-198 competitive endogenous RNA (ceRNA) to regulate FGFR1 expression. CONCLUSIONS In summary, circRNA circITGA7 may play a regulatory role in TC and may be a potential marker for TC diagnosis or progression.
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Affiliation(s)
- Siqi Li
- College of Life Sciences, Inner Mongolia Normal University, Hohhot, Inner Mongolia 010022, China
| | - Junmei Yang
- College of Life Sciences, Inner Mongolia Normal University, Hohhot, Inner Mongolia 010022, China
| | - Xiaoting Liu
- College of Life Sciences, Inner Mongolia Normal University, Hohhot, Inner Mongolia 010022, China
| | - Rui Guo
- Hefei Laboratory Center, Ping An Healthcare Investment Management Co., Ltd., China
| | - Ruidong Zhang
- College of Life Sciences, Inner Mongolia Normal University, Hohhot, Inner Mongolia 010022, China
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20
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Zhan H, Tu S, Zhang F, Shao A, Lin J. MicroRNAs and Long Non-coding RNAs in c-Met-Regulated Cancers. Front Cell Dev Biol 2020; 8:145. [PMID: 32219093 PMCID: PMC7078111 DOI: 10.3389/fcell.2020.00145] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 02/21/2020] [Indexed: 12/16/2022] Open
Abstract
MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are components of many signaling pathways associated with tumor aggressiveness and cancer metastasis. Some lncRNAs are classified as competitive endogenous RNAs (ceRNAs) that bind to specific miRNAs to prevent interaction with target mRNAs. Studies have shown that the hepatocyte growth factor/mesenchymal-epithelial transition factor (HGF/c-Met) pathway is involved in physiological and pathological processes such as cell growth, angiogenesis, and embryogenesis. Overexpression of c-Met can lead to sustained activation of downstream signals, resulting in carcinogenesis, metastasis, and resistance to targeted therapies. In this review, we evaluated the effects of anti-oncogenic and oncogenic non-coding RNAs (ncRNAs) on c-Met, and the interactions among lncRNAs, miRNAs, and c-Met in cancer using clinical and tissue chromatin immunoprecipition (ChIP) analysis data. We summarized current knowledge of the mechanisms and effects of the lncRNAs/miR-34a/c-Met axis in various tumor types, and evaluated the potential therapeutic value of lncRNAs and/or miRNAs targeted to c-Met on drug-resistance. Furthermore, we discussed the functions of lncRNAs and miRNAs in c-Met-related carcinogenesis and potential therapeutic strategies.
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Affiliation(s)
- Hong Zhan
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Sheng Tu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Feng Zhang
- School of Medicine, Zhejiang University Hangzhou, Hangzhou, China
| | - Anwen Shao
- Department of Neurosurgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Lin
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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21
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Wang H, Rao B, Lou J, Li J, Liu Z, Li A, Cui G, Ren Z, Yu Z. The Function of the HGF/c-Met Axis in Hepatocellular Carcinoma. Front Cell Dev Biol 2020; 8:55. [PMID: 32117981 PMCID: PMC7018668 DOI: 10.3389/fcell.2020.00055] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Accepted: 01/22/2020] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, leading to a large global cancer burden. Hepatocyte growth factor (HGF) and its high-affinity receptor, mesenchymal epithelial transition factor (c-Met), are closely related to the onset, progression, and metastasis of multiple tumors. The HGF/c-Met axis is involved in cell proliferation, movement, differentiation, invasion, angiogenesis, and apoptosis by activating multiple downstream signaling pathways. In this review, we focus on the function of the HGF/c-Met axis in HCC. The HGF/c-Met axis promotes the onset, proliferation, invasion, and metastasis of HCC. Moreover, it can serve as a biomarker for diagnosis and prognosis, as well as a therapeutic target for HCC. In addition, it is closely related to drug resistance during HCC treatment.
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Affiliation(s)
- Haiyu Wang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Benchen Rao
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jiamin Lou
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianhao Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenguo Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ang Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guangying Cui
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhigang Ren
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zujiang Yu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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22
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Liu X, Sun R, Chen J, Liu L, Cui X, Shen S, Cui G, Ren Z, Yu Z. Crosstalk Mechanisms Between HGF/c-Met Axis and ncRNAs in Malignancy. Front Cell Dev Biol 2020; 8:23. [PMID: 32083078 PMCID: PMC7004951 DOI: 10.3389/fcell.2020.00023] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 01/13/2020] [Indexed: 12/24/2022] Open
Abstract
Several lines of evidence have confirmed the magnitude of crosstalk between HGF/c-Met axis (hepatocyte growth factor and its high-affinity receptor c-mesenchymal-epithelial transition factor) and non-coding RNAs (ncRNAs) in tumorigenesis. Through activating canonical or non-canonical signaling pathways, the HGF/c-Met axis mediates a range of oncogenic processes such as cell proliferation, invasion, apoptosis, and angiogenesis and is increasingly becoming a promising target for cancer therapy. Meanwhile, ncRNAs are a cluster of functional RNA molecules that perform their biological roles at the RNA level and are essential regulators of gene expression. The expression of ncRNAs is cell/tissue/tumor-specific, which makes them excellent candidates for cancer research. Many studies have revealed that ncRNAs play a crucial role in cancer initiation and progression by regulating different downstream genes or signal transduction pathways, including HGF/c-Met axis. In this review, we discuss the regulatory association between ncRNAs and the HGF/c-Met axis by providing a comprehensive understanding of their potential mechanisms and roles in cancer development. These findings could reveal their possible clinical applications as biomarkers for therapeutic interventions.
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Affiliation(s)
- Xin Liu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ranran Sun
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianan Chen
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Liwen Liu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xichun Cui
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shen Shen
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guangying Cui
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhigang Ren
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zujiang Yu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Niu L, Zhou Y, Zhang W, Ren Y. Long noncoding RNA LINC00473 functions as a competing endogenous RNA to regulate MAPK1 expression by sponging miR-198 in breast cancer. Pathol Res Pract 2019; 215:152470. [DOI: 10.1016/j.prp.2019.152470] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 05/13/2019] [Accepted: 05/23/2019] [Indexed: 12/21/2022]
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MicroRNA-198 inhibits proliferation and induces apoptosis by directly suppressing FGFR1 in gastric cancer. Biosci Rep 2019; 39:BSR20181258. [PMID: 31138759 PMCID: PMC6558723 DOI: 10.1042/bsr20181258] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 04/09/2019] [Accepted: 04/30/2019] [Indexed: 01/05/2023] Open
Abstract
MicroRNAs (miRNAs) are increasingly recognized as important therapeutic targets in cancer. Here we aim to investigate the role of miR-198, a broad-spectrum tumor suppressor, in gastric cancer (GC). MiR-198 overexpression was achieved by transfection of miR-198 mimics, followed by evaluation of cell viability using cell-counting kit 8. Cell cycle arrest and apoptosis were assessed by Annexin-V-FITC/Propidium Iodide (PI) staining flow cytometry respectively. The target of miR-198 was identified by bioinformatical analysis and confirmed by dual-luciferase assay, along with real-time PCR and Western blot analyses of target gene expression after transfection of miR-198 mimics. GC tissues were characterized by miR-198 down-regulation. Restoration of miR-198 expression attenuated GC cell proliferation and colony formation, meanwhile inducing significant G0/G1 arrest. Furthermore, combinatory therapy of cisplatin and miR-198 induced greater anti-tumor effects than treatment with cisplatin single therapy. We also identified fibroblast growth factor receptor 1 (FGFR1) as a direct target gene of miR-198. Furthermore, FGFR1 silencing elicited a similar tumor-suppressive effect as miR-198 overexpression. FGFR1 overexpression antagonized the anti-tumor effects of miR-198 overexpression. MiR-198/FGFR1 axis plays an important role in proliferation and apoptosis of GC. Therapies targeted to miR-198 can potentially improve GC treatment.
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25
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Han W, Yu G, Meng X, Hong H, Zheng L, Wu X, Zhang D, Yan B, Ma Y, Li X, Wang Q. Potential of C1QTNF1-AS1 regulation in human hepatocellular carcinoma. Mol Cell Biochem 2019; 460:37-51. [PMID: 31222560 PMCID: PMC6745033 DOI: 10.1007/s11010-019-03569-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 04/13/2019] [Indexed: 12/27/2022]
Abstract
The aim of our study is to explore the regulation of C1QTNF1-AS1 on its target miR-221-3p/SOCS3 in human hepatocellular carcinoma (HCC). To explore the underlying molecular regulation of non-coding RNA for HCC, differentially expressed patterns of lncRNAs and genes were examined by RNA-seq. GO and KEGG pathway analysis were done based on the function of mRNAs that mediated by differentially expressed lncRNAs. RT-qPCR and western blot were conducted to detect the mRNA and protein level expression of C1QTNF1-AS1, miR-221-3p, SOCS3 and key proteins in JAK/STAT signaling pathway in HCC tissues and cells. The target miRNA of differentially expressed C1QTNF1-AS1 and SOCS3 was miR-221-3p predicted by bioinformatics analysis. C1QTNF1-AS1 and SOCS3 was downregulated and miR-221-3p was upregulated in HCC tissues and cells. In HepG2 and Huh-7 cells, the overexpression of C1QTNF1-AS1 or SOCS3, and silencing of miR-221-3p inhibited proliferation, migration, invasion and JAK/STAT signaling pathway, while promoted cell apoptosis. The results of dual-luciferase assay indicated that C1QTNF1-AS1 regulated miR-221-3p and miR-221-3p targeted SOCS3 by directly binding. And the growth of HCC in vivo was impeded when C1QTNF1-AS1 was upregulated. Overexpression of C1QTNF1-AS1 could downregulate miR-221-3p thereby inhibited the proliferation, migration and invasion of HCC cells.
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Affiliation(s)
- Weijie Han
- Department of Digestive Minimally Invasive Surgery, The Second Affiliated Hospital of Baotou Medical College, Baotou, 014030, Neimenggu, China
| | - Guofeng Yu
- General Surgery, Suzhou Integrative Traditional Chinese and Western Medicine Hospital, Suzhou, 215101, Jiangsu, China
| | - Xianmei Meng
- Department of Digestive Minimally Invasive Surgery, The Second Affiliated Hospital of Baotou Medical College, Baotou, 014030, Neimenggu, China
| | - Hong Hong
- Nursing Department, The Second Affiliated Hospital of Baotou Medical College, Baotou, 014030, Neimenggu, China
| | - Liansheng Zheng
- Department of Digestive Minimally Invasive Surgery, The Second Affiliated Hospital of Baotou Medical College, Baotou, 014030, Neimenggu, China
| | - Xiaobo Wu
- Department of Digestive Minimally Invasive Surgery, The Second Affiliated Hospital of Baotou Medical College, Baotou, 014030, Neimenggu, China
| | - Dongsheng Zhang
- Department of Digestive Minimally Invasive Surgery, The Second Affiliated Hospital of Baotou Medical College, Baotou, 014030, Neimenggu, China
| | - Boshi Yan
- Department of Digestive Minimally Invasive Surgery, The Second Affiliated Hospital of Baotou Medical College, Baotou, 014030, Neimenggu, China
| | - Yongqiang Ma
- Department of Digestive Minimally Invasive Surgery, The Second Affiliated Hospital of Baotou Medical College, Baotou, 014030, Neimenggu, China
| | - Xiaolong Li
- Department of Digestive Minimally Invasive Surgery, The Second Affiliated Hospital of Baotou Medical College, Baotou, 014030, Neimenggu, China
| | - Qiuhong Wang
- Department of Digestive Minimally Invasive Surgery, The Second Affiliated Hospital of Baotou Medical College, Baotou, 014030, Neimenggu, China.
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26
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Li H, Zhang B, Ding M, Lu S, Zhou H, Sun D, Wu G, Gan X. C1QTNF1-AS1 regulates the occurrence and development of hepatocellular carcinoma by regulating miR-221-3p/SOCS3. Hepatol Int 2019; 13:277-292. [PMID: 31069760 DOI: 10.1007/s12072-019-09944-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 03/21/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND The aim of our study was to explore how C1QTNF1-AS1 regulated miR-221-3p/SOCS3 axis in human hepatocellular carcinoma (HCC). METHODS Differentially expressed lncRNAs and genes were examined via RNA-seq. GO analysis and KEGG pathway enrichment analysis were carried out based on the function of dys-regulated mRNAs. RT-qPCR was employed to detect the relative mRNA expression level of C1QTNF1-AS1, miR-221-3p, SOCS3 and key genes in the JAK/STAT signaling pathway in HCC tissues and cells, and western blot analysis was conducted to detect the relative protein expression levels of SOCS3 and key proteins in the JAK/STAT signaling pathway in HCC tissues and cells. MTT assay, transwell assay and flow cytometry were utilized to assess HCC cell proliferation, invasion, migration and apoptosis. Dual luciferase reporter gene assay was used to verify the targeted relationship between C1QTNF1-AS1 and miR-221-3p, as well as between miR-221-3p and SOCS3. A tumorigenicity assay in nude mice was conducted to investigate the effects of C1QTNF1-AS1 on HCC tumor growth in vivo. RESULTS C1QTNF1-AS1 and SOCS3 were down-regulated, while miR-221-3p was up-regulated in HCC tissues and cells. In HepG2 and Huh7 cells, overexpression of C1QTNF1-AS1 or SOCS3, as well as silence of miR-221-3p inhibited HCC cell proliferation, migration, and invasion and promoted HCC cell apoptosis. The results of the dual luciferase reporter gene assay indicated that miR-221-3p could directly target both C1QTNF1-AS1 and SOCS3. In addition, up-regulation of C1QTNF1-AS1 suppressed HCC tumor growth in vivo. CONCLUSION Overexpression of C1QTNF1-AS1 down-regulated miR-221-3p and subsequently up-regulated SOCS3, thereby inhibiting HCC cell proliferation, migration and invasion and promoting apoptosis through the JAK/STAT signaling pathway.
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Affiliation(s)
- Hang Li
- Department of Hepatobiliary and Pancreas Surgery, China-Japan Union Hospital, Jilin University, Changchun, 130033, Jilin, China
| | - Bo Zhang
- Department of Pediatric Neurology, The First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Meng Ding
- Department of Endoscopy Center, China-Japan Union Hospital, Jilin University, Changchun, 130033, Jilin, China
| | - Shang Lu
- Department of Anesthesiology, China-Japan Union Hospital, Jilin University, Changchun, 130033, Jilin, China
| | - Hui Zhou
- Department of Hepatobiliary and Pancreas Surgery, China-Japan Union Hospital, Jilin University, Changchun, 130033, Jilin, China
| | - Dajun Sun
- Department of Vascular Surgery, China-Japan Union Hospital, Jilin University, No. 126 Xiantai Street, Changchun, 130033, Jilin, China.
| | - Gang Wu
- Department of Hepatobiliary Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China
| | - Xianfeng Gan
- Department of Hepatobiliary Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China
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27
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Paeoniflorin Inhibits Hepatocyte Growth Factor- (HGF-) Induced Migration and Invasion and Actin Rearrangement via Suppression of c-Met-Mediated RhoA/ROCK Signaling in Glioblastoma. BIOMED RESEARCH INTERNATIONAL 2019; 2019:9053295. [PMID: 30886866 PMCID: PMC6388352 DOI: 10.1155/2019/9053295] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 12/05/2018] [Accepted: 01/24/2019] [Indexed: 02/04/2023]
Abstract
Paeoniflorin (PF), as one of the important valid natural compounds of the total glucosides of peony, has displayed a potential effect in cancer prevention and treatment. Aggressive migration and invasion, as an important process, can contribute to tumor progression through infiltrating the surround normal tissue. Actin cytoskeleton rearrangement plays a key role in cells migration and invasion, involving multiple signal pathways. HGF/c-Met signal, as an important couple of oncoprotein, has been demonstrated to regulate actin cytoskeleton rearrangement. In our study, we aim to explore whether paeoniflorin can inhibit migration and invasion and actin cytoskeleton rearrangement via regulation of HGF/c-Met/RhoA/ROCK signal. Various approaches were applied to demonstrate the mechanism of paeoniflorin-mediated anticancer effect, including cell wound healing assay, invasion assay, immunofluorescence staining and transfection, and western blotting. We observed that paeoniflorin inhibited HGF-induced migration and invasion and actin cytoskeleton rearrangement in glioblastoma cells. Furthermore, the inhibition of HGF-induced migration and invasion and actin cytoskeleton rearrangement involved c-Met-mediated RhoA/ROCK signaling in glioblastoma. Thus, our study proved that paeoniflorin could inhibit migration and invasion and actin cytoskeleton rearrangement through inhibition of HGF/c-Met/RhoA/ROCK signaling in glioblastoma, suggesting that paeoniflorin might be a candidate compound to treat glioblastoma.
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Sadri Nahand J, Bokharaei-Salim F, Salmaninejad A, Nesaei A, Mohajeri F, Moshtzan A, Tabibzadeh A, Karimzadeh M, Moghoofei M, Marjani A, Yaghoubi S, Keyvani H. microRNAs: Key players in virus-associated hepatocellular carcinoma. J Cell Physiol 2018; 234:12188-12225. [PMID: 30536673 DOI: 10.1002/jcp.27956] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 11/19/2018] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is known as one of the major health problems worldwide. Pathological analysis indicated that a variety of risk factors including genetical (i.e., alteration of tumor suppressors and oncogenes) and environmental factors (i.e., viruses) are involved in beginning and development of HCC. The understanding of these risk factors could guide scientists and clinicians to design effective therapeutic options in HCC treatment. Various viruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV) via targeting several cellular and molecular pathways involved in HCC pathogenesis. Among various cellular and molecular targets, microRNAs (miRNAs) have appeared as key players in HCC progression. miRNAs are short noncoding RNAs which could play important roles as oncogenes or tumor suppressors in several malignancies such as HCC. Deregulation of many miRNAs (i.e., miR-222, miR-25, miR-92a, miR-1, let-7f, and miR-21) could be associated with different stages of HCC. Besides miRNAs, exosomes are other particles which are involved in HCC pathogenesis via targeting different cargos, such as DNAs, RNAs, miRNAs, and proteins. In this review, we summarize the current knowledge of the role of miRNAs and exosomes as important players in HCC pathogenesis. Moreover, we highlighted HCV- and HBV-related miRNAs which led to HCC progression.
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Affiliation(s)
- Javid Sadri Nahand
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Arash Salmaninejad
- Drug Applied Research Center, Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran.,Department of Medical Genetics, Medical Genetics Research Center, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abolfazl Nesaei
- Department of Basic Sciences, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Fatemeh Mohajeri
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Azadeh Moshtzan
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Alireza Tabibzadeh
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Mohsen Moghoofei
- Department of Microbiology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Arezo Marjani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | - Shoeleh Yaghoubi
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Hossein Keyvani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
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29
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Georges S, Calleja LR, Jacques C, Lavaud M, Moukengue B, Lecanda F, Quillard T, Gabriel MT, Cartron PF, Baud'huin M, Lamoureux F, Heymann D, Ory B. Loss of miR-198 and -206 during primary tumor progression enables metastatic dissemination in human osteosarcoma. Oncotarget 2018; 9:35726-35741. [PMID: 30515265 PMCID: PMC6254661 DOI: 10.18632/oncotarget.26284] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 10/23/2018] [Indexed: 01/04/2023] Open
Abstract
The metastatic dissemination is a complex multistep process by which tumor cells from a primary site enter into the systemic circulation to finally spread at distant sites. Even if this mechanism is rare at the tumor level, it remains the major cause of Osteosarcoma-patients’ relapse and mortality. MicroRNAs (miRNAs) have recently been described as novel epigenetics’ genes’ expression regulators actively implicated in cancer progression and dissemination. The understanding of their implication in the metastatic spreading could help clinicians to improve the outcome of osteosarcoma. We established the miRNA’s expression-profile between primary bone-tumors (PTs), circulating tumor cells (CTCs) and lung metastatic (META) samples from in vivo mice xenograft models. Our results show that the expression level of the miR-198 and -206 was decreased in META samples, in which the expression of the metastasis-related receptor C-Met was up-regulated. Those expression variations were validated in osteosarcoma patient biopsies from matching primary tumors and lung metastasis. We validated in vitro the endogenous miRNAs inhibitory effects on both migration and invasion, as well as we confirmed by luciferase assays that the C-Met receptor is one of their bona-fide targets. The anti-metastatic effect of these miRNAs was also validated in vivo, as their direct injections into the tumors reduce the number of lung-metastases and prolongs the overall survival of the treated animals. All together, our results suggest the absence of the miR-198 and -206 as powerful predictive biomarkers of the tumor cell dissemination and the rationale of their potential therapeutic use in the treatment of Osteosarcoma.
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Affiliation(s)
- Steven Georges
- INSERM, UMR-S 1238, Nantes 44035, France.,PhyOs, Sarcomes Osseux et Remodelage des Tissus Calcifiés, Université de Nantes, Nantes 44035, France
| | - Lidia Rodriguez Calleja
- INSERM, UMR-S 1238, Nantes 44035, France.,PhyOs, Sarcomes Osseux et Remodelage des Tissus Calcifiés, Université de Nantes, Nantes 44035, France
| | - Camille Jacques
- INSERM, UMR-S 1238, Nantes 44035, France.,PhyOs, Sarcomes Osseux et Remodelage des Tissus Calcifiés, Université de Nantes, Nantes 44035, France
| | - Melanie Lavaud
- INSERM, UMR-S 1238, Nantes 44035, France.,PhyOs, Sarcomes Osseux et Remodelage des Tissus Calcifiés, Université de Nantes, Nantes 44035, France
| | - Brice Moukengue
- INSERM, UMR-S 1238, Nantes 44035, France.,PhyOs, Sarcomes Osseux et Remodelage des Tissus Calcifiés, Université de Nantes, Nantes 44035, France
| | - Fernando Lecanda
- Division of Oncology, Adhesion and Metastasis Laboratory, Center for Applied Medic al Research, University of Navarra, Pamplona, Navarra 31008, Spain
| | - Thibaut Quillard
- INSERM, UMR-S 1238, Nantes 44035, France.,PhyOs, Sarcomes Osseux et Remodelage des Tissus Calcifiés, Université de Nantes, Nantes 44035, France
| | - Marta Tellez Gabriel
- INSERM, UMR-S 1238, Nantes 44035, France.,European Associated Laboratory Sarcoma Research Unit, INSERM, University of Sheffield, Sheffield S10 2TN, UK
| | - Pierre-François Cartron
- Equipe Apoptose et Progression Tumorale, Centre de Recherche en Cancérologie et Immunologie Nantes Angers, CRCINA, INSERM, U1232, Université de Nantes, Université d'Angers, Nantes 44035, France.,LaBCT, Institut de Cancérologie de l'Ouest, Saint Herblain 44800, France.,European Associated Laboratory Sarcoma Research Unit, INSERM, University of Sheffield, Sheffield S10 2TN, UK.,Cancéropole Grand-Ouest, Réseau Epigénétique (RepiCGO), France
| | - Marc Baud'huin
- INSERM, UMR-S 1238, Nantes 44035, France.,PhyOs, Sarcomes Osseux et Remodelage des Tissus Calcifiés, Université de Nantes, Nantes 44035, France
| | - François Lamoureux
- INSERM, UMR-S 1238, Nantes 44035, France.,PhyOs, Sarcomes Osseux et Remodelage des Tissus Calcifiés, Université de Nantes, Nantes 44035, France
| | - Dominique Heymann
- Equipe Apoptose et Progression Tumorale, Centre de Recherche en Cancérologie et Immunologie Nantes Angers, CRCINA, INSERM, U1232, Université de Nantes, Université d'Angers, Nantes 44035, France.,European Associated Laboratory Sarcoma Research Unit, INSERM, University of Sheffield, Sheffield S10 2TN, UK
| | - Benjamin Ory
- INSERM, UMR-S 1238, Nantes 44035, France.,PhyOs, Sarcomes Osseux et Remodelage des Tissus Calcifiés, Université de Nantes, Nantes 44035, France.,Cancéropole Grand-Ouest, Réseau Epigénétique (RepiCGO), France
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Duan X, Jiang B, Yang J, Zhou L, Tian B, Mao X. FOXP3 inhibits MYC expression via regulating miR-198 and influences cell viability, proliferation and cell apoptosis in HepG2. Cancer Med 2018; 7:6182-6192. [PMID: 30378283 PMCID: PMC6308052 DOI: 10.1002/cam4.1780] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 07/24/2018] [Accepted: 08/22/2018] [Indexed: 12/12/2022] Open
Abstract
Objective Our study aimed to explore the effects of FOXP3 expression on liver neoplasms cells and to further investigate the relationship between FOXP3 and proto‐oncogene MYC. Methods QRT‐PCR was used for assessment of FOXP3 expression in liver neoplasms tissues and para‐carcinoma tissues. The effects of FOXP3 on cell viability were determined by CCK8 assay, clone formation experiment, and flow cytometry. For miRNA selection, chips were used to figure out the differentially expressed miRNAs in FOXP3‐overexpressing HepG2 cells. The result was followed by bioinformatics prediction to screen the possible MYC‐targeted miRNAs, and it was examined by dual luciferase assay and ChIP assay. The expression levels of MYC protein and apoptosis‐associated proteins (bcl2 and bax) were measured by Western blot assay. Results It showed an under‐regulated expression of FOXP3 in liver neoplasm tissues from qRT‐PCR results. Overexpression of FOXP3 contributed to cell apoptosis as well as suppressed tumor cells’ proliferation. MiR‐198 was detected to be highly expressed in FOXP3‐overexpressing HepG2 cells. FOXP3 regulated the transcription level of miR‐198 by binding to its promoter sequence and overexpressed miR‐198 could suppress tumor cells’ proliferation and promote cell apoptosis. There existed targeted relationship between miR‐198 and MYC gene. MiR‐198 inhibited cancer by suppressing the expression of MYC in liver neoplasm. Conclusion FOXP3 up‐regulated miR‐198 expression by binding to its promoter sequence specifically, while miR‐198 inhibited proto‐oncogene MYC via targeted relationship. High level of miR‐198 contributed to the apoptosis of tumor cells and suppressed cell viability meanwhile.
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Affiliation(s)
- Xiaohui Duan
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, Changsha, China
| | - Bo Jiang
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, Changsha, China
| | - Jianhui Yang
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, Changsha, China
| | - Lixue Zhou
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, Changsha, China
| | - Bingzhang Tian
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, Changsha, China
| | - Xianhai Mao
- Department of Hepatobiliary Surgery/Research Laboratory of Hepatobiliary Tumor, Hunan Provincial People's Hospital, Changsha, China
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31
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HGF/c-MET: A Promising Therapeutic Target in the Digestive System Cancers. Int J Mol Sci 2018; 19:ijms19113295. [PMID: 30360560 PMCID: PMC6274736 DOI: 10.3390/ijms19113295] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 10/10/2018] [Accepted: 10/15/2018] [Indexed: 02/07/2023] Open
Abstract
The HGF/c-MET pathway is active in the development of digestive system cancers, indicating that inhibition of HGF/c-MET signaling may have therapeutic potential. Various HGF/c-MET signaling inhibitors, mainly c-MET inhibitors, have been tested in clinical trials. The observed efficacy and adverse events of some c-MET inhibitors were not very suitable for treating digestive system cancers. The development of new HGF/c-MET inhibitors in preclinical studies may bring promising treatments and synergistic combination (traditional anticancer drugs and c-MET inhibitors) strategies provided anacceptable safety and tolerability. Insights into miRNA biology and miRNA therapeutics have made miRNAs attractive tools to inhibit HGF/c-MET signaling. Recent reports show that several microRNAs participate in inhibiting HGF/c-MET signaling networks through antagonizing c-MET or HGF in digestive system cancers, and the miRNAs-HGF/c-MET axis plays crucial and novel roles for cancer treatment. In the current review, we will discuss recent findings about inhibitors of HGF/c-MET signaling in treating digestive system cancers, and how miRNAs regulate digestive system cancers via mediating HGF/c-MET pathway.
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Zhu L, Xue F, Xu X, Xu J, Hu S, Liu S, Cui Y, Gao C. MicroRNA-198 inhibition of HGF/c-MET signaling pathway overcomes resistance to radiotherapy and induces apoptosis in human non-small-cell lung cancer. J Cell Biochem 2018; 119:7873-7886. [PMID: 29943841 DOI: 10.1002/jcb.27204] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 05/24/2018] [Indexed: 12/20/2022]
Abstract
Non-small-cell lung cancer (NSCLC) is the most common cause of death from cancer worldwide. MicroRNAs (miRNAs) are a group of important regulators in NSCLC, including miR-198. However, the underlying molecular mechanisms of miR-198 involvement in intrinsic resistance to radiotherapy in NSCLC remain to be elucidated. In this study, to investigate the clinical significance of miR-198 in NSCLC in relation to the response to radiotherapy, we determined the expression patterns of miR-198 between responders and nonresponders after 2 months of radiotherapy and found that decreased expressions of miR-198 were associated with radiotherapy resistance. In addition, we altered the endogenous miR-198 using mimics or inhibitors to examine the effects of miR-198 on 4-Gy-irradiated A549 and SPCA-1 cells in vitro. Upregulating miR-198 was shown to inhibit cell proliferation, migration, and invasion and induce apoptosis. MiR-198 inhibition produced a reciprocal result. PHA665752, a selective small-molecule c-Met inhibitor, potently inhibited hepatocyte growth factor (HGF)-stimulated and constitutive c-Met phosphorylation and rescued 4-Gy-irradiated A549 and SPCA-1 cells from miR-198 inhibition. Most importantly, we established tumor xenografts of 4-Gy-irradiated A549 and SPCA-1 cells in nude mice and found that miR-198 could suppress tumor formation. Hence, our data delineates the molecular pathway by which miR-198 inhibits NSCLC cellular proliferation and induces apoptosis following radiotherapy, providing a novel target aimed at improving the radiotherapeutic response in NSCLC.
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Affiliation(s)
- Lin Zhu
- Department of Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Feng Xue
- Department of Medical Oncology, Heilongjiang Provincial Hospital, Harbin, China
| | - Xiangying Xu
- Department of Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China.,The Third Affiliated Hospital of SUN YAT-SEN University, Guangzhou, China
| | - Jianyu Xu
- Department of Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Songliu Hu
- Department of Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Shanshan Liu
- Department of Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Ying Cui
- Department of Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Chunzi Gao
- The Second Ward of Oncology Department, The First Clinical Hospital affiliated to Harbin Medical University, Harbin, China
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Wei D, Miao Y, Yu L, Wang D, Wang Y. Downregulation of microRNA‑198 suppresses cell proliferation and invasion in retinoblastoma by directly targeting PTEN. Mol Med Rep 2018; 18:595-602. [PMID: 29749457 DOI: 10.3892/mmr.2018.8979] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 04/20/2018] [Indexed: 11/05/2022] Open
Abstract
A number of studies have highlighted that aberrantly expressed microRNAs (miRNAs/miRs) serve crucial roles in the tumorigenesis and tumor development of retinoblastoma (RB). Hence, a full investigation of the biological roles and regulatory mechanisms of miRNAs in RB may provide novel therapeutic targets for patients with this malignancy. miR‑198 is frequently abnormally expressed in various types of human cancers. However, the expression level, biological roles and underlying mechanisms of miR‑198 in RB remain to be elucidated. In the present study, miR‑198 expression was upregulated in RB tissues and cell lines. Silencing of miR‑198 attenuated cell proliferation and invasion in RB. In addition, phosphatase and tensin homolog deleted on chromosome ten (PTEN) was predicted as a potential target of miR‑198 using bioinformatics analysis. Subsequent luciferase reporter assay indicated that the 3'‑untranslated region of PTEN can be directly targeted by miR‑198. Furthermore, miR‑198 inhibition increased the PTEN expression at the mRNA and protein levels in RB cells. In addition, PTEN mRNA expression was downregulated in RB tissues, and this downregulation was inversely associated with the expression level of miR‑198. PTEN knockdown rescued the inhibitory effects of miR‑198 underexpression on cell proliferation and invasion in RB. Notably, the downregulation of miR‑198 inactivated the phosphoinositide 3‑kinase (PI3K)/protein kinase B (AKT) signaling pathway in RB. These results demonstrated that miR‑198 may serve oncogenic roles in RB by directly targeting PTEN and regulating the PI3K/AKT signaling pathway. Hence, miR‑198 may be a promising therapeutic target for patients with RB.
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Affiliation(s)
- Dongdong Wei
- Department of Ophthalmology, Dezhou People's Hospital, Dezhou, Shandong 253000, P.R. China
| | - Yingbin Miao
- Department of Ophthalmology, Dezhou People's Hospital, Dezhou, Shandong 253000, P.R. China
| | - Lianxia Yu
- Department of Ophthalmology, The Second People Hospital of Dezhou, Dezhou, Shandong 253024, P.R. China
| | - Degong Wang
- Department of Ophthalmology, Dezhou People's Hospital, Dezhou, Shandong 253000, P.R. China
| | - Yingli Wang
- Department of Ophthalmology, Yantai Yeda Hospital, Yantai, Shandong 264006, P.R. China
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Liang YY, Huang JC, Tang RX, Chen WJ, Chen P, Cen WL, Shi K, Gao L, Gao X, Liu AG, Peng XT, Chen G, Huang SN, Fang YY, Gu YY. Clinical value of miR-198-5p in lung squamous cell carcinoma assessed using microarray and RT-qPCR. World J Surg Oncol 2018; 16:22. [PMID: 29394946 PMCID: PMC5797354 DOI: 10.1186/s12957-018-1320-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2017] [Accepted: 01/16/2018] [Indexed: 12/20/2022] Open
Abstract
Background To examine the clinical value of miR-198-5p in lung squamous cell carcinoma (LUSC). Methods Gene Expression Omnibus (GEO) microarray datasets were used to explore the miR-198-5p expression and its diagnostic value in LUSC. Real-time reverse transcription quantitative polymerase chain reaction was used to evaluate the expression of miR-198-5p in 23 formalin-fixed, paraffin-embedded (FFPE) LUSC tissues and corresponding non-cancerous tissues. The correlation between miR-198-5p expression and clinic pathological features was assessed. Meanwhile, putative target messenger RNAs of miR-198-5p were identified based on the analysis of differentially expressed genes in the Cancer Genome Atlas (TCGA) and 12 miRNA prediction tools. Subsequently, the putative target genes were sent to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Results MiR-198-5p was low expressed in LUSC tissues. The combined standard mean difference (SMD) values of miR-198-5p expression based on GEO datasets were − 0.30 (95% confidence interval (CI) − 0.54, − 0.06) and − 0.39 (95% CI − 0.83, 0.05) using fixed effect model and random effect model, respectively. The sensitivity and specificity were not sufficiently high, as the area under the curve (AUC) was 0.7749 (Q* = 0.7143) based on summarized receiver operating characteristic (SROC) curves constructed using GEO datasets. Based on the in-house RT-qPCR, miR-198-5p expression was 4.3826 ± 1.7660 in LUSC tissues and 4.4522 ± 1.8263 in adjacent normal tissues (P = 0.885). The expression of miR-198-5p was significantly higher in patients with early TNM stages (I-II) than that in cases with advanced TNM stages (III-IV) (5.4400 ± 1.5277 vs 3.5690 ± 1.5228, P = 0.008). Continuous variable-based meta-analysis of GEO and PCR data displayed the SMD values of − 0.26 (95% CI − 0.48, − 0.04) and − 0.34 (95% CI − 0.71, 0.04) based on fixed and random effect models, respectively. As for the diagnostic value of miR-198-5p, the AUC based on the SROC curve using GEO and PCR data was 0.7351 (Q* = 0.6812). In total, 542 genes were identified as the targets of miR-198-5p. The most enriched Gene Ontology terms were epidermis development among biological processes, cell junction among cellular components, and protein dimerization activity among molecule functions. The pathway of non-small cell lung cancer was the most significant pathway identified using Kyoto Encyclopedia of Genes and Genomes analysis. Conclusion The expression of miR-198-5p is related to the TNM stage. Thus, miR-198-5p might play an important role via its target genes in LUSC.
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Affiliation(s)
- Yue-Ya Liang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Jia-Cheng Huang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Rui-Xue Tang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Wen-Jie Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Peng Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Wei-Luan Cen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Ke Shi
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Li Gao
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Xiang Gao
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - An-Gui Liu
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Xiao-Tong Peng
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Su-Ning Huang
- Department of Radiotherapy, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
| | - Ye-Ying Fang
- Department of Radiotherapy, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China.
| | - Yong-Yao Gu
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China.
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Role of circulatory microRNAs in the pathogenesis of hepatitis C virus. Virusdisease 2017; 28:360-367. [PMID: 29291226 DOI: 10.1007/s13337-017-0407-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Accepted: 11/03/2017] [Indexed: 12/17/2022] Open
Abstract
Hepatitis C virus (HCV) is associated with one of the major health problem in world that ultimate results in the liver cirrhosis and leads to carcinoma of hepatocellular components round the world. More than 185 million people were found to be infected with HCV. MicroRNAs are small oligonucleotide RNA having 18-22 nucleotides. Circulating mi-RNAs regulate the replication of HCV and HCV-induced liver fibrosis and HCC. By comparing the expression profiles of mi-RNAs of normal individuals with HCV infected patients, aberrant changes in expression of different mi-RNAs have been observed so it can be predicted that these mi-RNAs are associated with and play a central role in the hepatitis C infection and diseases associated with it. This review demonstrates the major role of circulatory microRNAs in the HCV and HCV associated ailments.
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Qin Z, Wei X, Jin N, Wang Y, Zhao R, Hu Y, Yan W, Li J, Zhou Q. MiR-199a targeting ROCK1 to affect kidney cell proliferation, invasion and apoptosis. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2017; 46:1920-1925. [PMID: 29130345 DOI: 10.1080/21691401.2017.1396224] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Renal cell carcinoma (RCC) is one of the three most common cancers of urinary tract cancer, accounting for 2-3% of all systemic cancers. Recent studies have found that miR-199a is lowly expressed in RCC, may act as a tumour suppressor gene to induce the occurrence of kidney cancer. In the present study, we investigated the role of miR-199a in the progression and metastasis of RCC. The results showed that miR-199a significantly downregulated in RCC and cell lines. Overexpression of miR-199a in RCC cell lines significantly inhibited cell proliferation, migration and invasion. Furthermore, the qRT-PCR and western blot results showed that miR-199a overexpression significantly downregulated ROCK-1 mRNA and protein levels. ROCK1 was identified as a target of miR-199a, and ectopic expression of miR-199a downregulated ROCK1 by direct binding to its 3' untranslated region. Together, these findings indicate that miR-199a acts as a tumour suppressor and its downregulation in tumour tissues may contribute to the progression and metastasis of RCC through a mechanism involving ROCK1, suggesting miR-199a as a potential new diagnostic and therapeutic target for the treatment of RCC.
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Affiliation(s)
- Zhigang Qin
- a Department of Neurosurgery , China-Japan Union Hospital of Jilin University , Changchun , China
| | - Xin Wei
- b Department of Urology , China-Japan Union Hospital of Jilin University , Changchun , China
| | - Ning Jin
- b Department of Urology , China-Japan Union Hospital of Jilin University , Changchun , China
| | - Yao Wang
- b Department of Urology , China-Japan Union Hospital of Jilin University , Changchun , China
| | - Rui Zhao
- b Department of Urology , China-Japan Union Hospital of Jilin University , Changchun , China
| | - Yangqing Hu
- c Department of Nephrology , The Affiliated Hospital of Shao Yang University , Shaoyang , China
| | - Weijian Yan
- c Department of Nephrology , The Affiliated Hospital of Shao Yang University , Shaoyang , China
| | - Junke Li
- c Department of Nephrology , The Affiliated Hospital of Shao Yang University , Shaoyang , China
| | - Qiaoling Zhou
- d Department of Nephrology , Xiangya Hospital Central South University , Changsha , China
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Liu S, Qu D, Li W, He C, Li S, Wu G, Zhao Q, Shen L, Zhang J, Zheng J. miR‑647 and miR‑1914 promote cancer progression equivalently by downregulating nuclear factor IX in colorectal cancer. Mol Med Rep 2017; 16:8189-8199. [PMID: 28990086 PMCID: PMC5779906 DOI: 10.3892/mmr.2017.7675] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2017] [Accepted: 09/19/2017] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs/miRs) have been investigated as diagnostic and prognostic biomarkers for cancer; however, the significance of miRNAs in colorectal cancer (CRC) remains to be elucidated. The aim of the present study was to determine the genetic profiles of CRC tissue, and screen for miRNAs implicated in CRC cell proliferation and migration. RNA sequencing of 10 paired specimens was performed to for screen genes that were upregulated or downregulated in CRC. miRNA expression in CRC specimens and cell lines was confirmed using qPCR analysis. The significance of indicated miRNAs in CRC cell proliferation and migration was evaluated using MTT and scratch wound-healing assays. Online computational prediction, isobaric tags for relative and absolute quantification analysis and a luciferase reporter assay were applied to determine candidate targeted genes for the miRNAs. RNA-seq data revealed miR-1914 as the most prominent miRNA in CRC specimens. qPCR analysis also suggested that the expression of miR-1914, as well as its counterpart miR-647 were elevated in CRC specimens and cell lines. Suppression of miR-647/1914 using small interfering RNAs inhibited CRC SW480 and SW620 cell proliferation, and migration. Nuclear factor I/X (NFIX) was demonstrated to be a candidate for miR-647/1914 and mediated the oncogenic activity of miR-647/1914. In all, miR-647 and miR-1914 were demonstrated to promote the proliferation and migration of CRC cells by directly targeting NFIX. Therapeutic delivery of siRNAs targeting miR-647/1914 and overexpression of NFIX may be feasible approaches for CRC treatment.
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Affiliation(s)
- Shaoqing Liu
- Department of Digestive Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Dingding Qu
- Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Weiping Li
- Department of Neurology, Second Affiliated Hospital, Shaanxi University of Chinese Medicine, Xi'an, Shaanxi 712046, P.R. China
| | - Chenxiang He
- Department of Digestive Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Shisen Li
- Department of Digestive Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Guosheng Wu
- Department of Digestive Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Qingchuan Zhao
- Department of Digestive Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Liangliang Shen
- Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Jian Zhang
- Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Jianyong Zheng
- Department of Digestive Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
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TINCR expression is associated with unfavorable prognosis in patients with hepatocellular carcinoma. Biosci Rep 2017; 37:BSR20170301. [PMID: 28546230 PMCID: PMC5529205 DOI: 10.1042/bsr20170301] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 05/24/2017] [Accepted: 05/25/2017] [Indexed: 12/12/2022] Open
Abstract
Emerging evidence are accumulating that long noncoding RNAs (lncRNAs) have recently been identified to participate in various cellular processes. Terminal differentiation induced ncRNA (TINCR) is a newly identified lncRNA with its functional roles not fully elucidated in human malignancy. The current study aims to identify the clinical significance of TINCR in prognosis and malignant progression of hepatocellular carcinoma (HCC). TINCR expression in HCC specimens at various stages of tumorigenesis were measured by quantitative real-time RT PCR (qRT-PCR). The matched para-carcinoma tissues were used as controls. The associations of TINCR with clinicopathological characteristics, disease-free survival (DFS) and overall survival (OS) of patients were further evaluated. Results revealed that high TINCR expression was significantly correlated with tumor size (P=0.005), tumor differentiation status (P=0.017), TNM stage (P=0.010), and vascular invasion (P=0.004). Moreover, Kaplan-Meier analysis demonstrated that TINCR was correlated to both DFS and OS in HCC cohorts. Patients with high TINCR expression tended to have worse prognosis. Multivariate Cox regression analysis indicated that TINCR was an independent poor prognostic indicator for DFS (HR =1.32, 95% CI: 1.00-1.57, P=0.000) and OS (HR =1.57, 95% CI: 1.30-1.86, P=0.004) in HCC. TINCR was demonstrated as a direct target of miR-137 and miR-133a, and was suppressed by miR-137/miR-133a These results provide the first evidence that the expression of TINCR in HCC may play an oncogenic role in HCC differentiation, invasion, and metastasis. miR-137/miR-133a-TINCR pathway may serve as a promising target for tumor recurrence and prognosis of patients with HCC.
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Tan S, Ding K, Chong QY, Zhao J, Liu Y, Shao Y, Zhang Y, Yu Q, Xiong Z, Zhang W, Zhang M, Li G, Li X, Kong X, Ahmad A, Wu Z, Wu Q, Zhao X, Lobie PE, Zhu T. Post-transcriptional regulation of ERBB2 by miR26a/b and HuR confers resistance to tamoxifen in estrogen receptor-positive breast cancer cells. J Biol Chem 2017. [PMID: 28637868 DOI: 10.1074/jbc.m117.780973] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Tamoxifen-resistant (TAMR) estrogen receptor-positive (ER+) breast cancer is characterized by elevated Erb-B2 receptor tyrosine kinase 2 (ERBB2) expression. However, the underlying mechanisms responsible for the increased ERBB2 expression in the TAMR cells remain poorly understood. Herein, we reported that the ERBB2 expression is regulated at the post-transcriptional level by miR26a/b and the RNA-binding protein human antigen R (HuR), both of which associate with the 3'-UTR of the ERBB2 transcripts. We demonstrated that miR26a/b inhibits the translation of ERBB2 mRNA, whereas HuR enhances the stability of the ERBB2 mRNA. In TAMR ER+ breast cancer cells with elevated ERBB2 expression, we observed a decrease in the level of miR26a/b and an increase in the level of HuR. The forced expression of miR26a/b or the depletion of HuR decreased ERBB2 expression in the TAMR cells, resulting in the reversal of tamoxifen resistance. In contrast, the inactivation of miR26a/b or forced expression of HuR decreased tamoxifen responsiveness of the parental ER+ breast cancer cells. We further showed that the increase in HuR expression in the TAMR ER+ breast cancer cells is attributable to an increase in the HuR mRNA isoform with shortened 3'-UTR, which exhibits increased translational activity. This shortening of the HuR mRNA 3'-UTR via alternative polyadenylation (APA) was observed to be dependent on cleavage stimulation factor subunit 2 (CSTF2/CstF-64), which is up-regulated in the TAMR breast cancer cells. Taken together, we have characterized a model in which the interplay between miR26a/b and HuR post-transcriptionally up-regulates ERBB2 expression in TAMR ER+ breast cancer cells.
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Affiliation(s)
- Sheng Tan
- From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.,Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230026, China
| | - Keshuo Ding
- From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.,the Department of Pathology, Anhui Medical University, Meishan Road, Hefei 230032, China
| | - Qing-Yun Chong
- the Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore 117599, Singapore
| | - Junsong Zhao
- From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Yuan Liu
- From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Yunying Shao
- From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Yuanyuan Zhang
- From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Qing Yu
- From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.,Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230026, China
| | - Zirui Xiong
- From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Weijie Zhang
- From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.,Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230026, China
| | - Min Zhang
- From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.,Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230026, China
| | - Gaopeng Li
- From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Xiaoni Li
- From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.,Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230026, China
| | - Xiangjun Kong
- From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.,Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230026, China
| | - Akhlaq Ahmad
- From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Zhengsheng Wu
- the Department of Pathology, Anhui Medical University, Meishan Road, Hefei 230032, China
| | - Qiang Wu
- the Department of Pathology, Anhui Medical University, Meishan Road, Hefei 230032, China
| | - Xiaodong Zhao
- the School of Biomedical Engineering, Bio-ID Center, Shanghai Jiao Tong University, Shanghai 200240, China, and
| | - Peter E Lobie
- the Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore 117599, Singapore, .,the National Cancer Institute of Singapore, National University Health System, Singapore 119074, Singapore.,the Tsinghua Berkeley Shenzhen Institute (TBSI), Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China
| | - Tao Zhu
- From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China, .,Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230026, China
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Hu CT, Wu JR, Cheng CC, Wu WS. The Therapeutic Targeting of HGF/c-Met Signaling in Hepatocellular Carcinoma: Alternative Approaches. Cancers (Basel) 2017; 9:cancers9060058. [PMID: 28587113 PMCID: PMC5483877 DOI: 10.3390/cancers9060058] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 04/23/2017] [Accepted: 05/24/2017] [Indexed: 12/22/2022] Open
Abstract
The poor prognosis of hepatocellular carcinoma (HCC), one of the most devastating cancers worldwide, is due to frequent recurrence and metastasis. Among the metastatic factors in the tumor microenvironment, hepatocyte growth factor (HGF) has been well known to play critical roles in tumor progression, including HCC. Therefore, c-Met is now regarded as the most promising therapeutic target for the treatment of HCC. However, there are still concerns about resistance and the side effects of using conventional inhibitors of c-Met, such as tyrosine kinase inhibitors. Recently, many alternative strategies of c-Met targeting have been emerging. These include targeting the downstream effectors of c-Met, such as hydrogen peroxide-inducible clone 5 (Hic-5), to block the reactive oxygen species (ROS)-mediated signaling for HCC progression. Also, inhibition of endosomal regulators, such as PKCε and GGA3, may perturb the c-Met endosomal signaling for HCC cell migration. On the other hand, many herbal antagonists of c-Met-dependent signaling, such as saponin, resveratrol, and LZ-8, were identified. Taken together, it can be anticipated that more effective and safer c-Met targeting strategies for preventing HCC progression can be established in the future.
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Affiliation(s)
- Chi-Tan Hu
- Research Centre for Hepatology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien 970, Taiwan.
| | - Jia-Ru Wu
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien 970, Taiwan.
| | - Chuan-Chu Cheng
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien 970, Taiwan.
| | - Wen-Sheng Wu
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien 970, Taiwan.
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41
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Li Y, Luo H, Xiao N, Duan J, Wang Z, Wang S. Long Noncoding RNA SChLAP1 Accelerates the Proliferation and Metastasis of Prostate Cancer via Targeting miR-198 and Promoting the MAPK1 Pathway. Oncol Res 2017; 26:131-143. [PMID: 28492138 PMCID: PMC7844842 DOI: 10.3727/096504017x14944585873631] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Prostate cancer has become the most commonly diagnosed and the second leading cause of cancer-related deaths in males. The long noncoding RNA second chromosome locus associated with prostate-1 (SChLAP1) has been found to be overexpressed in a subset of prostate cancer. However, the significance and mechanism of SChLAP1 in prostate cancer are not well known. In this study, we explored the role of SChLAP1 in prostate cancer tissues, cell lines, and mouse models. The effect of SChLAP1 on miR-198 and MAPK1 was specifically examined. We found that SChLAP1 expression was significantly increased in prostate cancer cells and tissues. Knockdown of SChLAP1 promoted apoptosis and inhibited cell proliferation and invasion in vitro and in vivo. In addition, a potential bonding site between miR-198 and SChLAP1 was predicted, and a low expression of miR-198 was found in prostate cancer tissues and cells. Knockdown of SChLAP1 significantly increased the expression of miR-198, and SChLAP1 overexpression markedly decreased it, indicating that SChLAP1 acted as a negative regulator in the expression of miR-198. Furthermore, our results showed that SChLAP1 interacted with miR-198 and subsequently modulated the MAPK1 signaling pathway in prostate cancer. In conclusion, our study has identified a novel pathway through which SChLAP1 exerts its oncogenic role in prostate cancer at the level of miRNAs and provided a molecular basis for potential applications of SChLAP1 in the prognosis and treatment of prostate cancer.
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Affiliation(s)
- Ye Li
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, P.R. China
| | - Haihong Luo
- Department of Medical Services, Lanzhou University Second Hospital, Lanzhou, P.R. China
| | - Nan Xiao
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, P.R. China
| | - Jianmin Duan
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, P.R. China
| | - Zhiping Wang
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, P.R. China
| | - Shuanke Wang
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, P.R. China
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42
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Nie E, Jin X, Wu W, Yu T, Zhou X, Shi Z, Zhang J, Liu N, You Y. MiR-198 enhances temozolomide sensitivity in glioblastoma by targeting MGMT. J Neurooncol 2017; 133:59-68. [DOI: 10.1007/s11060-017-2425-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 04/11/2017] [Indexed: 12/19/2022]
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43
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Zhuang PH, Xu L, Gao L, Lu W, Ruan LT, Yang J. Correlations of microvascular blood flow of contrast-enhanced ultrasound and HGF/c-Met signaling pathway with clinicopathological features and prognosis of patients with hepatocellular carcinoma. Onco Targets Ther 2017; 10:847-857. [PMID: 28243120 PMCID: PMC5317332 DOI: 10.2147/ott.s113353] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The study is designed to explore the correlations of microvascular blood flow of contrast-enhanced ultrasound (CEUS) and hepatocyte growth factor (HGF)/c-Met signaling pathway with clinicopathological features and prognosis of patients with hepatocellular carcinoma (HCC). One hundred and eighteen patients pathologically diagnosed as primary HCC were selected. All HCC patients underwent CEUS examination before operation. HCC tissues and adjacent normal tissue specimens were obtained to detect the protein rates of HGF and c-Met expressions by immunohistochemistry. The mRNA expressions of HGF and c-Met were detected by quantitative real-time polymerase chase reaction assay. The microvessel density (MVD) was tested by CD34 immunohistochemistry. Compared with liver parenchyma, the HCC lesions had higher MVD, preoperative peak intensity (PI), area under the curve (AUC), lower preoperative time to peak (TTP), and washout time (WOT). Compared with adjacent normal tissues, the protein and mRNA expressions of HGF were reduced in HCC tissues, but the protein and mRNA expressions of c-Met and MVD were increased. The protein expressions of HGF and c-Met exhibited evident correlations with TNM stage, tumor size, vascular invasion, liver cirrhosis, and hepatitis B virus and hepatitis C virus infection of HCC patients. The tumor size and number, vascular invasion, the protein expressions of HGF and c-Met, and MVD were associated with the TTP, PI, WOT, and AUC of CEUS in HCC patients. The protein expressions of HGF and c-Met, MVD and preoperative PI revealed negative associations with the prognosis of HCC patients. In conclusion, quantitative parameters of CEUS and HGF/c-Met signaling pathway-related proteins may be helpful for early diagnosis and prognosis prediction of HCC patients.
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Affiliation(s)
| | | | - Lu Gao
- Department of Internal Medicine, The Hospital of Xi'an Jiao Tong University
| | - Wei Lu
- Department of Gastroenterology, Xi'an First Hospital
| | - Li-Tao Ruan
- Department of Ultrasound, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, People's Republic of China
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44
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Hu Y, Tang Z, Jiang B, Chen J, Fu Z. miR-198 functions as a tumor suppressor in breast cancer by targeting CUB domain-containing protein 1. Oncol Lett 2017; 13:1753-1760. [PMID: 28454320 DOI: 10.3892/ol.2017.5673] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2015] [Accepted: 08/05/2016] [Indexed: 12/25/2022] Open
Abstract
The molecular mechanisms underlying the dysregulation of microRNAs (miRs) have been previously documented in breast cancer. miR-198 has been reported to be deregulated in several human cancers. However, the detailed effects of miR-198 on breast cancer progression remain unclear. Using quantitative polymerase chain reaction analysis, we demonstrated in the present study that miR-198 was downregulated in breast cancer tissues and cell lines, and that downregulation of miR-198 was significantly correlated with lymph node metastasis. Functional studies revealed that miR-198 inhibited cell proliferation and migration and promoted cell adhesion in aggressive breast cancer cells in vitro. In addition, we observed that CUB domain-containing protein 1 (CDCP1) was a direct target of miR-198, and that knockdown of CDCP1 inhibited cell proliferation and migration, and promoted cell adhesion, which was similar to the effects of overexpression of miR-198. Taken together, we provide evidence to characterize the role of miR-198/CDCP1 interaction in breast cancer, which may be useful in breast cancer therapy.
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Affiliation(s)
- Yingbin Hu
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
| | - Ziyuan Tang
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
| | - Bonian Jiang
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
| | - Juying Chen
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
| | - Zhongpin Fu
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
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45
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Wu L, Bai X, Xie Y, Yang Z, Yang X, Lin J, Zhu C, Wang A, Zhang H, Miao R, Wu Y, Robson SC, Zhao Y, Sang X, Zhao H. MetastamiRs: A promising choice for antihepatocellular carcinoma nucleic acid drug development. Hepatol Res 2017; 47:80-94. [PMID: 27138942 DOI: 10.1111/hepr.12737] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 04/18/2016] [Accepted: 04/29/2016] [Indexed: 12/23/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide, which can be explained at least in part by its propensity towards metastasis and the limited efficacy of adjuvant therapy. MetastamiRs are miRNAs that promote or suppress migration and metastasis of cancer cells, and their functional status is significantly correlated with HCC prognosis. Unlike targeted therapy, metastamiRs have the potential to target multiple genes and signaling pathways and dramatically suppress cancer metastasis. In this review, we discuss the regulatory role of metastamiRs in the HCC invasion-metastasis cascade. Moreover, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis has shown that many extensively studied metastamiRs target several critical signaling pathways and these have remarkable therapeutic potential in HCC. The information reviewed here may assist in further anti-HCC miRNA drug screening and development.
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Affiliation(s)
- Liangcai Wu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Intelligent Information Processing, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China
| | - Xue Bai
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuan Xie
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhen Yang
- Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai, China
| | - Xiaobo Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianzhen Lin
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chengpei Zhu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Anqiang Wang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haohai Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ruoyu Miao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Liver Center and The Transplant Institute, Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline, Massachusetts, USA
| | - Yan Wu
- Liver Center and The Transplant Institute, Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline, Massachusetts, USA
| | - Simon C Robson
- Liver Center and The Transplant Institute, Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline, Massachusetts, USA
| | - Yi Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Intelligent Information Processing, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China
| | - Xinting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haitao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Center of Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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46
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Huang WT, Wang HL, Yang H, Ren FH, Luo YH, Huang CQ, Liang YY, Liang HW, Chen G, Dang YW. Lower expressed miR-198 and its potential targets in hepatocellular carcinoma: a clinicopathological and in silico study. Onco Targets Ther 2016; 9:5163-80. [PMID: 27578984 PMCID: PMC5001667 DOI: 10.2147/ott.s108828] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Purpose To investigate the clinicopathological value and potential roles of microRNA-198 (miR-198) in hepatocellular carcinoma (HCC). Methods Ninety-five formalin-fixed paraffin-embedded HCC and the para-cancerous liver tissues were gathered. Real-time reverse transcription quantitative polymerase chain reaction was applied to determine the miR-198 expression. The association between the miR-198 expression and clinicopathological features was examined. Meanwhile, potential target messenger RNAs of miR-198 in HCC were obtained from 14 miRNA prediction databases and natural language processing method, in which we pooled the genes related to the tumorigenesis and progression of HCC and classified them by their frequency. The selected target genes were finally analyzed in the Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway. Results miR-198 expression was significantly lower in HCC than that in adjacent noncancerous liver tissues (1.30±0.72 vs 2.01±0.58, P<0.001). Low miR-198 expression was also correlated to hepatitis C virus infection (r=−0.48, P<0.001), tumor capsular infiltration (r=−0.43, P<0.001), metastasis (r=−0.26, P<0.010), number of tumor nodes (r=−0.25, P=0.013), vaso-invasion (r=−0.24, P=0.017), and clinical tumor node metastasis stage (r=−0.23, P=0.024). Altogether, 1,048 genes were achieved by the concurrent prediction from at least four databases and natural language processing indicated 1,800 genes for HCC. Further, 127 overlapping targets were further proceeded with for pathway analysis. The most enriched Gene Ontology terms in the potential target messenger RNAs of miR-198 were cell motion, cell migration, cell motility, and regulation of cell proliferation in biological process; organelle lumen, membrane-enclosed lumen, and nuclear lumen in cellular component; and enzyme binding, protein domain-specific binding, and protein kinase activity in molecular function. Kyoto Encyclopedia of Genes and Genomes analysis showed that these target genes were obviously involved in focal adhesion and pathways in cancer. Conclusion Lower expression of miR-198 was related to several clinicopathological parameters in HCC patients. miR-198 might play a regulatory role through its target genes in the development of HCC.
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Affiliation(s)
| | | | - Hong Yang
- Department of Ultrasonography, First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
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Targeting oncomiRNAs and mimicking tumor suppressor miRNAs: Νew trends in the development of miRNA therapeutic strategies in oncology (Review). Int J Oncol 2016; 49:5-32. [PMID: 27175518 PMCID: PMC4902075 DOI: 10.3892/ijo.2016.3503] [Citation(s) in RCA: 186] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 04/29/2016] [Indexed: 12/16/2022] Open
Abstract
MicroRNA (miRNA or miR) therapeutics in cancer are based on targeting or mimicking miRNAs involved in cancer onset, progression, angiogenesis, epithelial-mesenchymal transition and metastasis. Several studies conclusively have demonstrated that miRNAs are deeply involved in tumor onset and progression, either behaving as tumor-promoting miRNAs (oncomiRNAs and metastamiRNAs) or as tumor suppressor miRNAs. This review focuses on the most promising examples potentially leading to the development of anticancer, miRNA-based therapeutic protocols. The inhibition of miRNA activity can be readily achieved by the use of miRNA inhibitors and oligomers, including RNA, DNA and DNA analogues (miRNA antisense therapy), small molecule inhibitors, miRNA sponges or through miRNA masking. On the contrary, the enhancement of miRNA function (miRNA replacement therapy) can be achieved by the use of modified miRNA mimetics, such as plasmid or lentiviral vectors carrying miRNA sequences. Combination strategies have been recently developed based on the observation that i) the combined administration of different antagomiR molecules induces greater antitumor effects and ii) some anti-miR molecules can sensitize drug-resistant tumor cell lines to therapeutic drugs. In this review, we discuss two additional issues: i) the combination of miRNA replacement therapy with drug administration and ii) the combination of antagomiR and miRNA replacement therapy. One of the solid results emerging from different independent studies is that miRNA replacement therapy can enhance the antitumor effects of the antitumor drugs. The second important conclusion of the reviewed studies is that the combination of anti-miRNA and miRNA replacement strategies may lead to excellent results, in terms of antitumor effects.
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48
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Zhang S, Zhao Y, Wang L. MicroRNA-198 inhibited tumorous behaviors of human osteosarcoma through directly targeting ROCK1. Biochem Biophys Res Commun 2016; 472:557-65. [PMID: 26970302 DOI: 10.1016/j.bbrc.2016.03.040] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Accepted: 03/09/2016] [Indexed: 10/22/2022]
Abstract
Osteosarcoma is an aggressive primary sarcoma of bone and occurs mainly in adolescents and young adults. The prognosis of OS remains poor, and most of them will die due to local relapse or metastases. The discovery of microRNAs provides a new possibility for the early diagnosis and treatment of OS. Thus, the aim of this study was to explore the expression and functions of microRNA-198 (miR-198) in osteosarcoma. The expression levels of miR-198 were determined by qRT-PCR in osteosarcoma tissues and cell lines. Cell proliferation assays, migration and invasion assays were adopted to investigate the effects of miR-198 on tumorous behaviors of osteosarcoma cells. The results showed that miR-198 expression levels were lower in osteosarcoma tissues and cell lines. In addition, low miR-198 expression levels were correlated with TNM stage and distant metastasis. After miR-198 mimics transfection, cell proliferation, migration and invasion were significantly suppressed in the osteosarcoma cells. Furthermore, ROCK1 was identified as a novel direct target of miR-198 in osteosarcoma. These findings suggested that miR-198 may act not only as a novel prognostic marker, but also as a potential target for molecular therapy of osteosarcoma.
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Affiliation(s)
- Shilian Zhang
- Department of Pediatrics, Affiliated Hospital of Weifang Medical University, China.
| | - Yuehua Zhao
- Department of Pediatrics, Affiliated Hospital of Weifang Medical University, China
| | - Lijie Wang
- Department of Pediatrics, Affiliated Hospital of Weifang Medical University, China
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49
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Mizuguchi Y, Takizawa T, Yoshida H, Uchida E. Dysregulated miRNA in progression of hepatocellular carcinoma: A systematic review. Hepatol Res 2016; 46:391-406. [PMID: 26490438 DOI: 10.1111/hepr.12606] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 10/13/2015] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most frequent cancer and the third cause of cancer-related mortality worldwide. The primary risk factor for HCC is liver cirrhosis secondary to persistent infection with hepatitis B virus or hepatitis C virus. Although a number of cellular phenomena and molecular events have been reported to facilitate tumor initiation, progression and metastasis, the exact etiology of HCC has not yet been fully uncovered. miRNA, a class of non-coding RNA, negatively regulate post-transcriptional processes that participate in crucial biological processes, including development, differentiation, apoptosis and proliferation. In the liver, specific miRNA can be negative regulators of gene expression. Recent studies have uncovered the contribution of miRNA to cancer pathogenesis as they can function as oncogenes or tumor suppressor genes. In addition, other studies have demonstrated their potential value in the clinical management of patients with HCC as some miRNA may be used as prognostic or diagnostic markers. In this review, we summarize the current knowledge about the roles of miRNA in the carcinogenesis and progression of HCC.
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Affiliation(s)
| | | | - Hiroshi Yoshida
- Department of Surgery, Nippon Medical School Hospital, Tokyo, Japan
| | - Eiji Uchida
- Department of Surgery, Nippon Medical School Hospital, Tokyo, Japan
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50
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Cui Z, Zheng X, Kong D. Decreased miR-198 expression and its prognostic significance in human gastric cancer. World J Surg Oncol 2016; 14:33. [PMID: 26852230 PMCID: PMC4744396 DOI: 10.1186/s12957-016-0784-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2015] [Accepted: 01/27/2016] [Indexed: 12/31/2022] Open
Abstract
Background MicroRNAs (miRNAs) have been proved to play important roles in the tumorigenesis and development of human gastric cancer (GC). Our study aims to investigate the expression and clinical significance of miR-198 in GC patients. Methods Quantitative real-time polymerase chain reaction (RT-PCR) was performed to evaluate miR-198 levels in 106 pairs of GC specimens and adjacent noncancerous tissues. Then, the associations of miR-198 expression with clinicopathological factors and patient’s survival were determined. Results The expression levels of miR-198 in GC tissues were significantly lower than those in corresponding noncancerous tissues (p < 0.01). Decreased miR-198 expression was significantly associated with larger tumor size, deeper invasion depth, positive lymph node metastasis, advanced tumor-node-metastasis (TNM) stage, and shorter overall survival. Moreover, multivariate regression analysis identified low miR-198 expression as an independent predictor of poor survival. Conclusions These findings suggested that miR-198 downregulation may be associated with progression of GC and that this miR may be an independent prognostic marker for GC patients.
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Affiliation(s)
- Zhigang Cui
- Department of Oncology, Tianjin Nankai Hospital, No.6 of Changjiang Road, Nankai District, Tianjin, 300100, People's Republic of China
| | - Xin Zheng
- Department of Oncology, Tianjin Nankai Hospital, No.6 of Changjiang Road, Nankai District, Tianjin, 300100, People's Republic of China
| | - Di Kong
- Department of Oncology, Tianjin Nankai Hospital, No.6 of Changjiang Road, Nankai District, Tianjin, 300100, People's Republic of China.
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