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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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Yang Y, Razak SRA, Ismail IS, Ma Y, Yunus MA. Molecular mechanisms of miR-192 in cancer: a biomarker and therapeutic target. Cancer Cell Int 2025; 25:94. [PMID: 40087755 PMCID: PMC11908092 DOI: 10.1186/s12935-025-03666-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 01/29/2025] [Indexed: 03/17/2025] Open
Abstract
Cancer remains a major global health challenge due to its rising prevalence and high mortality rates. The field of microRNAs (miRNAs) has made significant progress in the understanding of tumorigenesis and has broadened our knowledge of their targeting, especially in cancer therapy. miRNAs, a class of small non-coding RNAs, participate in post-transcriptional gene regulation by translational inhibition or mRNA degradation. Among these, microRNA-192 (miR-192) is located on human chromosome 11q13.1, and is highly correlated with the occurrence and development of various human cancers. Dysregulation of miR-192 has been extensively studied in various pathological processes, including tumorigenesis, making it a valuable biomarker for cancer diagnosis and prognosis. The functional role of miR-192 varies across cancer types, acting as either a tumor suppressor or as an oncogene through the modulation of multiple gene expressions and downstream signaling pathways. However, the roles of miR-192 in cancer appear inconsistent across types, with current research often focused on specific genes or pathways, limiting insight into its broader impact on cellular signaling networks. Therefore, this review aims to provide a comprehensive overview of miR-192 research. The paper reviews differences in miR-192 expression in cancer and systematically summarizes the role of miR-192 in cancers. The review further explores the complex roles of miR-192 in various pathological processes, emphasizing its regulatory pathways, interaction networks, and association with tumor progression. This review also illustrates the clinical application of miR-192 as a diagnostic and prognostic biomarker for non-invasive cancer detection, as it is consistently present in both serum and exosomes. A comprehensive summary and analysis of the relationship between miR-192 and various cancers may provide valuable insights, potentially guiding novel approaches in clinical diagnosis, therapeutic strategies, and foundational cancer research.
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Affiliation(s)
- Yang Yang
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Kepala Batas, Pulau Pinang, Malaysia
- School of Medical Technology, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
| | - Siti Razila Abdul Razak
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Kepala Batas, Pulau Pinang, Malaysia
| | - Ida Shazrina Ismail
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Kepala Batas, Pulau Pinang, Malaysia
| | - Yanxia Ma
- School of Medical Technology, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China.
| | - Muhammad Amir Yunus
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Kepala Batas, Pulau Pinang, Malaysia.
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Jeng LB, Chan WL, Teng CF. Independent prognostic significance of tissue and circulating microrna biomarkers in hepatocellular carcinoma. Discov Oncol 2025; 16:281. [PMID: 40056315 DOI: 10.1007/s12672-025-02043-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 03/04/2025] [Indexed: 03/10/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Although many therapeutic modalities have been established for treating HCC patients, the outcomes of patients remain unsatisfactory. Development of independent prognostic biomarkers is thus an important need to allow for early diagnosis and timely treatment. MicroRNAs (miRNAs) are the most studied class of small non-coding RNAs. It has been shown that miRNAs play essential roles in the multiple steps of HCC tumorigenesis and progression. Furthermore, the baseline expression levels of many miRNAs are altered in tumor tissues and blood circulation of HCC patients. Therefore, miRNAs have emerged as independent biomarkers for the prediction of HCC prognosis. This review provides a comprehensive literature-based summary of tissue and circulating miRNA biomarkers with independent prognostic significance in HCC.
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Affiliation(s)
- Long-Bin Jeng
- Organ Transplantation Center, China Medical University Hospital, Taichung, 404, Taiwan
- Department of Surgery, China Medical University Hospital, Taichung, 404, Taiwan
- Cell Therapy Center, China Medical University Hospital, Taichung, 404, Taiwan
| | - Wen-Ling Chan
- Department of Public Health, College of Public Health, China Medical University, Taichung, 404, Taiwan
- Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, 413, Taiwan
| | - Chiao-Fang Teng
- Organ Transplantation Center, China Medical University Hospital, Taichung, 404, Taiwan.
- Graduate Institute of Biomedical Sciences, China Medical University, No. 91, Hsueh-Shih Rd., Northern Dist., Taichung, 404, Taiwan.
- Master Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, 404, Taiwan.
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4
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Elshafie NO, Gribskov M, Lichti NI, Sayedahmed EE, Childress MO, Pires dos Santos A. MicroRNAs implicated in canine diffuse large B-cell lymphoma prognosis. FEBS Open Bio 2024; 14:1899-1913. [PMID: 39218619 PMCID: PMC11532975 DOI: 10.1002/2211-5463.13887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 07/16/2024] [Accepted: 08/14/2024] [Indexed: 09/04/2024] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin lymphoma (NHL) in domestic dogs, with many similarities to its human counterpart. The progression of the disease is rapid, and treatment must be initiated early to achieve cancer remission and extend life. This study examined the relationship between progression-free survival (PFS) and microRNA (miRNA) expression in dogs with DLBCL. miRNAs are small non-coding RNA molecules that typically regulate gene expression post-transcriptionally. They are involved in several pathophysiological processes, including the growth and progression of cancer. Based on the analysis of small RNA sequencing (sRNA-seq) data, we validated a group of miRNAs in lymph nodes from 44 DLBCL-affected dogs with known outcomes. We used quantitative PCR to quantify their expression and report a specific subset of miRNAs is associated with decreased PFS in dogs with DLBCL. The miR-192-5p and miR-16-5p expression were significantly downregulated in dogs with increased PFS. These results indicate that miRNA profiling may potentially identify dogs with DLBCL that will experience poor outcomes following treatment. Identifying specific miRNAs that correlate with the progression of canine DLBCL could aid the development of individualized treatment regimens for dogs.
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Affiliation(s)
- Nelly O. Elshafie
- Department of Comparative PathobiologyPurdue UniversityWest LafayetteINUSA
| | - Michael Gribskov
- Department of Biological SciencesPurdue UniversityWest LafayetteINUSA
| | | | | | - Michael O. Childress
- Department of Veterinary Clinical SciencesPurdue UniversityWest LafayetteINUSA
- Purdue Institute for Cancer ResearchPurdue UniversityWest LafayetteINUSA
| | - Andrea Pires dos Santos
- Department of Comparative PathobiologyPurdue UniversityWest LafayetteINUSA
- Department of Biological SciencesPurdue UniversityWest LafayetteINUSA
- Bindley Bioscience CenterPurdue UniversityWest LafayetteINUSA
- Department of Veterinary Clinical SciencesPurdue UniversityWest LafayetteINUSA
- Purdue Institute for Cancer ResearchPurdue UniversityWest LafayetteINUSA
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Shabangu CS, Su WH, Li CY, Yu ML, Dai CY, Huang JF, Chuang WL, Wang SC. Systematic integration of molecular and clinical approaches in HCV-induced hepatocellular carcinoma. J Transl Med 2024; 22:268. [PMID: 38475805 PMCID: PMC10935926 DOI: 10.1186/s12967-024-04925-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 01/23/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) play a crucial role in gene expression and regulation, with dysregulation of miRNA function linked to various diseases, including hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). There is still a gap in understanding the regulatory relationship between miRNAs and mRNAs in HCV-HCC. This study aimed to investigate the function and effects of persistent HCV-induced miRNA expression on gene regulation in HCC. METHODS MiRNA array data were used to identify differentially expressed miRNAs and their targets, and miRNAs were analyzed via DIANA for KEGG pathways, gene ontology (GO) functional enrichment, and Ingenuity Pathways Analysis (IPA) for hepatotoxicity, canonical pathways, associated network functions, and interactive networks. RESULTS Seventeen miRNAs in L-HCV and 9 miRNAs in S-HCV were differentially expressed, and 5 miRNAs in L-HCV and 5 miRNAs in S-HCV were significantly expressed in liver hepatocellular carcinoma (LIHC) tumors. Grouped miRNA survival analysis showed that L-HCV miRNAs were associated with survival in LIHC, and miRNA‒mRNA targets regulated viral carcinogenesis and cell cycle alteration through cancer pathways in LIHC. MiRNA-regulated RCN1 was suppressed through miRNA-oncogene interactions, and suppression of RCN1 inhibited invasion and migration in HCC. CONCLUSION Persistent HCV infection induced the expression of miRNAs that act as tumor suppressors by inhibiting oncogenes in HCC. RCN1 was suppressed while miRNAs were upregulated, demonstrating an inverse relationship. Therefore, hsa-miR-215-5p, hsa-miR-10b-5p, hsa-let-7a-5p and their target RCN1 may be ideal biomarkers for monitoring HCV-HCC progression.
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Affiliation(s)
- Ciniso Sylvester Shabangu
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Wen-Hsiu Su
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Chia-Yang Li
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Chia-Yen Dai
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Jee-Fu Huang
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Wan-Long Chuang
- Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- Hepatitis Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Shu-Chi Wang
- Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
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Salaheldin M, Aly H, Lau L, Afify S, El-Kassas M. Nonalcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma: The Next Threat after Viral Hepatitis. Diagnostics (Basel) 2023; 13:2631. [PMID: 37627890 PMCID: PMC10453181 DOI: 10.3390/diagnostics13162631] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 07/26/2023] [Accepted: 07/28/2023] [Indexed: 08/27/2023] Open
Abstract
For many years, we have faced the complications of viral hepatitis and alcohol-related liver diseases such as cirrhosis, decompensation, portal hypertension, and hepatocellular carcinoma (HCC). Recently, we have seen a dynamic change in the field of hepatology. With the significant achievements in eradicating the hepatitis C virus by direct-acting antiviral agents and the rising epidemic of obesity, diabetes mellitus, and metabolic syndrome, there is a paradigm shift in the leading cause of liver cirrhosis and cancer to nonalcoholic fatty liver disease (NAFLD). Current data highlight the rapidly rising incidence of NAFLD-related HCC worldwide and expose the unseen part of the iceberg. In this review, we aim to update knowledge about the pathogenesis of NAFLD-induced HCC, surveillance difficulties, and promising disease markers. Molecular biomarkers, for example, may become a promising cornerstone for risk-stratified surveillance, early detection, and treatment selection for NAFLD-related HCC. Physicians can offer personalized and tailor-made clinical decisions for this unique patient subgroup.
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Affiliation(s)
- Mohamed Salaheldin
- Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt; (M.S.); (H.A.)
| | - Heba Aly
- Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt; (M.S.); (H.A.)
| | - Louis Lau
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 518172, China;
| | - Shimaa Afify
- National Hepatology and Tropical Medicine Research Institute, Cairo 11796, Egypt
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo 11795, Egypt
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Rusu I, Pirlog R, Chiroi P, Nutu A, Puia VR, Fetti AC, Rusu DR, Berindan-Neagoe I, Al Hajjar N. The Implications of Noncoding RNAs in the Evolution and Progression of Nonalcoholic Fatty Liver Disease (NAFLD)-Related HCC. Int J Mol Sci 2022; 23:12370. [PMID: 36293225 PMCID: PMC9603983 DOI: 10.3390/ijms232012370] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/12/2022] [Accepted: 10/13/2022] [Indexed: 11/07/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver pathology worldwide. Meanwhile, liver cancer represents the sixth most common malignancy, with hepatocellular carcinoma (HCC) as the primary, most prevalent subtype. Due to the rising incidence of metabolic disorders, NAFLD has become one of the main contributing factors to HCC development. However, although NAFLD might account for about a fourth of HCC cases, there is currently a significant gap in HCC surveillance protocols regarding noncirrhotic NAFLD patients, so the majority of NAFLD-related HCC cases were diagnosed in late stages when survival chances are minimal. However, in the past decade, the focus in cancer genomics has shifted towards the noncoding part of the genome, especially on the microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), which have proved to be involved in the regulation of several malignant processes. This review aims to summarize the current knowledge regarding some of the main dysregulated, noncoding RNAs (ncRNAs) and their implications for NAFLD and HCC development. A central focus of the review is on miRNA and lncRNAs that can influence the progression of NAFLD towards HCC and how they can be used as potential screening tools and future therapeutic targets.
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Affiliation(s)
- Ioana Rusu
- Department of Pathology, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
| | - Radu Pirlog
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Paul Chiroi
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Andreea Nutu
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Vlad Radu Puia
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Alin Cornel Fetti
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Daniel Radu Rusu
- Department of Pathology, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Nadim Al Hajjar
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
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Saravanan R, Balasubramanian V, Swaroop Balamurugan SS, Ezhil I, Afnaan Z, John J, Sundaram S, Gouthaman S, Pakala SB, Rayala SK, Venkatraman G. Zinc transporter LIV1: A promising cell surface target for triple negative breast cancer. J Cell Physiol 2022; 237:4132-4156. [PMID: 36181695 DOI: 10.1002/jcp.30880] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 08/22/2022] [Accepted: 08/30/2022] [Indexed: 11/05/2022]
Abstract
Breast cancer is one of the leading causes contributing to the global cancer burden. The triple negative breast cancer (TNBC) molecular subtype accounts for the most aggressive type. Despite progression in therapeutic options and prognosis in breast cancer treatment options, there remains a high rate of distant relapse. With advancements in understanding the role of zinc and zinc carriers in the prognosis and treatment of the disease, the scope of precision treatment/targeted therapy has been expanded. Zinc levels and zinc transporters play a vital role in maintaining cellular homeostasis, tumor surveillance, apoptosis, and immune function. This review focuses on the zinc transporter, LIV1, as an essential target for breast cancer prognosis and emerging treatment options. Previous studies give an insight into the role of LIV1 in fulfilling the most important hallmarks of cancer such as apoptosis, metastasis, invasion, and evading the immune system. Normal tissue expression of LIV1 is limited. Higher expression of LIV1 has been linked to Epithelial-Mesenchymal Transition, histological grade of cancer, and early node metastasis. LIV1 was found to be one of the attractive targets in the therapeutic hunt for TNBCs. TNBCs are an immunogenic breast cancer subtype. As zinc transporters are known to serve as the metabolic gatekeepers of immune cells, this review bridges tumor infiltrating lymphocytes, TNBC and LIV1. In addition, the suitability of LIV1 as an antibody-drug conjugate (Seattle genetics [SGN]-LIV1A) target in TNBC, represents a promising strategy for patients. Early clinical trial results reveal that this novel agent reduces tumor burden by inducing mitotic arrest, immunomodulation, and immunogenic cell death, warranting further investigation of SGN-LIV1A in combination with immuno-oncology agents. Priming the patient's immune response in combination with SGN-LIV1A could eventually change the landscape for the TNBC patient population.
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Affiliation(s)
- Roshni Saravanan
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Vaishnavi Balasubramanian
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Srikanth Swamy Swaroop Balamurugan
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Inemai Ezhil
- Department of Biotechnology, Indian Institute of Technology-Madras, Chennai, Tamil Nadu, India
| | - Zeba Afnaan
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Jisha John
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Sandhya Sundaram
- Department of Pathology, Sri Ramachandra Medical College and Research Institute, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Shanmugasundaram Gouthaman
- Department of Surgical Oncology, Sri Ramachandra Medical College and Research Institute, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Suresh B Pakala
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
| | - Suresh Kumar Rayala
- Department of Biotechnology, Indian Institute of Technology-Madras, Chennai, Tamil Nadu, India
| | - Ganesh Venkatraman
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
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Serra M, Pal R, Puliga E, Sulas P, Cabras L, Cusano R, Giordano S, Perra A, Columbano A, Kowalik MA. mRNA-miRNA networks identify metabolic pathways associated to the anti-tumorigenic effect of thyroid hormone on preneoplastic nodules and hepatocellular carcinoma. Front Oncol 2022; 12:941552. [PMID: 36203462 PMCID: PMC9530455 DOI: 10.3389/fonc.2022.941552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 08/30/2022] [Indexed: 11/13/2022] Open
Abstract
Background Thyroid hormones (THs) inhibit hepatocellular carcinoma (HCC) through different mechanisms. However, whether microRNAs play a role in the antitumorigenic effect of THs remains unknown. Methods By next generation sequencing (NGS) we performed a comprehensive comparative miRNomic and transcriptomic analysis of rat hepatic preneoplastic lesions exposed or not to a short-term treatment with triiodothyronine (T3). The expression of the most deregulated miRs was also investigated in rat HCCs, and in human hepatoma cell lines, treated or not with T3. Results Among miRs down-regulated in preneoplastic nodules following T3, co-expression networks revealed those targeting thyroid hormone receptor-β (Thrβ) and deiodinase1, and Oxidative Phosphorylation. On the other hand, miRs targeting members of the Nrf2 Oxidative Pathway, Glycolysis, Pentose Phosphate Pathway and Proline biosynthesis – all involved in the metabolic reprogramming displayed by preneoplastic lesions– were up-regulated. Notably, while the expression of most miRs deregulated in preneoplastic lesions was not altered in HCC or in hepatoma cells, miR-182, a miR known to target Dio1 and mitochondrial complexes, was down-deregulated by T3 treatment at all stages of hepatocarcinogenesis and in hepatocarcinoma cell lines. In support to the possible critical role of miR-182 in hepatocarcinogenesis, exogenous expression of this miR significantly impaired the inhibitory effect of T3 on the clonogenic growth capacity of human HCC cells. Conclusions This work identified several miRNAs, so far never associated to T3. In addition, the precise definition of the miRNA-mRNA networks elicited by T3 treatment gained in this study may provide a better understanding of the key regulatory events underlying the inhibitory effect of T3 on HCC development. In this context, T3-induced down-regulation of miR-182 appears as a promising tool.
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Affiliation(s)
- Marina Serra
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Rajesh Pal
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Elisabetta Puliga
- Department of Oncology, University of Turin, Turin, Italy
- Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy
| | - Pia Sulas
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Lavinia Cabras
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Roberto Cusano
- Centro di Ricerca, Sviluppo e Studi Superiori in Sardegna (CRS4), Pula, Italy
| | - Silvia Giordano
- Department of Oncology, University of Turin, Turin, Italy
- Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy
| | - Andrea Perra
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Amedeo Columbano
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
- *Correspondence: Amedeo Columbano, ; Marta Anna Kowalik,
| | - Marta Anna Kowalik
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
- *Correspondence: Amedeo Columbano, ; Marta Anna Kowalik,
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10
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Panoramic view of microRNAs in regulating cancer stem cells. Essays Biochem 2022; 66:345-358. [PMID: 35996948 DOI: 10.1042/ebc20220007] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/05/2022] [Accepted: 08/08/2022] [Indexed: 12/17/2022]
Abstract
Cancer stem cells (CSCs) are a subgroup of tumor cells, possessing the abilities of self-renewal and generation of heterogeneous tumor cell lineages. They are believed to be responsible for tumor initiation, metastasis, as well as chemoresistance in human malignancies. MicroRNAs (miRNAs) are small noncoding RNAs that play essential roles in various cellular activities including CSC initiation and CSC-related properties. Mature miRNAs with ∼22 nucleotides in length are generated from primary miRNAs via its precursors by miRNA-processing machinery. Extensive studies have demonstrated that mature miRNAs modulate CSC initiation and stemness features by regulating multiple pathways and targeting stemness-related factors. Meanwhile, both miRNA precursors and miRNA-processing machinery can also affect CSC properties, unveiling a new insight into miRNA function. The present review summarizes the roles of mature miRNAs, miRNA precursors, and miRNA-processing machinery in regulating CSC properties with a specific focus on the related molecular mechanisms, and also outlines the potential application of miRNAs in cancer diagnosis, predicting prognosis, as well as clinical therapy.
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11
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Ashour H, Farghaly ME, Khowailed AA, Aboulhoda BE, Rashed LA, Elsebaie MM, Gaber SS. Modulation of miR-192/NF-κB/ TGF-β/ E-cadherin by thymoquinone protects against diethylnitrosamine /carbon tetrachloride hepatotoxicity. Physiol Int 2022. [PMID: 36001412 DOI: 10.1556/2060.2022.00163] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 02/26/2022] [Accepted: 05/16/2022] [Indexed: 02/18/2024]
Abstract
Scientific efforts have been made for a better understanding of the pathogenesis of hepatocellular carcinoma (HCC). We investigated the possible role of miR-192/nuclear factor-κB (NF-κB)/transforming growth factor-β (TGF-β)/E-cadherin in hepatic tumorigenesis. We expected a modulatory impact of thymoquinone. Thirty adult male rats were assigned into 3 groups (n = 10); (1) Control group. Group (2): Experimental HCC induced by intraperitoneal injection of diethylnitrosamine (DENA) followed by carbon tetrachloride (CCl4). Group (3): Thymoquinone 20 mg kg-1/oral supplementation starting from the model induction to the end of the 8th week. The HCC (DENA-CCL4) model was confirmed by elevated serum levels of alpha-fetoprotein and transaminases (ALT, AST) and by histopathological examination which denoted marked cellular atypia and features of neoplasia. Suppressed hepatic miR-192 and E-cadherin expression were detected in the HCC (DENA-CCL4) group accompanied by elevated tumor necrosis factor (TNF-α), interleukin (IL6)/NF-κB & TGF-β1. Thymoquinone treatment protected the rat livers from hepatic tumorigenesis. Thymoquinone diminished (P < 0.001) alpha-fetoprotein and improved ALT, AST. It preserved hepatic miR-192 and normal E-cadherin expression. Thymoquinone-treated rats showed abrogated TNF-α, IL6/NF-κB/TGF-β. Thymoquinone increased cell apoptosis markers Bax/Bcl2 and diminished cellular atypia. Pearson's correlations revealed positive association between miR-192 expression and E-cadherin and Bax/Bcl2 as well, and it was negatively correlated to alpha-fetoprotein, NF-κB and TGF-β and the cellular atypia score. In conclusion, thymoquinone protected the liver tissues through preserving miR-192 and E-cadherin and aborting NF-κB & TGF-β signaling. The current results highlight a new role for thymoquinone in preventing hepatic tumorigenesis.
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Affiliation(s)
- Hend Ashour
- 1 Department of Medical Physiology, Faculty of Medicine, King Khalid University, Abha, Saudi Arabia
- 2 Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Maha Eid Farghaly
- 3 Department of Medical Physiology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | | | - Basma Emad Aboulhoda
- 4 Department of Anatomy and Embryology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Laila Ahmed Rashed
- 5 Department of Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | - Safy Salah Gaber
- 3 Department of Medical Physiology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
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12
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Matuszyk J. MALAT1-miRNAs network regulate thymidylate synthase and affect 5FU-based chemotherapy. Mol Med 2022; 28:89. [PMID: 35922756 PMCID: PMC9351108 DOI: 10.1186/s10020-022-00516-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 07/22/2022] [Indexed: 12/12/2022] Open
Abstract
Background The active metabolite of 5-Fluorouracil (5FU), used in the treatment of several types of cancer, acts by inhibiting the thymidylate synthase encoded by the TYMS gene, which catalyzes the rate-limiting step in DNA replication. The major failure of 5FU-based cancer therapy is the development of drug resistance. High levels of TYMS-encoded protein in cancerous tissues are predictive of poor response to 5FU treatment. Expression of TYMS is regulated by various mechanisms, including involving non-coding RNAs, both miRNAs and long non-coding RNAs (lncRNAs). Aim To delineate the miRNAs and lncRNAs network regulating the level of TYMS-encoded protein. Main body Several miRNAs targeting TYMS mRNA have been identified in colon cancers, the levels of which can be regulated to varying degrees by lncRNAs. Due to their regulation by the MALAT1 lncRNA, these miRNAs can be divided into three groups: (1) miR-197-3p, miR-203a-3p, miR-375-3p which are downregulated by MALAT1 as confirmed experimentally and the levels of these miRNAs are actually reduced in colon and gastric cancers; (2) miR-140-3p, miR-330-3p that could potentially interact with MALAT1, but not yet supported by experimental results; (3) miR-192-5p, miR-215-5p whose seed sequences do not recognize complementary response elements within MALAT1. Considering the putative MALAT1-miRNAs interaction network, attention is drawn to the potential positive feedback loop causing increased expression of MALAT1 in colon cancer and hepatocellular carcinoma, where YAP1 acts as a transcriptional co-factor which, by binding to the TCF4 transcription factor/ β-catenin complex, may increase the activation of the MALAT1 gene whereas the MALAT1 lncRNA can inhibit miR-375-3p which in turn targets YAP1 mRNA. Conclusion The network of non-coding RNAs may reduce the sensitivity of cancer cells to 5FU treatment by upregulating the level of thymidylate synthase.
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Affiliation(s)
- Janusz Matuszyk
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 R. Weigla Street, 53-114, Wroclaw, Poland.
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13
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Liu FF, Pei Y. MicroRNA192 Promotes Metastasis and Invasion of Breast Cancer via Targeting Tensin1 and Enhancing Cell Division Control Protein 42 Homolog (CDC42) Expression. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.3068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
We aimed to dissect the biological impacts and mechanisms of MicroRNA192 in breast cancer metastasis and invasion. Tumor tissues from patients and breast cancer cells were used to measure miR-192 level via RT-PCR. The miR-192 mimics, miR-192 inhibitor, si-Tensin1 and corresponding negative
controls were transfected into cells followed by analysis of cell invasion by transwell assay and CDC42 level by western blot. Afterwards, a tumor transplantation model was established to assess the malignancy progression and migration. The human miR-192 accounted for approximately 14% of
those overexpressed miRNAs. Overexpression of miR-192 promoted malignant cell invasion, while knockdown of endogenous miR-192 significantly decreased cell invasion, which suggested that miR-192 could exert a promotive factor in the invasive characteristic of breast cancer cells in vitro.
In contrast to control group, tumor metastasis was significantly provoked in the miR-192 overexpression group. miR-192 directly targeted and suppressed the expression of Tensin1. miR-192 enhanced the malignant invasiveness by regulating Cdc42 and was corrected with correlation with the survival
of patients. High miR-192 level is related to the malignant invasiveness and metastatic behavior, as well as the poor prognosis of patients with breast cancer via activating Cdc42 and targeting Tensin1.
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Affiliation(s)
- Fang-Fang Liu
- Department of Thyroid and Breast Surgery, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huaian, Jiangsu, 223002, China
| | - Yin Pei
- Department of Nuclear Medicine, The First Hospital of Hebei Medicine University, Shijiazhuang, Hebei, 050000, China
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14
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Yi C, Yu AM. MicroRNAs in the Regulation of Solute Carrier Proteins Behind Xenobiotic and Nutrient Transport in Cells. Front Mol Biosci 2022; 9:893846. [PMID: 35755805 PMCID: PMC9220936 DOI: 10.3389/fmolb.2022.893846] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 05/02/2022] [Indexed: 11/16/2022] Open
Abstract
Altered metabolism, such as aerobic glycolysis or the Warburg effect, has been recognized as characteristics of tumor cells for almost a century. Since then, there is accumulating evidence to demonstrate the metabolic reprogramming of tumor cells, addiction to excessive uptake and metabolism of key nutrients, to support rapid proliferation and invasion under tumor microenvironment. The solute carrier (SLC) superfamily transporters are responsible for influx or efflux of a wide variety of xenobiotic and metabolites that are needed for the cells to function, as well as some medications. To meet the increased demand for nutrients and energy, SLC transporters are frequently dysregulated in cancer cells. The SLCs responsible for the transport of key nutrients for cancer metabolism and energetics, such as glucose and amino acids, are of particular interest for their roles in tumor progression and metastasis. Meanwhile, rewired metabolism is accompanied by the dysregulation of microRNAs (miRNAs or miRs) that are small, noncoding RNAs governing posttranscriptional gene regulation. Studies have shown that many miRNAs directly regulate the expression of specific SLC transporters in normal or diseased cells. Changes of SLC transporter expression and function can subsequently alter the uptake of nutrients or therapeutics. Given the important role for miRNAs in regulating disease progression, there is growing interest in developing miRNA-based therapies, beyond serving as potential diagnostic or prognostic biomarkers. In this article, we discuss how miRNAs regulate the expression of SLC transporters and highlight potential influence on the supply of essential nutrients for cell metabolism and drug exposure toward desired efficacy.
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Affiliation(s)
- Colleen Yi
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA, United States
| | - Ai-Ming Yu
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA, United States
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15
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Wan Z, Wang X. Role of SLC39A6 in the development and progression of liver cancer. Oncol Lett 2022; 23:77. [PMID: 35111246 PMCID: PMC8771636 DOI: 10.3892/ol.2022.13197] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 12/21/2021] [Indexed: 12/11/2022] Open
Abstract
Liver cancer is one of the most common malignant solid tumor types worldwide. The solute carrier (SLC)39A family is a main member of the SLC group of membrane transport proteins, which transfer zinc to the cytoplasm when cells are depleted of zinc; thus, it may provide a novel therapeutic target for human cancer. However, the prognostic value of SLC39A genes in patients with liver cancer has remained elusive. Therefore, the present study aimed to explore whether SLC39A family genes are associated with the survival rate of patients with liver cancer and to investigate the role of key genes of the SLC39A family in liver cancer. The mRNA expression of the SLC39A family in liver cancer was obtained from the UALCAN database. Survival curve analysis was performed to investigate the prognostic value of SLC39A family genes in the overall survival of patients with liver cancer. In addition to the bioinformatics analysis, SLC39A6 was knocked down in HepG2 and Hep3B cells to examine the effect on the proliferation, migration and invasion of liver cancer cells. The results suggested that SLC39A6 was significantly upregulated in liver cancer tissues compared with normal liver tissues. High expression of SLC39A6 was significantly associated with poor overall survival of patients with liver cancer. Furthermore, knockdown of SLC39A6 inhibited the proliferation, migration and invasion of liver cancer cells in vitro and in vivo. Collectively, the results of the present study suggested that SLC39A6 may be a promising prognostic biomarker for liver cancer and is associated with the proliferation, migration and invasion of liver cancer.
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Affiliation(s)
- Zhen Wan
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xuzhen Wang
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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16
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Wang X, Tang W, Lu Y, You J, Han Y, Zheng Y. Prognostic Significance of Alternative Splicing Genes in Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma. Int J Gen Med 2021; 14:7933-7949. [PMID: 34785939 PMCID: PMC8590485 DOI: 10.2147/ijgm.s335475] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 10/20/2021] [Indexed: 01/16/2023] Open
Abstract
Background Alternative splicing (AS) acts on many tumors and its relationship with cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) needs to be researched. Methods RNA sequencing data and clinical information of CESC cohorts were obtained from the Cancer Genome Atlas (TCGA) and SpliceSeq was used to analyze the splicing profile of mRNA in CESC. UpSetR displayed the intersections among AS events and univariate analysis chose survival-associated AS and splicing factor (SF) genes. Functional analysis was operated on Enrichr, STRING database and MCODE analysis were used to evaluate protein-protein interaction (PPI) information. LASSO and multivariate analysis constructed prognostic model and risk analysis of tumor infiltrating immune cells was also conducted. Results A total of 402 AS-generated genes were found to be associated with CESC prognosis. Functional analysis showed that Golgi to lysosome transport was enriched. PPI network suggested that UBA52 was most functional. Dendritic cells activated, dendritic cells resting, macrophages M0, mast cells resting, T cells CD4 memory activated and T cells CD8 were most correlative with the risk score. Conclusion SFs and AS events can directly or indirectly affect the prognosis of CESC patients and this study identified SNRPA and CELF2 as two CESC-engaged SFs.
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Affiliation(s)
- Xiaoyu Wang
- Department of Obstetrics and Gynecology, Nantong First People's Hospital, Nantong, Jiangsu, 226001, People's Republic of China
| | - Weichun Tang
- Department of Obstetrics and Gynecology, Nantong First People's Hospital, Nantong, Jiangsu, 226001, People's Republic of China
| | - Yilin Lu
- Department of Obstetrics and Gynecology, Nantong First People's Hospital, Nantong, Jiangsu, 226001, People's Republic of China
| | - Jun You
- Department of Obstetrics and Gynecology, Nantong First People's Hospital, Nantong, Jiangsu, 226001, People's Republic of China
| | - Yun Han
- Department of Obstetrics and Gynecology, Nantong First People's Hospital, Nantong, Jiangsu, 226001, People's Republic of China
| | - Yanli Zheng
- Department of Obstetrics and Gynecology, Nantong First People's Hospital, Nantong, Jiangsu, 226001, People's Republic of China
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17
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Liu L, Wang P, Wang YS, Zhang YN, Li C, Yang ZY, Liu ZH, Zhan TZ, Xu J, Xia CM. MiR-130a-3p Alleviates Liver Fibrosis by Suppressing HSCs Activation and Skewing Macrophage to Ly6C lo Phenotype. Front Immunol 2021; 12:696069. [PMID: 34421906 PMCID: PMC8375151 DOI: 10.3389/fimmu.2021.696069] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 07/15/2021] [Indexed: 11/18/2022] Open
Abstract
Emerging evidences have highlighted the crucial role of microRNAs (miRNAs) in the liver cirrhosis, but the relationship between miR-130a-3p and liver cirrhosis is not entirely clear. As we all know, schistosomiasis, as one of the zoonoses, can lead to liver cirrhosis when it advances. In this study, we investigated the biological functions of miR-130a-3p on the liver fibrosis of schistosomiasis in vivo and in vitro. The mice infected with Schistosoma japonicum (S. japonicum) were treated with lentivirus vector (LV)-miR-130a-3p by hydrodynamic injection through the tail vein. Our findings showed significantly decreased expression of miR-130a-3p both in the serum of patients with cirrhosis and in the liver of mice infected with S. japonicum. The results showed that LV-miR-130a-3p could effectively enter into the liver and alleviate liver granulomatous inflammation and collagen deposition. Simultaneously, LV-miR-130a-3p-promoted macrophages presented the Ly6Clo phenotype, concomitant with the decreased expression of the tissue inhibitor of metalloproteinases (TIMP) 1, and increased the expression of matrix metalloproteinase (MMP) 2, which contributed to the dissolution of collagen. Furthermore, overexpression of miR-130a-3p not only inhibited the activation and proliferation of hepatic stellate cells (HSCs) but also induced the apoptosis of HSCs. In addition, we also confirmed that miR-130a-3p enables to bind with mitogen-activated protein kinase (MAPK) 1 and transforming growth factor-beta receptors (TGFBR) 1 and TGFBR2 genes and inhibit the expressions of these genes. Our findings suggested that miR-130a-3p might represent as the potential candidate biomarker and therapeutic target for the prognosis identification and treatment of schistosomiasis liver fibrosis.
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Affiliation(s)
- Lei Liu
- Department of Parasitology, Medical College of Soochow University, Suzhou, China
| | - Peng Wang
- Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Yun-Sheng Wang
- Department of Endocrinology, Second People’s Hospital of Hefei, Anhui, China
| | - Ya-Nan Zhang
- Department of Parasitology, Medical College of Soochow University, Suzhou, China
| | - Chen Li
- Department of Parasitology, Medical College of Soochow University, Suzhou, China
| | - Zi-Yin Yang
- Department of Parasitology, Medical College of Soochow University, Suzhou, China
| | - Zi-Hao Liu
- Department of Parasitology, Medical College of Soochow University, Suzhou, China
| | - Ting-Zheng Zhan
- Department of Parasitology, Guangxi Medical University, Nanning, China
| | - Jing Xu
- Department of Parasitology, Medical College of Soochow University, Suzhou, China
| | - Chao-Ming Xia
- Department of Parasitology, Medical College of Soochow University, Suzhou, China
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18
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Vajen B, Greiwe L, Schäffer V, Eilers M, Huge N, Stalke A, Schlegelberger B, Illig T, Skawran B. MicroRNA-192-5p inhibits migration of triple negative breast cancer cells and directly regulates Rho GTPase activating protein 19. Genes Chromosomes Cancer 2021; 60:733-742. [PMID: 34296808 DOI: 10.1002/gcc.22982] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 07/05/2021] [Accepted: 07/08/2021] [Indexed: 01/10/2023] Open
Abstract
Among the different breast cancer subtypes, triple-negative breast cancer (TNBC) is associated with a poor prognosis, low survival rates, and high expression of histone deacetylases. Treatment with histone deacetylase inhibitor trichostatin A (TSA) leads to an increased expression of potential tumor-suppressive miRNAs. Characterization of these miRNAs can help to find new molecular targets for treatment of TNBC. We identified differentially expressed miRNAs by microarray analyses after treatment with TSA in the TNBC cell lines HCC38, HCC1395, and HCC1935. The gene locus of hsa-miRNA-192-5p (miR-192) and hsa-miR-194-2 (miR-194-2) with its host gene, long noncoding RNA miR-194-2HG, has been linked to inhibition of migration in different tumor types. Therefore, we examined tumor-relevant functional effects using WST-1-based proliferation, capsase-3/7-based apoptosis, and trans-well migration assays after transfection with miRNA mimics or specific siRNAs. We demonstrated the tumor-suppressive capacity of miR-192 in TNBC cells, which was exerted through inhibition of proliferation, induction of apoptosis, and reduction of migration. Gene expression and bioinformatics analyses of TNBC cell lines transfected with miR-192 mimics, identified a number of genes involved in migration including the Rho GTPase Activating Protein ARHGAP19. Through RNA immunoprecipitation we demonstrated the direct binding of miR-192 and ARHGAP19. Downregulation of ARHGAP19 expression by either miR-192 or siRNA inhibited migration of TNBC cells significantly. Our findings demonstrate that overexpression of epigenetically deregulated miR-192 decreases proliferation, promotes apoptosis, and inhibits migration of TNBC cell lines.
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Affiliation(s)
- Beate Vajen
- Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Luisa Greiwe
- Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Vera Schäffer
- Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Marlies Eilers
- Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Nicole Huge
- Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Amelie Stalke
- Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | | | - Thomas Illig
- Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Britta Skawran
- Department of Human Genetics, Hannover Medical School, Hannover, Germany
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HCV Proteins Modulate the Host Cell miRNA Expression Contributing to Hepatitis C Pathogenesis and Hepatocellular Carcinoma Development. Cancers (Basel) 2021; 13:cancers13102485. [PMID: 34069740 PMCID: PMC8161081 DOI: 10.3390/cancers13102485] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/12/2021] [Accepted: 05/17/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary According to the last estimate by the World Health Organization (WHO), more than 71 million individuals have chronic hepatitis C worldwide. The persistence of HCV infection leads to chronic hepatitis, which can evolve into liver cirrhosis and ultimately into hepatocellular carcinoma (HCC). Although the pathogenic mechanisms are not fully understood, it is well established that an interplay between host cell factors, including microRNAs (miRNA), and viral components exist in all the phases of the viral infection and replication. Those interactions establish a complex equilibrium between host cells and HCV and participate in multiple mechanisms characterizing hepatitis C pathogenesis. The present review aims to describe the role of HCV structural and non-structural proteins in the modulation of cellular miRNA during HCV infection and pathogenesis. Abstract Hepatitis C virus (HCV) genome encodes for one long polyprotein that is processed by cellular and viral proteases to generate 10 polypeptides. The viral structural proteins include the core protein, and the envelope glycoproteins E1 and E2, present at the surface of HCV particles. Non-structural (NS) proteins consist of NS1, NS2, NS3, NS4A, NS4B, NS5a, and NS5b and have a variable function in HCV RNA replication and particle assembly. Recent findings evidenced the capacity of HCV virus to modulate host cell factors to create a favorable environment for replication. Indeed, increasing evidence has indicated that the presence of HCV is significantly associated with aberrant miRNA expression in host cells, and HCV structural and non-structural proteins may be responsible for these alterations. In this review, we summarize the recent findings on the role of HCV structural and non-structural proteins in the modulation of host cell miRNAs, with a focus on the molecular mechanisms responsible for the cell re-programming involved in viral replication, immune system escape, as well as the oncogenic process. In this regard, structural and non-structural proteins have been shown to modulate the expression of several onco-miRNAs or tumor suppressor miRNAs.
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Wang J, Yin G, Bian H, Yang J, Zhou P, Yan K, Liu C, Chen P, Zhu J, Li Z, Xue T. LncRNA XIST upregulates TRIM25 via negatively regulating miR-192 in hepatitis B virus-related hepatocellular carcinoma. Mol Med 2021; 27:41. [PMID: 33858324 PMCID: PMC8050905 DOI: 10.1186/s10020-021-00278-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 02/03/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Long non-coding RNA (lncRNA) XIST has been implicated in the progression of a variety of tumor diseases. The purpose of this study was to explore the molecular role of lncRNA XIST in human hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). METHODS The expression levels of lncRNA XIST, miR-192 and TRIM25 in HBV-related HCC tissues and HepG2.2.15 cells were detected by qRT-PCR. Biological information and luciferin gene reporter assay were performed to detect the interaction among lncRNA XIST, miR-192 and TRIM25. CCk-8 assay, wound healing assay and colony formation assay were conducted to detect the proliferation and migration ability of HepG2.2.15 cells. RESULTS qRT-PCR results showed that the expression levels of lncRNA XIST were remarkably increased in HBV-related HCC tissues and HepG2.2.15 cells. In addition, miR-192 was a direct target gene of lncRNA XIST, and the expression of miR-192 and lncRNA XIST were negatively correlated. Moreover, overexpression of miR-192 observably inhibited the proliferation and migration of HCC cells, while overexpression of lncRNA XIST showed an opposite effect. Furthermore, TRIM25 was a direct target of miR-192, and lncRNA XIST could up-regulate the expression of TRIM25 by targeting miR-192. CONCLUSION LncRNA XIST could up-regulate the expression of TRIM25 by targeting and binding to miR-192, thus accelerating the occurrence and development of HCC.
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Affiliation(s)
- Jiancheng Wang
- The People's Hospital of Lianshui County, Huai'an City, 223400, Jiangsu Province, People's Republic of China
| | - Gang Yin
- Department of Intervention, The Second People's Hospital of Huai'an City, Huai'an City, 223002, Jiangsu Province, People's Republic of China
| | - Hu Bian
- Department of Pain and Intervention, Huaiyin Hospital of Huai'an City, Huai'an City, 223300, Jiangsu Province, People's Republic of China
| | - Jiangli Yang
- Department of Interventional Radiology, Huaian Hospital of Huai'an City, No. 161 Zhenhuailou East Road, Huai'an City, 223200, Jiangsu Province, People's Republic of China
| | - Pengcheng Zhou
- Department of Interventional Radiology, Huaian Hospital of Huai'an City, No. 161 Zhenhuailou East Road, Huai'an City, 223200, Jiangsu Province, People's Republic of China
| | - Kai Yan
- Department of Interventional Radiology, Huaian Hospital of Huai'an City, No. 161 Zhenhuailou East Road, Huai'an City, 223200, Jiangsu Province, People's Republic of China
| | - Cheng Liu
- Department of Interventional Radiology, Huaian Hospital of Huai'an City, No. 161 Zhenhuailou East Road, Huai'an City, 223200, Jiangsu Province, People's Republic of China
| | - Pei Chen
- Department of Interventional Radiology, Huaian Hospital of Huai'an City, No. 161 Zhenhuailou East Road, Huai'an City, 223200, Jiangsu Province, People's Republic of China
| | - Jun Zhu
- The Third People's Hospital of Yancheng City, No. 75 Juchang Road, Yancheng City, 224001, Jiangsu Province, People's Republic of China
| | - Zhi Li
- Department of Interventional Radiology, First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Soochow City, 215006, Jiangsu Province, People's Republic of China
| | - Tongqing Xue
- Department of Interventional Radiology, Huaian Hospital of Huai'an City, No. 161 Zhenhuailou East Road, Huai'an City, 223200, Jiangsu Province, People's Republic of China.
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Cao QG, Guo Q, Bai J, Dong Y, Zhang XH, Hong WL. The apoptosis mechanisms of HepG2 cells induced by bitter melon seed. J Food Biochem 2021; 45:e13683. [PMID: 33844303 DOI: 10.1111/jfbc.13683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 02/02/2021] [Accepted: 02/02/2021] [Indexed: 11/30/2022]
Abstract
Liver cancer is one of the leading causes of cancer-related deaths in the world. Bitter melon seed (BMS) is well known for anti-inflammatory and anticancer properties. MicroRNA-421 (miR-421) is considered as a regulator of cancer initiation, tumor metastasis, and progression, interfering with transcription of the mRNAs responsible for the cancer pathogenesis. HepG2 cells were treated with BMS water extract (BMSW) for 24 hr, and the IC50 was 586.27 ± 0.07 µg/ml. The ROS, mitochondrial membrane potential, the protein expression, and the nuclear fragmentation after the treatment of BMSW were respectively detected. The increase of ROS resulted in the decrease of mitochondrial membrane potential, which induced the apoptosis of cells subsequently. BMSW inhibited the proliferation of HepG2 cells by blocking cell cycle in the S phase and influenced the nuclei and the expression of protein, leading to cellular laxity and apoptosis. The expression level of miR-421 in HepG2 was distinctly down-regulated by 13.74 fold with 600 µg/ml of BMSW. Comprehensive microarray and RT-PCR analysis identified six putative target genes of miR-421 (GADD45B, DUSP6, DUSP3, DUSP10, CASP3, and CAPN2). The relationships of DUSP6, CASP3, and miR-421 were further confirmed by miR-421 mimics/inhibitor transfection by RT-PCR and western blot. The CASP3 was identified as target gene of miR-421. BMSW induced the apoptosis of HepG2 cell by regulating miR-421 and CASP3. PRACTICAL APPLICATIONS: Hepatocellular carcinoma (HCC) is a malignant tumour with the fourth highest mortality rate in the world. Bitter melon seed (BMS) as edible and medical food has significant anticancer activity. Our study indicated the anticancer mechanisms of BMS and provided the scientific basis for the application of BMS in healthy or novel functional foods. BMS can be used as dietary supplements or nutritional fortifiers to improve the survival status of patients with liver cancer due to safety and effectiveness.
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Affiliation(s)
- Qing-Guo Cao
- Department of College of Tea and Food Science and Technology, Jiangsu Vocational College of Agriculture and Forestry, Zhenjiang, China
| | - Qin Guo
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China
| | - Jie Bai
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China
| | - Ying Dong
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China
| | - Xiao-Hua Zhang
- Department of College of Tea and Food Science and Technology, Jiangsu Vocational College of Agriculture and Forestry, Zhenjiang, China
| | - Wen-Long Hong
- Department of College of Tea and Food Science and Technology, Jiangsu Vocational College of Agriculture and Forestry, Zhenjiang, China
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22
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Geh D, Anstee QM, Reeves HL. NAFLD-Associated HCC: Progress and Opportunities. J Hepatocell Carcinoma 2021; 8:223-239. [PMID: 33854987 PMCID: PMC8041650 DOI: 10.2147/jhc.s272213] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 03/08/2021] [Indexed: 12/13/2022] Open
Abstract
Due to an increase in the obesity-associated metabolic syndrome of epidemic proportions, nonalcoholic fatty liver disease (NAFLD) is becoming a leading cause of hepatocellular carcinoma (HCC) in western countries. This presents added challenges, as NAFLD-associated HCC tends to present at an advanced stage in older patients with co-morbidities. Their prognosis is generally poor with the benefits of standard therapies less certain. The pathogenesis of NAFLD-associated HCC is multifactorial and not well understood, although the risk of HCC developing undoubtedly increases as NAFLD progresses to steatohepatitis and cirrhosis. Recent advances in our understanding of the drivers of NAFLD and HCC will hopefully lead to the development of clinically relevant biomarkers, tools and strategies to aid the identification of high-risk patients, inform preventive measures, and introduction of better tolerated targeted therapies. Lifestyle modification and chemoprevention with drugs such as anti-platelets, statins and anti-diabetics are being evaluated for HCC prevention. The landmark IMBrave150 study introducing the combination of atezolizumab and bevacizumab has recently transformed the landscape of systemic therapies in HCC, with follow-up analyses and real-world data for patients with NAFLD-associated HCC eagerly anticipated. While responses may vary in ways not yet appreciated, the rate of discovery and progress suggests imminent change and opportunities.
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Affiliation(s)
- Daniel Geh
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Quentin M Anstee
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.,The Liver Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
| | - Helen L Reeves
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.,The Liver Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.,Hepatopancreatobiliary Multidisciplinary Team, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
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23
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Wang T, Li W, Li H, Li W. Dysregulation of exosomal miR-192 and miR-194 expression in lung adenocarcinoma patients. Saudi J Biol Sci 2021; 28:1561-1568. [PMID: 33732041 PMCID: PMC7938118 DOI: 10.1016/j.sjbs.2021.01.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 01/06/2021] [Accepted: 01/07/2021] [Indexed: 12/25/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is the main reason of cancer linked mortality and around 80% of cases diagnosed in advanced stage. Therefore current study designed to evaluate the deregulation of miRNA-194 and miRNA-192 in different body fluid of Non small cell lung cancer participants. Present study recruited newly diagnosed histopathologically confirmed. It was observed that the 40% NSCLC participants showed elevated miR-194 expression and 60% NSCLC participants showed reduced miR-194 expression in serum sample while in Bronchial wash, only 20% NSCLC participants showed elevated miR-194 expression while 80% showed reduced miR-194 expression (p = 0.003). It was found that the 54% NSCLC participants showed elevated miR-192 expression and 55% NSCLC participants showed reduced miR-192 expression in serum sample while In Bronchial wash sample, only 25% NSCLC participants showed high miR-192 expression while 75% showed low miR-192 expression (P = 0.0004). Expression of miR-194 was significantly associated with TNM stages (p < 0.0001, p < 0.0001), distant organ metastases (p < 0.0001, p < 0.0001), pathological grade (p = 0.0009, p = 0.0005) among serum sample and bronchial wash sample. Same observation was found with expression of miR-192 and it was significantly associated with TNM stages (p < 0.0001, p < 0.0001), distant organ metastases (p < 0.0001, p < 0.0001), pathological grade (p = 0.006, p = 0.001) among serum sample and bronchial wash sample. It was observed that the NSCLC participants who had high serum based miR-194 expression showed 22 months of overall median survival while low expression of serum based miR-194 expression showed 18 months of overall median survival. Present study suggests that decreased expression of miR-194 and miR-192 was significantly associated with different clinical features of NSCLC cases. However, significantly higher number of NSCLC cases showed low expression of miR-194 and miR-192 in bronchial lavage sample. Decreased poor overall survival was found to be associated with bronchial wash sample with respect to low miR-194 and miR-192 expression while NSCLC participants showed better overall survival with high miR-194 and miR-192 expression. This suggested decreased expression of miR-192 and miR-194 expression could be the potential prognostic marker among NSCLC participants.
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Affiliation(s)
- Tongfei Wang
- Department of Oncology, Xi’an No. 3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, Shaanxi 710018, China
| | - Wei Li
- Department of Orthopedics, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710038, China
| | - Haitao Li
- Department of Oncology, Xi’an No. 3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, Shaanxi 710018, China
| | - Weina Li
- Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi’an, Shaanxi 710032, China
- Corresponding author.
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24
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Solute carriers as potential oncodrivers or suppressors: their key functions in malignant tumor formation. Drug Discov Today 2021; 26:1689-1701. [PMID: 33737072 DOI: 10.1016/j.drudis.2021.03.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 02/15/2021] [Accepted: 03/07/2021] [Indexed: 01/17/2023]
Abstract
Solute carrier (SLC) transporters are primarily known for their function in the transportation of various exogenous/endogenous substances via influx/efflux mechanisms. In addition to their diverse role in several tumor-modulating functions, such as proliferation, migration, angiogenesis, epithelial-mesenchymal transition (EMT), epigenetic modification, chemoresistance, immunoregulation, and oncometabolism, influx/efflux-independent contributions of SLCs in the activation of various signaling network cascades that might drive metastatic tumor formation have also been uncovered. Disappointingly, even after two decades and the discovery of >450 SLCs, many of their members remain orphans in terms of cancer pathogenesis. In this review, we summarize the current understanding of the tumor-modulating functions, mechanisms, and complexity of SLCs, as well as their potential as targets for cancer therapy.
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25
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Diagnostic and Prognostic Role of miR-192 in Different Cancers: A Systematic Review and Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:8851035. [PMID: 33614788 PMCID: PMC7878092 DOI: 10.1155/2021/8851035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 12/17/2020] [Accepted: 01/15/2021] [Indexed: 12/18/2022]
Abstract
Introduction It has been shown that miR-192 is abnormally expressed in a variety of cancer types and participates in different kinds of signaling pathways. The role of miR-192 in the diagnosis and prognosis of cancer has not been verified. This article is aimed at exploring the diagnostic and prognostic value of miR-192 through a systematic review and meta-analysis. Methods A systematic search was performed through PubMed, Embase, Web of Science, and Cochrane Library databases up to June 16, 2020. A total of 16 studies were enrolled in the meta-analyses, of which 11 articles were used for diagnostic meta-analysis and 5 articles were used for prognostic meta-analysis. The values of sensitivity and specificity using miR-192 expression as a diagnostic tool were pooled in the diagnostic meta-analysis. The hazard ratios (HRs) of overall survival (OS) with 95 confidence intervals (CIs) were extracted from the studies, and pooled HRs were evaluated in the prognostic meta-analysis. Eleven studies including 667 cancer patients and 514 controls met the eligibility criteria for the diagnostic meta-analysis. Five studies including 166 patients with high miR-192 expression and 236 patients with low miR-192 expression met the eligibility criteria for the prognostic meta-analysis. Results The overall diagnostic accuracy was as follows: sensitivity 0.79 (95%CI = 0.75-0.82), specificity 0.74 (95%CI = 0.64-0.82), positive likelihood ratio 3.03 (95%CI = 2.11-4.34), negative likelihood ratio 0.29 (95%CI = 0.23-0.37), diagnostic odds ratio 10.50 (95%CI = 5.89-18.73), and area under the curve ratio (AUC) 0.82 (95%CI = 0.78-0.85). The overall prognostic analysis showed that high expression of miR-192 in patients was associated with positive survival (HR = 0.62, 95%CI : 0.41-0.93, p = 0.020). Conclusion Our results revealed that miR-192 was a potential biomarker with good sensitivity and specificity in cancers. Moreover, highly expressed miR-192 predicted a good prognosis for patients.
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26
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López-Riera M, Conde I, Castell JV, Jover R. A Novel MicroRNA Signature for Cholestatic Drugs in Human Hepatocytes and Its Translation into Novel Circulating Biomarkers for Drug-Induced Liver Injury Patients. Toxicol Sci 2020; 173:229-243. [PMID: 31198949 DOI: 10.1093/toxsci/kfz138] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Drug-induced liver injury (DILI) diagnosis and classification (hepatocellular, cholestatic, and mixed) relies on traditional clinical biomarkers (eg ALT and ALP), despite limitations such as extrahepatic interferences, narrow dynamic ranges, and low mechanistic value. microRNAs may be very useful for complementing traditional DILI biomarkers but most studies in this direction have considered only paracetamol poisoning. Thus the value of microRNAs (miRNAs) as biomarkers for idiosyncratic DILI has not yet been demonstrated. In this study, we first examined the effect of model cholestatic drugs on the human hepatocyte miRNome by RNAseq and RT-qPCR. Results demonstrated that chlorpromazine, cyclosporin A, and ANIT induced (miR-21-3p, -21-5p, -22-3p, -27a-5p, -1260b, -34a-5p, and -98-5p) and repressed (-122-5p, -192-5p, -30c-5p, -424-5p, and -16-5p) specific miRNAs in sandwich-cultured upcyte hepatocytes. However, no common signature was found for cholestatic drugs. Next we investigated the levels of these miRNA in human serum and found that most were also significantly altered in cholestatic/mixed DILI patients upon hospital/ambulatory admission. However, miR-122-5p, -192-5p, -34a-5p, and -22-3p demonstrated a much more significant induction in patients with hepatocellular DILI, thus revealing better specificity for hepatocellular damage. Time-course analyses demonstrated that -1260b and -146 had a very similar profile to ALP, but with wider dynamic ranges, while -16-5p and -451a showed a negative correlation. Conversely, -122-5p and -192-5p correlated with ALT but with wider dynamic ranges and faster recoveries. Finally, the 122/451a and 122/16 ratios showed excellent prediction performances in both the study [area under the receiver operating characteristic curve (AUROC) >0.93] and the validation cohort (AUROC > 0.82), and can, therefore, be postulated for the first time as circulating miRNA biomarkers for idiosyncratic DILI.
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Affiliation(s)
- Mireia López-Riera
- *Unidad Mixta en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain
| | - Isabel Conde
- *Unidad Mixta en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain.,Medicina Digestiva, Sección Hepatología, Hospital La Fe, 46026 Valencia, Spain
| | - José V Castell
- *Unidad Mixta en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain.,Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
| | - Ramiro Jover
- *Unidad Mixta en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain.,Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
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27
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Gu Y, Ji F, Liu N, Zhao Y, Wei X, Hu S, Jia W, Wang XW, Budhu A, Ji J, Zhao B, Roessler S, Zheng X, Ji J. Loss of miR-192-5p initiates a hyperglycolysis and stemness positive feedback in hepatocellular carcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:268. [PMID: 33256802 PMCID: PMC7708108 DOI: 10.1186/s13046-020-01785-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 11/20/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Emerging studies revealed that cancer stem cells (CSCs) possessed peculiar metabolic properties, which however remained largely unknown in hepatocellular carcinoma (HCC). Genetic silencing of liver-abundant miR-192-5p was a key feature for multiple groups of CSC-positive HCCs. We thus aimed to investigate essential metabolic features of hepatic CSCs via using HCCs with miR-192-5p silencing as a model. METHODS Datasets from two independent HCC cohorts were used. Data integration analyses of miR-192-5p with metabolome and mRNA transcriptome data in HCC Cohort 1 were performed to investigate miR-192-5p related metabolic features, which was further validated in Cohort 2. Cellular and molecular assays were performed to examine whether and how miR-192-5p regulated the identified metabolic features. Co-culture systems consisting of HCC cells and LX2 (human hepatic stellate cell line) or THP1 (human monocyte cell line) were established to explore effects of the identified metabolic properties on stemness features of HCC cells via interacting with co-cultured non-tumor cells. RESULTS High levels of glycolysis-related metabolites and genes were present in HCCs with low miR-192-5p and CSC-positive HCCs in two independent HCC cohorts. miR-192-5p knockout cells displayed CSC features and miR-192-5p loss led to an enhanced glycolytic phenotype via upregulating three bona fide targets, GLUT1 and PFKFB3 (two glycolytic enzymes) and c-Myc (regulating glycolytic genes' expression). Meanwhile, c-Myc suppressed miR-192-5p transcription, ensuring a low-miR-192-5p/high-c-Myc loop to maintain hyperglycolysis. Moreover, over-produced lactic acid from hyperglycolytic HCC cells stimulated the ERK phosphorylation of co-cultured LX2 and THP1 non-tumor cells partially via NDRG3 and MCT1, which in turn promoted cell malignancy and stemness of HCC cells. Consistently, HCC patients with low level of miR-192-5p in their tumor tissues and high level of NDRG3 or MCT1 in their non-tumor tissues had the shortest overall survival. CONCLUSIONS In CSC-positive HCCs, miR-192-5p loss enhanced glycolysis and over produced lactate might further increase HCC malignant features via interacting with environmental non-tumor cells.
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Affiliation(s)
- Yuanzhuo Gu
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang Province, China
| | - Fubo Ji
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang Province, China
| | - Niya Liu
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang Province, China
| | - Yongzhi Zhao
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang Province, China
| | - Xiyang Wei
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang Province, China
| | - Shiyuan Hu
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang Province, China
| | - Wei Jia
- Hong Kong Baptist University, HongKong, China
| | - Xin Wei Wang
- Liver Carcinogenesis Section, The Lab of Human Carcinogenesis, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Anuradha Budhu
- Liver Carcinogenesis Section, The Lab of Human Carcinogenesis, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Juling Ji
- Department of Pathology, Medical School of Nantong University, Nantong, 226019, Jiangsu Province, China
| | - Bin Zhao
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang Province, China
| | - Stephanie Roessler
- Institute of Pathology, University Hospital Heidelberg, 69120, Heidelberg, Germany
| | - Xin Zheng
- EZKIT L.L.C, Honolulu, HI, 96825, USA
| | - Junfang Ji
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, Zhejiang Province, China.
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28
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Waidmann O, Pleli T, Weigert A, Imelmann E, Kakoschky B, Schmithals C, Döring C, Frank M, Longerich T, Köberle V, Hansmann ML, Brüne B, Zeuzem S, Piiper A, Dikic I. Tax1BP1 limits hepatic inflammation and reduces experimental hepatocarcinogenesis. Sci Rep 2020; 10:16264. [PMID: 33004985 PMCID: PMC7530720 DOI: 10.1038/s41598-020-73387-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 09/09/2020] [Indexed: 02/07/2023] Open
Abstract
The nuclear factor kappa beta (NFκB) signaling pathway plays an important role in liver homeostasis and cancer development. Tax1-binding protein 1 (Tax1BP1) is a regulator of the NFκB signaling pathway, but its role in the liver and hepatocellular carcinoma (HCC) is presently unknown. Here we investigated the role of Tax1BP1 in liver cells and murine models of HCC and liver fibrosis. We applied the diethylnitrosamine (DEN) model of experimental hepatocarcinogenesis in Tax1BP1+/+ and Tax1BP1-/- mice. The amount and subsets of non-parenchymal liver cells in in Tax1BP1+/+ and Tax1BP1-/- mice were determined and activation of NFκB and stress induced signaling pathways were assessed. Differential expression of mRNA and miRNA was determined. Tax1BP1-/- mice showed increased numbers of inflammatory cells in the liver. Furthermore, a sustained activation of the NFκB signaling pathway was found in hepatocytes as well as increased transcription of proinflammatory cytokines in isolated Kupffer cells from Tax1BP1-/- mice. Several differentially expressed mRNAs and miRNAs in livers of Tax1BP1-/- mice were found, which are regulators of inflammation or are involved in cancer development or progression. Furthermore, Tax1BP1-/- mice developed more HCCs than their Tax1BP1+/+ littermates. We conclude that Tax1BP1 protects from liver cancer development by limiting proinflammatory signaling.
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Affiliation(s)
- Oliver Waidmann
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie Und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany. .,Institut für Biochemie 2, Universitätsklinikum Frankfurt, Goethe-Universität, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.
| | - Thomas Pleli
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie Und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany
| | - Andreas Weigert
- Institut für Biochemie 1, Universitätsklinikum Frankfurt, Goethe-Universität, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany
| | - Esther Imelmann
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie Und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany
| | - Bianca Kakoschky
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie Und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany
| | - Christian Schmithals
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie Und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany
| | - Claudia Döring
- Senckenbergsches Institut für Pathologie, Universitätsklinikum Frankfurt, Goethe-Universität, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany
| | - Matthias Frank
- Senckenbergsches Institut für Pathologie, Universitätsklinikum Frankfurt, Goethe-Universität, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany
| | - Thomas Longerich
- Sektion Translationale Gastrointestinale Pathologie, Institut für Pathologie, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Verena Köberle
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie Und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany
| | - Martin-Leo Hansmann
- Senckenbergsches Institut für Pathologie, Universitätsklinikum Frankfurt, Goethe-Universität, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany
| | - Bernhard Brüne
- Institut für Biochemie 1, Universitätsklinikum Frankfurt, Goethe-Universität, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany
| | - Stefan Zeuzem
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie Und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany
| | - Albrecht Piiper
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie Und Hepatologie, Universitätsklinikum Frankfurt, Goethe-Universität, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany
| | - Ivan Dikic
- Institut für Biochemie 2, Universitätsklinikum Frankfurt, Goethe-Universität, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany
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29
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Mishan MA, Tabari MAK, Parnian J, Fallahi J, Mahrooz A, Bagheri A. Functional mechanisms of miR-192 family in cancer. Genes Chromosomes Cancer 2020; 59:722-735. [PMID: 32706406 DOI: 10.1002/gcc.22889] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 07/14/2020] [Accepted: 07/21/2020] [Indexed: 12/11/2022] Open
Abstract
By growing research on the mechanisms and functions of microRNAs (miRNAs, miRs), the role of these noncoding RNAs gained more attention in healthcare. Due to the remarkable regulatory role of miRNAs, any dysregulation in their expression causes cellular functional impairment. In recent years, it has become increasingly apparent that these small molecules contribute to development, cell differentiation, proliferation, apoptosis, and tumor growth. In many studies, the miR-192 family has been suggested as a potential prognostic and diagnostic biomarker and even as a possible therapeutic target for several cancers. However, the mechanistic effects of the miR-192 family on cancer cells are still controversial. Here, we have reviewed each family member of the miR-192 including miR-192, miR-194, and miR-215, and discussed their mechanistic roles in various cancers.
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Affiliation(s)
- Mohammad Amir Mishan
- Ocular Tissue Engineering Research Center, Research Institute for Ophthalmology and Vision Science, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Amin Khazeei Tabari
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
- USERN Office, Mazandaran University of Medical Sciences, Sari, Iran
| | - Javad Parnian
- Department of Biotechnology, Iranian Research Organization for Science and Technology, Tehran, Iran
| | - Jafar Fallahi
- Molecular Medicine Department, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abdolkarim Mahrooz
- Department of Clinical Biochemistry and Medical Genetics, Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Abouzar Bagheri
- Department of Clinical Biochemistry and Medical Genetics, Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
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30
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Sartorius K, Swadling L, An P, Makarova J, Winkler C, Chuturgoon A, Kramvis A. The Multiple Roles of Hepatitis B Virus X Protein (HBx) Dysregulated MicroRNA in Hepatitis B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) and Immune Pathways. Viruses 2020; 12:v12070746. [PMID: 32664401 PMCID: PMC7412373 DOI: 10.3390/v12070746] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Currently, the treatment of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) [HBV-HCC] relies on blunt tools that are unable to offer effective therapy for later stage pathogenesis. The potential of miRNA to treat HBV-HCC offer a more targeted approach to managing this lethal carcinoma; however, the complexity of miRNA as an ancillary regulator of the immune system remains poorly understood. This review examines the overlapping roles of HBx-dysregulated miRNA in HBV-HCC and immune pathways and seeks to demonstrate that specific miRNA response in immune cells is not independent of their expression in hepatocytes. This interplay between the two pathways may provide us with the possibility of using candidate miRNA to manipulate this interaction as a potential therapeutic option.
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg 2050, South Africa
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
- UKZN Gastrointestinal Cancer Research Centre, Durban 4041, South Africa
- Correspondence:
| | - Leo Swadling
- Division of Infection and Immunity, University College London, London WC1E6BT, UK;
| | - Ping An
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Julia Makarova
- National Research University Higher School of Economics, Faculty of Biology and Biotechnology, 10100 Moscow, Russia;
| | - Cheryl Winkler
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Anil Chuturgoon
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2050, South Africa;
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31
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Ma X, Mo M, Tan HJJ, Tan C, Zeng X, Zhang G, Huang D, Liang J, Liu S, Qiu X. LINC02499, a novel liver-specific long non-coding RNA with potential diagnostic and prognostic value, inhibits hepatocellular carcinoma cell proliferation, migration, and invasion. Hepatol Res 2020; 50:726-740. [PMID: 32039538 DOI: 10.1111/hepr.13491] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 01/07/2020] [Accepted: 01/29/2020] [Indexed: 12/14/2022]
Abstract
AIM Liver-specific non-coding RNAs have been reported to play crucial roles in hepatocellular carcinoma (HCC). We investigated the possible biological performance of a novel liver-specific long non-coding RNA, LINC02499, in HCC. METHODS The association between LINC02499 expression and HCC was evaluated based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and then confirmed in a HCC cohort by quantitative real-time polymerase chain reaction. The effects of LINC02499 on HCC cells were verified by gain- and loss-of-function assays. Pathway enrichment analyses were used to explore the potential mechanism of LINC02499 in HCC. RESULTS LINC02499 expression was remarkably decreased in HCC tissues compared to adjacent non-tumor tissues based on TCGA (P < 0.001) and GEO databases (P < 0.001) and our HCC cohort (P < 0.001). Decreased LINC02499 was also significantly associated with poorer overall survival in both the TCGA database (P = 0.009) and our HCC cohort (P = 0.002). Furthermore, the receiver operating characteristic analysis indicated that LINC02499 showed a good performance in HCC diagnosis (area under the curve = 0.879, P < 0.001), and both sensitivity and specificity were 83.8%. In addition, up- and downregulated LINC02499 significantly impacted proliferation, migration, and invasion abilities of HCC cells in vitro. Pathway enrichment analyses revealed that the potential target genes of LINC02499 were involved in "Complement and coagulation cascades" and "Butanoate metabolism" pathways. CONCLUSION LINC02499 could be a potential novel diagnostic and prognostic biomarker for HCC patients, and it could exert a tumor suppressor role in the progression of HCC.
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Affiliation(s)
- Xiaoyun Ma
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, China
| | - Meile Mo
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, China
| | | | - Chao Tan
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, China
| | - Xiaoyun Zeng
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, China
| | - Guoqiang Zhang
- Hospital-acquired Infection Control Department, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, China
| | - Dongping Huang
- Department of Sanitary Chemistry, School of Public Health, Guangxi Medical University, Nanning, China
| | - Jun Liang
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, China
| | - Shun Liu
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, China
| | - Xiaoqiang Qiu
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, China
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Tavakolian S, Goudarzi H, Faghihloo E. Evaluating the expression level of miR-9-5p and miR-192-5p in gastrointestinal cancer: introducing novel screening biomarkers for patients. BMC Res Notes 2020; 13:226. [PMID: 32307002 PMCID: PMC7168809 DOI: 10.1186/s13104-020-05071-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 04/12/2020] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE It has been indicated that there is a tight association between cancer and different factors, such as environment and genetics, including aberrantly expressed microRNAs. The crucial role of microRNAs in the regulation of diverse signaling pathways in gastrointestinal cancer has been established in several studies. In this study, we aimed to evaluate the expression of microRNA-9 and -192 in colon and gastric cancers. After extracting the RNA from tissues and serum samples of patients, suffering from colon and gastric cancer, cDNA was synthesized. Then by performing quantitative real-time PCR, we evaluated the expression level of miR-9-5p and miR-192-5p in collected samples. RESULTS Unlike to colon cancer in which the expression level of miR-9-5p remained unchanged, the relative expression of this miRNA decreased remarkably in gastric cancer (with P value < 0.05), in comparison with normal adjacent tissues. In agreement with this finding, we also found that the expression level of miR-192-5p was decreased in gastric cancer tissues, compared to normal gastric tissue. Given the reduction in the expression level of miR-9-5p and miR-192-5p in gastric cancer, it could be postulated to consider these miRNAs as promising diagnostic biomarkers.
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Affiliation(s)
- Shaian Tavakolian
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 37517, Iran
| | - Hossein Goudarzi
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 37517, Iran
| | - Ebrahim Faghihloo
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 37517, Iran.
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33
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Zhou Y, Huan L, Wu Y, Bao C, Chen B, Wang L, Huang S, Liang L, He X. LncRNA ID2-AS1 suppresses tumor metastasis by activating the HDAC8/ID2 pathway in hepatocellular carcinoma. Cancer Lett 2020; 469:399-409. [DOI: 10.1016/j.canlet.2019.11.007] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 11/04/2019] [Accepted: 11/06/2019] [Indexed: 01/13/2023]
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34
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Ziogas IA, Sioutas G, Mylonas KS, Tsoulfas G. Role of MicroRNA in the Diagnosis and Management of Hepatocellular Carcinoma. Microrna 2020; 9:25-40. [PMID: 31218966 DOI: 10.2174/2211536608666190619155406] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 03/11/2019] [Accepted: 05/06/2019] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Hepatocellular Carcinoma (HCC) is one of the most common malignant tumors in the world and comes third in cancer-induced mortality. The need for improved and more specific diagnostic methods that can detect early-stage disease is immense, as it is amenable to curative modalities, while advanced HCC is associated with low survival rates. microRNA (miRNA) expression is deregulated in HCC and this can be implemented both diagnostically and therapeutically. OBJECTIVE To provide a concise review on the role of miRNA in diagnosis, prognosis, and treatment of HCC. METHODS We conducted a comprehensive review of the PubMed bibliographic database. RESULTS Multiple miRNAs are involved in the pathogenesis of HCC. Measurement of the levels of these miRNAs either in tumor tissue or in the blood constitutes a promising diagnostic, as well as prognostic tool. OncomiRs are miRNAs that promote tumorigenesis, thus inhibiting them by administering antagomiRs is a promising treatment option. Moreover, replacement of the depleted miRNAs is another potential therapeutic approach for HCC. Modification of miRNA levels may also regulate sensitivity to chemotherapeutic agents. CONCLUSION miRNA play a pivotal role in HCC pathogenesis and once the underlying mechanisms are elucidated, they will become part of everyday clinical practice against HCC.
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Affiliation(s)
- Ioannis A Ziogas
- Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Surgery Working Group, Society of Junior Doctors, Athens, Greece
| | - Georgios Sioutas
- Surgery Working Group, Society of Junior Doctors, Athens, Greece
- Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - Konstantinos S Mylonas
- Surgery Working Group, Society of Junior Doctors, Athens, Greece
- Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgios Tsoulfas
- 1st Department of Surgery, Aristotle University of Thessaloniki, Thessaloniki, Greece
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35
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Weidle UH, Schmid D, Birzele F, Brinkmann U. MicroRNAs Involved in Metastasis of Hepatocellular Carcinoma: Target Candidates, Functionality and Efficacy in Animal Models and Prognostic Relevance. Cancer Genomics Proteomics 2020; 17:1-21. [PMID: 31882547 PMCID: PMC6937123 DOI: 10.21873/cgp.20163] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/31/2019] [Accepted: 11/04/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is responsible for the second-leading cancer-related death toll worldwide. Although sorafenib and levantinib as frontline therapy and regorafenib, cabazantinib and ramicurimab have now been approved for second-line therapy, the therapeutic benefit is in the range of only a few months with respect to prolongation of survival. Aggressiveness of HCC is mediated by metastasis. Intrahepatic metastases and distant metastasis to the lungs, lymph nodes, bones, omentum, adrenal gland and brain have been observed. Therefore, the identification of metastasis-related new targets and treatment modalities is of paramount importance. In this review, we focus on metastasis-related microRNAs (miRs) as therapeutic targets for HCC. We describe miRs which mediate or repress HCC metastasis in mouse xenograft models. We discuss 18 metastasis-promoting miRs and 35 metastasis-inhibiting miRs according to the criteria as outlined. Six of the metastasis-promoting miRs (miR-29a, -219-5p, -331-3p, 425-5p, -487a and -1247-3p) are associated with unfavourable clinical prognosis. Another set of six down-regulated miRs (miR-101, -129-3p, -137, -149, -503, and -630) correlate with a worse clinical prognosis. We discuss the corresponding metastasis-related targets as well as their potential as therapeutic modalities for treatment of HCC-related metastasis. A subset of up-regulated miRs -29a, -219-5p and -425-5p and down-regulated miRs -129-3p and -630 were evaluated in orthotopic metastasis-related models which are suitable to mimic HCC-related metastasis. Those miRNAs may represent prioritized targets emerging from our survey.
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Affiliation(s)
- Ulrich H Weidle
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| | - Daniela Schmid
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
| | - Fabian Birzele
- Pharmaceutical Sciences, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland
| | - Ulrich Brinkmann
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
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36
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MicroRNAs in Animal Models of HCC. Cancers (Basel) 2019; 11:cancers11121906. [PMID: 31805631 PMCID: PMC6966618 DOI: 10.3390/cancers11121906] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 11/27/2019] [Accepted: 11/28/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. Molecular heterogeneity and absence of biomarkers for patient allocation to the best therapeutic option contribute to poor prognosis of advanced stages. Aberrant microRNA (miRNA) expression is associated with HCC development and progression and influences drug resistance. Therefore, miRNAs have been assayed as putative biomarkers and therapeutic targets. miRNA-based therapeutic approaches demonstrated safety profiles and antitumor efficacy in HCC animal models; nevertheless, caution should be used when transferring preclinical findings to the clinics, due to possible molecular inconsistency between animal models and the heterogeneous pattern of the human disease. In this context, models with defined genetic and molecular backgrounds might help to identify novel therapeutic options for specific HCC subgroups. In this review, we describe rodent models of HCC, emphasizing their representativeness with the human pathology and their usefulness as preclinical tools for assessing miRNA-based therapeutic strategies.
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37
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The Regulatory Role of MicroRNA in Hepatitis-B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) Pathogenesis. Cells 2019; 8:cells8121504. [PMID: 31771261 PMCID: PMC6953055 DOI: 10.3390/cells8121504] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/11/2019] [Accepted: 11/12/2019] [Indexed: 02/06/2023] Open
Abstract
The incidence and mortality of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) is an intractable public health problem in developing countries that is compounded by limited early detection and therapeutic options. Despite the early promise of utilizing the regulatory role of miRNA in liver cancer, this field remains largely in the work-in-progress phase. This exploratory review paper adopts a broad focus in order to collate evidence of the regulatory role of miRNA in each stage of the HBV-HCC continuum. This includes the regulatory role of miRNA in early HBV infection, chronic inflammation, fibrosis/cirrhosis, and the onset of HCC. The paper specifically investigates HBV dysregulated miRNA that influence the expression of the host/HBV genome in HBV-HCC pathogenesis and fully acknowledges that this does not cover the full spectrum of dysregulated miRNA. The sheer number of dysregulated miRNA in each phase support a hypothesis that future therapeutic interventions will need to consider incorporating multiple miRNA panels.
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38
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Tavakolian S, Goudarzi H, Torfi F, Faghihloo E. Evaluation of microRNA-9 and -192 expression levels as biomarkers in patients suffering from breast cancer. Biomed Rep 2019; 12:30-34. [PMID: 31839947 DOI: 10.3892/br.2019.1257] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Accepted: 10/02/2019] [Indexed: 12/18/2022] Open
Abstract
Given the global outbreak of breast cancer and its debilitating effect on women's health, it is not surprising that tremendous efforts have been made with an aim of shedding more light on the mechanisms involved in the pathogenesis of this type of cancer. Among the long list of risk factors associated with this malignancy, recently, the role of microRNAs (miRNAs or miRs) has turned into a hotspot for breast cancer investigations. miRNAs approximately 20 nucleotides in length and are located in either an exon or an intron, playing a role in the regulation of gene expression. In the present study, we extracted RNA from both the serum and cancerous tissue of breast cancer patients and after synthesizing the cDNA, we performed quantitative PCR to determine the expression levels of miR-9 and miR-192. The resulting data revealed that while the mRNA expression level of miR-9 was significantly decreased in the breast cancer tissues, there was no noticeable change in the expression level of this miRNA in the serum samples. Likewise, we found that the marked downregulation of miR-192 was only restricted to the cancerous tissues, but was not found in the serum of patients. Based on the meaningful downregulation of the expression of miR-9 and miR-192, this study provides a plausible framework for these miRNAs as effective biomarkers for breast cancer patients.
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Affiliation(s)
- Shaian Tavakolian
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran
| | - Hossein Goudarzi
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran
| | - Farhad Torfi
- Surgical Ward, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran
| | - Ebrahim Faghihloo
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran
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39
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Gao J, Ren W, Xiao C, Wang L, Huang Q, Zhang Z, Dang Y, Weng P, Wang H, Fang X, Zhuang M, Lin L, Chen S. Involvement of SLC39A6 in gastric adenocarcinoma and correlation of the SLC39A6 polymorphism rs1050631 with clinical outcomes after resection. BMC Cancer 2019; 19:1069. [PMID: 31703635 PMCID: PMC6839152 DOI: 10.1186/s12885-019-6222-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 09/30/2019] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND The single-nucleotide polymorphism SLC39A6 rs1050631 is strongly implicated in esophageal squamous cell carcinoma, leading us to question whether it may also play a role in gastric adenocarcima (GA). METHODS We genotyped the SLC39A6 rs1050631 in 512 patients who underwent GA resection. All study subjects lived in an area of China with high GA incidence. Genotypes were examined for possible correlation with survival and recurrence. The potential involvement of SLC39A6 in gastric cancer was explored in clinical samples and cell culture studies. RESULTS Multivariable analysis showed that patients with the CT + TT genotype at SLC39A6 rs1050631 were at greater risk of recurrence (hazard ratio, HR 1.387, p = 0.004) and death (HR 1.429, p = 0.002) than patients with CC genotype. Median recurrence-free and overall survival were significantly shorter in patients with the CT + TT genotype (20, 27 months) than in patients with the CC genotype (36, 43 months, p = 0.001, p < 0.001). Patients with the CT + TT genotype who were male or ≥ 60 years, or who had a tumor ≥5 cm or a moderately differentiated tumor were at significantly higher risk of recurrence and death. SLC39A6 was overexpressed in tissues from GA patients and in GA cell lines, and SLC39A6 knockdown in GA cell lines inhibited their proliferation, migration and invasion. CONCLUSION SLC39A6 rs1050631 correlates with post-resection prognosis of GA patients and SLC39A6 may participate in GA onset or progression.
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Affiliation(s)
- Jian Gao
- Department of General Surgery, Dongfang Hospital (900 Hospital of the Joint Logistics Team), 156 North Xi-er Huan Road, Fuzhou, 350025, Fujian, China
| | - Wenjun Ren
- Department of General Surgery, Dongfang Hospital (900 Hospital of the Joint Logistics Team), 156 North Xi-er Huan Road, Fuzhou, 350025, Fujian, China
| | - Chunhong Xiao
- Department of General Surgery, Dongfang Hospital (900 Hospital of the Joint Logistics Team), 156 North Xi-er Huan Road, Fuzhou, 350025, Fujian, China.,China Clinical Institute of Fuzhou General Hospital (900 Hospital of the Joint Logistics Team), Fujian Medical University, 156 North Xi-er Huan Road, Fuzhou, 350025, Fujian, China
| | - Lie Wang
- Department of General Surgery, Dongfang Hospital (900 Hospital of the Joint Logistics Team), 156 North Xi-er Huan Road, Fuzhou, 350025, Fujian, China.,China Clinical Institute of Fuzhou General Hospital (900 Hospital of the Joint Logistics Team), Fujian Medical University, 156 North Xi-er Huan Road, Fuzhou, 350025, Fujian, China
| | - Qiaojia Huang
- Department of Experimental Medicine, Dongfang Hospital (900 Hospital of the Joint Logistics Team), 156 North Xi-er Huan Road, Fuzhou, 350025, Fujian, China
| | - Zaizhong Zhang
- Department of General Surgery, Dongfang Hospital (900 Hospital of the Joint Logistics Team), 156 North Xi-er Huan Road, Fuzhou, 350025, Fujian, China.,China Clinical Institute of Fuzhou General Hospital (900 Hospital of the Joint Logistics Team), Fujian Medical University, 156 North Xi-er Huan Road, Fuzhou, 350025, Fujian, China
| | - Yuan Dang
- Fujian Meiya Aijiankang Health Management Co, Ltd. 4602#, Building 1, Shimao International Center, 108 Guangda Road, Fuzhou, 350025, Fujian, China
| | - Pengcheng Weng
- Union Medical College, Fujian Medical University, 29 XinQuan Road, Fuzhou, 350025, Fujian, China
| | - Hui Wang
- Union Medical College, Fujian Medical University, 29 XinQuan Road, Fuzhou, 350025, Fujian, China
| | - Xuehong Fang
- Union Medical College, Fujian Medical University, 29 XinQuan Road, Fuzhou, 350025, Fujian, China
| | - Minxian Zhuang
- Union Medical College, Fujian Medical University, 29 XinQuan Road, Fuzhou, 350025, Fujian, China
| | - Liying Lin
- Department of General Surgery, Dongfang Hospital (900 Hospital of the Joint Logistics Team), 156 North Xi-er Huan Road, Fuzhou, 350025, Fujian, China. .,China Clinical Institute of Fuzhou General Hospital (900 Hospital of the Joint Logistics Team), Fujian Medical University, 156 North Xi-er Huan Road, Fuzhou, 350025, Fujian, China.
| | - Shaoquan Chen
- Department of General Surgery, Dongfang Hospital (900 Hospital of the Joint Logistics Team), 156 North Xi-er Huan Road, Fuzhou, 350025, Fujian, China. .,China Clinical Institute of Fuzhou General Hospital (900 Hospital of the Joint Logistics Team), Fujian Medical University, 156 North Xi-er Huan Road, Fuzhou, 350025, Fujian, China.
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40
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Fan X, Jin S, Li Y, Khadaroo PA, Dai Y, He L, Zhou D, Lin H. Genetic And Epigenetic Regulation Of E-Cadherin Signaling In Human Hepatocellular Carcinoma. Cancer Manag Res 2019; 11:8947-8963. [PMID: 31802937 PMCID: PMC6801489 DOI: 10.2147/cmar.s225606] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 09/27/2019] [Indexed: 12/24/2022] Open
Abstract
E-cadherin is well known as a growth and invasion suppressor and belongs to the large cadherin family. Loss of E-cadherin is widely known as the hallmark of epithelial-to-mesenchymal transition (EMT) with the involvement of transcription factors such as Snail, Slug, Twist and Zeb1/2. Tumor cells undergoing EMT could migrate to distant sites and become metastases. Recently, numerous studies have revealed how the expression of E-cadherin is regulated by different kinds of genetic and epigenetic alteration, which are implicated in several crucial transcription factors and pathways. E-cadherin signaling plays an important role in hepatocellular carcinoma (HCC) initiation and progression considering the highly mutated frequency of CTNNB1 (27%). Combining the data from The Cancer Genome Atlas (TCGA) database and previous studies, we have summarized the roles of gene mutations, chromosome instability, DNA methylation, histone modifications and non-coding RNA in E-cadherin in HCC. In this review, we discuss the current understanding of the relationship between these modifications and HCC. Perspectives on E-cadherin-related research in HCC are provided.
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Affiliation(s)
- Xiaoxiao Fan
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
| | - Shengxi Jin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
- School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
| | - Yirun Li
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
| | - Parikshit Asutosh Khadaroo
- School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Yili Dai
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
- School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
| | - Lifeng He
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
| | - Daizhan Zhou
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
| | - Hui Lin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China
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41
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Liu SY. Abnormal regulation of non-coding RNAs plays a role in development and progression of hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2019; 27:1107-1113. [DOI: 10.11569/wcjd.v27.i18.1107] [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] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive tumor with a poor prognosis. Non-coding RNAs (ncRNAs) are RNAs transcribed from the genome but not translated into protein. In recent years, ncRNAs have been recognized to be key factors in tumorigenesis because of their ability to regulate multiple targets, cell proliferation, differentiation, apoptosis, and development. In this review, we discuss the pathological significance of ncRNAs (microRNAs, long-chain non-coding RNAs, and cyclic RNAs) in the development and progression of HCC. We also discuss the potential role of ncRNAs in the diagnosis and treatment of HCC.
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Affiliation(s)
- Shu-Ye Liu
- Clinical Laboratory, Tianjin Third Central Hospital, Tianjin 300170, China
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42
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Liu J, Nie S, Liang J, Jiang Y, Wan Y, Zhou S, Cheng W. Competing endogenous RNA network of endometrial carcinoma: A comprehensive analysis. J Cell Biochem 2019; 120:15648-15660. [PMID: 31056798 DOI: 10.1002/jcb.28831] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 02/23/2019] [Accepted: 02/28/2019] [Indexed: 12/18/2022]
Abstract
Competing endogenous RNA (ceRNA) network is dysregulated in the initiation and progression of tumors. In the present study, we explored the regulatory mechanism of ceRNA in endometrial carcinoma (EC) and the potential key molecules with potential value in the diagnosis, treatment, and prognosis of EC. The long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) expression profiles (552 EC tissues and 35 nontumor tissues) and microRNAs (miRNAs) expression profiles (546 EC tissues and 33 nontumor tissues) were downloaded from The Cancer Genome Atlas database to identify differentially expressed RNAs (DERNAs) in EC. An integrated bioinformatics analysis was used to construct an EC-specific ceRNA network and select key molecules. As a result, 96 differentially expressed lncRNAs (DElncRNAs), 29 differentially expressed miRNAs (DEmiRNAs), and 77 differentially expressed mRNAs (DEmRNAs) were identified. An EC-specific ceRNA network was built based on nine DElncRNAs significantly associated with overall survival. CCNB1 was found as a key gene in EC through the weighted gene coexpression network analysis and protein-protein interaction network analysis. Our ceRNA network showed C2orf48 and LINC00483 might upregulate CCNB1 via competing with miR-183. In addition, we found a subnetwork which contained survival-associated DERNAs (AC110491.1, LINC00483-miR-192-GRHL1). The results of reverse transcription quantitative polymerase chain reaction supported the relative expressions of C2orf48, LINC00483 were upregulated and that of AC110491.1 was downregulated in EC. We further found C2orf48 was upregulated in serous EC, endometrioid EC, and mixed serous and endometrioid EC. LINC00483 was upregulated in mixed serous and endometrioid EC compared with that in the normal tissues according to UALCAN database. In addition, candidate small molecular drugs were screened out by ConnectivityMap based on the 77 DEmRNAs in the ceRNA network. Eventually, C2orf48, LINC00483, and AC110491.1 were identified as three key lncRNAs in EC.
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Affiliation(s)
- Jinhui Liu
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Sipei Nie
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Junya Liang
- Hypertension Research Center, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yi Jiang
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yicong Wan
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shulin Zhou
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wenjun Cheng
- Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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Zhao H, Chen J, Chen J, Kong X, Zhu H, Zhang Y, Dong H, Wang J, Ren Q, Wang Q, Chen S, Deng Z, Chen Z, Cui Q, Zheng J, Lu J, Wang S, Tan J. miR-192/215-5p act as tumor suppressors and link Crohn's disease and colorectal cancer by targeting common metabolic pathways: An integrated informatics analysis and experimental study. J Cell Physiol 2019; 234:21060-21075. [PMID: 31020657 DOI: 10.1002/jcp.28709] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 04/02/2019] [Accepted: 04/11/2019] [Indexed: 12/25/2022]
Abstract
MicroRNAs have emerged as key regulators involved in a variety of biological processes. Previous studies have demonstrated that miR-192/215 participated in progression of Crohn's disease and colorectal cancer. However, their concrete relationships and regulation networks in diseases remain unclear. Here, we used bioinformatics methods to expound miR-192/215-5p macrocontrol regulatory networks shared by two diseases. For data mining and figure generation, several miRNA prediction tools, Human miRNA tissue atlas, FunRich, miRcancer, MalaCards, STRING, GEPIA, cBioPortal, GEO databases, Pathvisio, Graphpad Prism 6 software, etc . are extensively applied. miR-192/215-5p were specially distributed in colon tissues and enriched biological pathways were closely associated with human cancers. Emerging role of miR-192/215-5p and their common pathways in Crohn's disease and colorectal cancer was also analyzed. Based on results derived from multiple approaches, we identified the biological functions of miR-192/215-5p as a tumor suppressor and link Crohn's disease and colorectal cancer by targeting triglyceride synthesis and extracellular matrix remodeling pathways.
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Affiliation(s)
- Hu Zhao
- Department of Urology, Fujian Provincial Key Laboratory of Transplant Biology, 900 Hospital of the Joint Logistics Team, Xiamen University, Fuzhou, Fujian, China
| | - Junqiu Chen
- Department of Urology, Fujian Provincial Key Laboratory of Transplant Biology, 900 Hospital of the Joint Logistics Team, Xiamen University, Fuzhou, Fujian, China
| | - Jin Chen
- Department of Urology, Fujian Provincial Key Laboratory of Transplant Biology, 900 Hospital of the Joint Logistics Team, Xiamen University, Fuzhou, Fujian, China
| | - Xuhui Kong
- Department of Urology, Fujian Provincial Key Laboratory of Transplant Biology, 900 Hospital of the Joint Logistics Team, Xiamen University, Fuzhou, Fujian, China
| | - Hehuan Zhu
- Department of Urology, Fujian Provincial Key Laboratory of Transplant Biology, 900 Hospital of the Joint Logistics Team, Xiamen University, Fuzhou, Fujian, China
| | - Yongping Zhang
- Department of Neuro-oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Huiyue Dong
- Department of Urology, Fujian Provincial Key Laboratory of Transplant Biology, 900 Hospital of the Joint Logistics Team, Xiamen University, Fuzhou, Fujian, China
| | - Jie Wang
- Department of Urology, Fujian Provincial Key Laboratory of Transplant Biology, 900 Hospital of the Joint Logistics Team, Xiamen University, Fuzhou, Fujian, China
| | - Qun Ren
- Department of Urology, Fujian Provincial Key Laboratory of Transplant Biology, 900 Hospital of the Joint Logistics Team, Xiamen University, Fuzhou, Fujian, China
| | - Qinghua Wang
- Department of Urology, Fujian Provincial Key Laboratory of Transplant Biology, 900 Hospital of the Joint Logistics Team, Xiamen University, Fuzhou, Fujian, China
| | - Shushang Chen
- Department of Urology, Fujian Provincial Key Laboratory of Transplant Biology, 900 Hospital of the Joint Logistics Team, Xiamen University, Fuzhou, Fujian, China
| | - Zhen Deng
- Department of Urology, Fujian Provincial Key Laboratory of Transplant Biology, 900 Hospital of the Joint Logistics Team, Xiamen University, Fuzhou, Fujian, China
| | - Zhan Chen
- Department of Urology, Fujian Provincial Key Laboratory of Transplant Biology, 900 Hospital of the Joint Logistics Team, Xiamen University, Fuzhou, Fujian, China
| | - Qiang Cui
- Department of Urology, Fujian Provincial Key Laboratory of Transplant Biology, 900 Hospital of the Joint Logistics Team, Xiamen University, Fuzhou, Fujian, China
| | - Junqiong Zheng
- Department of Oncology, Longyan First Hospital, Affiliated to Fujian Medical University, Longyan, Fujian, China
| | - Jun Lu
- Department of Urology, Fujian Provincial Key Laboratory of Transplant Biology, 900 Hospital of the Joint Logistics Team, Xiamen University, Fuzhou, Fujian, China
| | - Shuiliang Wang
- Department of Urology, Fujian Provincial Key Laboratory of Transplant Biology, 900 Hospital of the Joint Logistics Team, Xiamen University, Fuzhou, Fujian, China
| | - Jianming Tan
- Department of Urology, Fujian Provincial Key Laboratory of Transplant Biology, 900 Hospital of the Joint Logistics Team, Xiamen University, Fuzhou, Fujian, China
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Luo J, Pan C, Xiang G, Yin Y. A Novel Cluster-Based Computational Method to Identify miRNA Regulatory Modules. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2019; 16:681-687. [PMID: 29993835 DOI: 10.1109/tcbb.2018.2824805] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
The identification of miRNA regulatory modules can help decipher miRNAs combinatorial regulation effects on the pathogenesis underlying complex diseases, especially in cancer. By integrating miRNA/mRNA expression profiles and sequence-based predicted target site information, we develop a novel cluster-based computational method named CoModule for identifying miRNA regulatory modules (MRMs). The ultimate goal of CoModule is to detect the MRMs, in which the miRNAs in each module are expected to present cooperative mechanisms in regulating their targets mRNAs. Here, the co-expression of miRNAs are believed to present cooperative regulatory relationship, therefore, the critical step of CoModule is first to partition the miRNAs with similar expression into a cluster by employing rough set clustering. After gaining credible miRNA clusters, the targets of regulator are naturally added into corresponding clusters to produce the final miRNA regulatory modules. We apply this present method to ovarian cancer datasets and make a comparison with the other two existing prominent approaches. The results indicate that the modules identified by CoModule perform better than the other two methods ranging from the topological aspects to the biological function. Survival analysis detects a number of prognostic modules with statistical significance, which can help reveal the potential diagnostic for ovarian cancer.
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Regulation of miRNAs by Snail during epithelial-to-mesenchymal transition in HT29 colon cancer cells. Sci Rep 2019; 9:2165. [PMID: 30770873 PMCID: PMC6377707 DOI: 10.1038/s41598-019-39200-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 01/04/2019] [Indexed: 01/06/2023] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) in cancer cells, represents early stages of metastasis and is a promising target in colorectal cancer (CRC) therapy. There have been many attempts to identify markers and key pathways induced throughout EMT but the process is complex and depends on the cancer type and tumour microenvironment. Here we used the colon cancer cell line HT29, which stably overexpressed Snail, the key transcription factor in early EMT, as a model for colorectal adenocarcinoma cells with a pro-metastatic phenotype. We investigated miRNA expression regulation during that phenotypic switching. We found that overexpression of Snail in HT29 cells triggered significant changes in individual miRNA levels but did not change the global efficiency of miRNA processing. Snail abundance repressed the expression of miR-192 and miR-194 and increased miR-205, let-7i and SNORD13 levels. These identified changes correlated with the reported transcriptomic alterations in Snail-overexpressing HT29 cells. We also investigated how Snail affected the miRNA content of extracellular vesicles (EVs) released from HT29 cells. Our data suggest that the presence of Snail significantly alters the complex mRNA/miRNA interactions in the early steps of metastasis and also has an impact on the content of EVs released from HT29 cells.
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46
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Heo MJ, Yun J, Kim SG. Role of non-coding RNAs in liver disease progression to hepatocellular carcinoma. Arch Pharm Res 2019; 42:48-62. [PMID: 30610616 DOI: 10.1007/s12272-018-01104-x] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 12/23/2018] [Indexed: 12/17/2022]
Abstract
Hepatocellular carcinoma (HCC) is a tumor with poor prognosis and frequently aggressive. The development of HCC is associated with fibrosis and cirrhosis, which mainly results from nonalcoholic fatty liver disease, excessive alcohol consumption, and viral infections. Non-coding RNAs (ncRNAs) are RNAs transcribed from the genome, but are not translated into proteins. Recently, ncRNAs emerged as key contributors to tumor development and progression because of their abilities to regulate various targets and modulate cell proliferation, differentiation, apoptosis, and development. In this review, we summarize the frequently activated pathways in HCC and discuss the pathological implications of ncRNAs in the context of human liver disease progression, in particular HCC development and progression. This review aims to summarize the role of ncRNA dysregulation in the diseases and discuss the diagnostic and therapeutic potentials of ncRNAs.
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Affiliation(s)
- Mi Jeong Heo
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanakro, Seoul, 08826, South Korea
| | - Jessica Yun
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanakro, Seoul, 08826, South Korea
| | - Sang Geon Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanakro, Seoul, 08826, South Korea.
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Chen ZJ, Yan YJ, Shen H, Zhou JJ, Yang GH, Liao YX, Zeng JM, Yang T. miR-192 Is Overexpressed and Promotes Cell Proliferation in Prostate Cancer. Med Princ Pract 2019; 28:124-132. [PMID: 30544100 PMCID: PMC6546031 DOI: 10.1159/000496206] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 12/13/2018] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE Prostate cancer (PCa) is one of the most prevalent types of cancer among men worldwide. The incidence of PCa is increasing in China. Therefore, there is an urgent need to identify novel diagnostic and prognostic markers for PCa to improve the treatment of the disease. METHODS The Cancer Genome Atlas (TCGA) and GEO database were used to analyze the expression of miR-192, and the relationship between miR-192 and the clinical features of patients with PCa. Cell cycle and cell proliferation assay were used to detect the functional roles of miR-192 in PCa. Bioinformatic analysis for miR-192-5p was performed using gene ontology and KEGG analysis. RESULTS By analyzing the dataset of TCGA, we found that miR-192 was overexpressed in PCa samples compared to normal tissues and was upregulated in high-grade PCa compared to low-grade PCa. We also observed that higher miR-192 expression was associated with a shorter biochemical recurrence-free survival time. Our results also demonstrated that miR-192 promoted PCa cell proliferation and cell cycle progression. CONCLUSION These results suggest that miR-192 may be considered for use as a potential diagnostic and therapeutic target of PCa.
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Affiliation(s)
- Zhong-Jun Chen
- Department of Urology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, China
| | - You-Ji Yan
- Department of Urology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, China
| | - Hao Shen
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China,
| | - Jia-Jie Zhou
- Department of Urology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, China
| | - Guang-Hua Yang
- Department of Urology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, China
| | - Yi-Xiang Liao
- Department of Urology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, China
| | - Jin-Min Zeng
- Department of Urology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, China
| | - Tao Yang
- Department of Urology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, China
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48
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Gu Y, Wei X, Sun Y, Gao H, Zheng X, Wong LL, Jin L, Liu N, Hernandez B, Peplowska K, Zhao X, Zhan QM, Feng XH, Tang ZY, Ji J. miR-192-5p Silencing by Genetic Aberrations Is a Key Event in Hepatocellular Carcinomas with Cancer Stem Cell Features. Cancer Res 2018; 79:941-953. [PMID: 30530815 DOI: 10.1158/0008-5472.can-18-1675] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 10/11/2018] [Accepted: 11/30/2018] [Indexed: 02/07/2023]
Abstract
Various cancer stem cell (CSC) biomarkers have been identified for hepatocellular carcinoma (HCC), but little is known about the implications of heterogeneity and shared molecular networks within the CSC population. Through miRNA profile analysis in an HCC cohort (n = 241) for five groups of CSC+ HCC tissues, i.e., EpCAM+, CD90+, CD133+, CD44+, and CD24+ HCC, we identified a 14-miRNA signature commonly altered among these five groups of CSC+ HCC. miR-192-5p, the top-ranked CSC miRNA, was liver-abundant and -specific and markedly downregulated in all five groups of CSC+ HCC from two independent cohorts (n = 613). Suppressing miR-192-5p in HCC cells significantly increased multiple CSC populations and CSC-related features through targeting PABPC4. Both TP53 mutation and hypermethylation of the mir-192 promoter impeded transcriptional activation of miR-192-5p in HCC cell lines and primary CSC+ HCC. This study reveals the circuit from hypermethylation of the mir-192 promoter through the increase in PABPC4 as a shared genetic regulatory pathway in various groups of primary CSC+ HCC. This circuit may be the driver that steers liver cells toward hepatic CSC cells, leading to hepatic carcinogenesis. SIGNIFICANCE: miR-192-5p and its regulatory pathway is significantly abolished in multiple groups of HCC expressing high levels of CSC markers, which may represent a key event for hepatic carcinogenesis.
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Affiliation(s)
- Yuanzhuo Gu
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Xiyang Wei
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Yulin Sun
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongjun Gao
- University of Hawai'i Cancer Center, Honolulu, Hawaii.,Clinical Laboratory, China Meitan General Hospital, Beijing, China
| | | | - Linda L Wong
- University of Hawai'i Cancer Center, Honolulu, Hawaii.,Department of Surgery, John A. Burns School of Medicine, University of Hawai'i, Honolulu, Hawaii
| | - Ling Jin
- University of Hawai'i Cancer Center, Honolulu, Hawaii
| | - Niya Liu
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang Province, China
| | | | | | - Xiaohang Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qi-Min Zhan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Xin-Hua Feng
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Zhao-You Tang
- Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Junfang Ji
- Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang Province, China.
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Bouyssou JM, Liu CJ, Bustoros M, Sklavenitis-Pistofidis R, Aljawai Y, Manier S, Yosef A, Sacco A, Kokubun K, Tsukamoto S, Perilla Glen A, Huynh D, Castillo JJ, Treon SP, Leblond V, Hermine O, Roccaro AM, Ghobrial IM, Capelletti M. Profiling of circulating exosomal miRNAs in patients with Waldenström Macroglobulinemia. PLoS One 2018; 13:e0204589. [PMID: 30286096 PMCID: PMC6171840 DOI: 10.1371/journal.pone.0204589] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 09/11/2018] [Indexed: 01/01/2023] Open
Abstract
Waldenström Macroglobulinemia (WM) is a low-grade B-cell lymphoma characterized by disease progression from IgM MGUS to asymptomatic and then symptomatic disease states. We profiled exosomes from the peripheral blood of patients with WM at different stages (30 smoldering/asymptomatic WM, 44 symptomatic WM samples and 10 healthy controls) to define their role as potential biomarkers of disease progression. In this study, we showed that circulating exosomes and their miRNA content represent unique markers of the tumor and its microenvironment. We observed similar levels of miRNAs in exosomes from patients with asymptomatic (smoldering) and symptomatic WM, suggesting that environmental and clonal changes occur in patients at early stages of disease progression before symptoms occur. Moreover, we identified a small group of miRNAs whose expression correlated directly or inversely with the disease status of patients, notably the known tumor suppressor miRNAs let-7d and the oncogene miR-21 as well as miR-192 and miR-320b. The study of these miRNAs’ specific effect in WM cells could help us gain further insights on the mechanisms underlying WM pathogenesis and reveal their potential as novel therapeutic targets for this disease.
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Affiliation(s)
- Juliette M. Bouyssou
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, United States of America
- Université Paris-Saclay / Hôpital Necker-Enfants Malades, Paris, France
| | - Chia-Jen Liu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, United States of America
- Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Mark Bustoros
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, United States of America
| | - Romanos Sklavenitis-Pistofidis
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, United States of America
| | - Yosra Aljawai
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, United States of America
| | - Salomon Manier
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, United States of America
| | - Amir Yosef
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, United States of America
| | - Antonio Sacco
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, United States of America
| | - Katsutoshi Kokubun
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, United States of America
| | - Shokichi Tsukamoto
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, United States of America
| | - Adriana Perilla Glen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, United States of America
| | - Daisy Huynh
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, United States of America
| | - Jorge J. Castillo
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, United States of America
| | - Steven P. Treon
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, United States of America
| | - Véronique Leblond
- Department of Hematology at Pitié Salpêtrière Hospital, Paris, France
| | - Olivier Hermine
- INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Paris, France
| | - Aldo M. Roccaro
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, United States of America
| | - Irene M. Ghobrial
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, United States of America
- * E-mail: (MC); (IMG)
| | - Marzia Capelletti
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, United States of America
- * E-mail: (MC); (IMG)
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50
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Prospects of Noncoding RNAs in Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2018; 2018:6579436. [PMID: 30148169 PMCID: PMC6083484 DOI: 10.1155/2018/6579436] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 05/16/2018] [Accepted: 06/06/2018] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a global health problem and one of the most common malignant tumors. Recent studies have shown that noncoding RNAs (ncRNAs) contribute to the pathogenesis of hepatocellular carcinoma (HCC). These RNAs may be involved in a variety of pathological processes such as cell proliferation, apoptosis, angiogenesis, invasion, and metastasis. In addition, abnormal expression of ncRNAs in HCC may provide potential prognostic or diagnostic biomarkers. This review provides an overview of the role and potential applications of ncRNAs, miRNAs, lncRNAs, circRNAs, and snoRNAs in liver cancer.
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