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Öz H, Canacankatan N, Antmen ŞE, Aytan H, Tuncel F. 'Investigation of miRNAs That Affect the PI3K/AKT/mTOR Signaling Pathway in Endometrial Cancer'. Cell Biochem Biophys 2025:10.1007/s12013-025-01694-6. [PMID: 39982560 DOI: 10.1007/s12013-025-01694-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/04/2025] [Indexed: 02/22/2025]
Abstract
Endometrial cancer is a prevalent type of cancer among women worldwide. The irregularity of the PI3K/AKT/mTOR signaling pathway plays a role in the pathogenesis of many cancer types. MicroRNAs are small noncoding RNAs that play crucial roles in the pathogenesis of different cancer types. MicroRNAs target many key components of the PI3K/AKT/mTOR pathway in human tumors. In this study the PI3K/AKT/mTOR pathway was affected in endometrial cancer, and the expression levels of miR-7, miR-17, miR-145, miR-155, miR-206, miR-221, miR-222 were determined. In addition, in silico analyses were examine the molecular interactions between miRNAs and target genes. Identifying dysregulated miRNA expression in endometrial cancer is important for developing miRNA-based therapeutic strategies. In our study, Grade 1 (n = 16), Grade 2 (n = 16), Grade 3 (n = 16), tissues diagnosed with endometrioid adeno carcinoma, control 1 (n = 16) secretory phase and control 2 (n = 16) proliferative phase healthy endometrial tissues without endometrial cancer were included. miRNA expression analysis was performed using the real-time PCR. In our study, the expression of miR-7-5p, miR-145-5p, and miR-206 decreased, whereas the expression of miR-17-5p, miR-221-3p, and miR-222-3p increased in endometrial cancer (p < 0,05). Statistically significant results were not obtained to for the expression levels of miR-21-5p and miR-155-5p. miR-7-5p targets PIK3CD, PIK3R3, PIK3CB and AKT3, miR-17-5p targets PIK3R1 and AKT3, miR-21-5p target PIK3R1, miR-145-5p target AKT3, miR-155-5p targets PIK3CA and PIK3R1, miR-206 target PIK3C2A, miR-221-3p and miR-222-3p target PIK3R1 as identified via in silico analysis. These results can shed light on the development of molecular-targeted therapy strategies. Treatment strategies can be developed by designing ASOs, LNAs, miRNA antagomirs, or miRNA sponges for upregulated miR-17-5p, miR-221-3p, and miR-222-3p, and miRNA mimics for downregulated miR-7-5p, miR-145-5p, and miR-206.
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Affiliation(s)
- Hasan Öz
- Department of Biochemistry, Faculty of Pharmacy, Mersin University, Mersin, Turkey
| | - Necmiye Canacankatan
- Department of Biochemistry, Faculty of Pharmacy, Mersin University, Mersin, Turkey.
| | - Şerife Efsun Antmen
- Department of Biochemistry, Faculty of Pharmacy, Mersin University, Mersin, Turkey
| | - Hakan Aytan
- Department of Obstetrics and Gynecology, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Ferah Tuncel
- Department of Pathology, Faculty of Medicine, Mersin University, Mersin, Turkey
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Younis MA, Harashima H. Understanding Gene Involvement in Hepatocellular Carcinoma: Implications for Gene Therapy and Personalized Medicine. Pharmgenomics Pers Med 2024; 17:193-213. [PMID: 38737776 PMCID: PMC11088404 DOI: 10.2147/pgpm.s431346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 04/09/2024] [Indexed: 05/14/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the dominant type of liver cancers and is one of the deadliest health threats globally. The conventional therapeutic options for HCC are hampered by low efficiency and intolerable side effects. Gene therapy, however, now offers hope for the treatment of many disorders previously considered incurable, and gene therapy is beginning to address many of the shortcomings of conventional therapies. Herein, we summarize the involvement of genes in the pathogenesis and prognosis of HCC, with a special focus on dysregulated signaling pathways, genes involved in immune evasion, and non-coding RNAs as novel two-edged players, which collectively offer potential targets for the gene therapy of HCC. Herein, the opportunities and challenges of HCC gene therapy are discussed. These include innovative therapies such as genome editing and cell therapies. Moreover, advanced gene delivery technologies that recruit nanomedicines for use in gene therapy for HCC are highlighted. Finally, suggestions are offered for improved clinical translation and future directions in this area of endeavor.
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Affiliation(s)
- Mahmoud A Younis
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan
- Department of Industrial Pharmacy, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt
| | - Hideyoshi Harashima
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan
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Wu L, Zhang Y, Ren J. Targeting non-coding RNAs and N 6-methyladenosine modification in hepatocellular carcinoma. Biochem Pharmacol 2024; 223:116153. [PMID: 38513741 DOI: 10.1016/j.bcp.2024.116153] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 03/08/2024] [Accepted: 03/18/2024] [Indexed: 03/23/2024]
Abstract
Hepatocellular carcinoma (HCC), the most common form of primary liver cancers, accounts for a significant portion of cancer-related death globally. However, the molecular mechanisms driving the onset and progression of HCC are still not fully understood. Emerging evidence has indicated that non-protein-coding regions of genomes could give rise to transcripts, termed non-coding RNA (ncRNA), forming novel functional driving force for aberrant cellular activity. Over the past decades, overwhelming evidence has denoted involvement of a complex array of molecular function of ncRNAs at different stages of HCC tumorigenesis and progression. In this context, several pre-clinical studies have highlighted the potentials of ncRNAs as novel therapeutic modalities in the management of human HCC. Moreover, N6-methyladenosine (m6A) modification, the most prevalent form of internal mRNA modifications in mammalian cells, is essential for the governance of biological processes within cells. Dysregulation of m6A in ncRNAs has been implicated in human carcinogenesis, including HCC. In this review, we will discuss dysregulation of several hallmark ncRNAs (miRNAs, lncRNAs, and circRNAs) in HCC and address the latest advances for their involvement in the onset and progression of HCC. We also focus on dysregulation of m6A modification and various m6A regulators in the etiology of HCC. In the end, we discussed the contemporary preclinical and clinical application of ncRNA-based and m6A-targeted therapies in HCC.
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Affiliation(s)
- Lin Wu
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Yingmei Zhang
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Jun Ren
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
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V Deligiorgi M, T Trafalis D. Refining personalized diagnosis, treatment and exploitation of hypothyroidism related to solid nonthyroid cancer. Per Med 2022; 20:87-105. [DOI: 10.2217/pme-2022-0052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
Hypothyroidism in the setting of cancer is a puzzling entity due to the dual role of the thyroid hormones (TH) in cancer – promoting versus inhibitory – and the complexity of the hypothyroidism itself. The present review provides a comprehensive overview of the personalized approach to hypothyroidism in patients with solid nonthyroid cancer, focusing on current challenges, unmet needs and future perspectives. Major electronic databases were searched from January 2011 until March 2022. The milestones of the refinement of such a personalized approach are prompt diagnosis, proper TH replacement and development of interventions and/or pharmaceutical agents to exploit hypothyroidism or, on the contrary, TH replacement as an anticancer strategy. Further elucidation of the dual role of TH in cancer – especially of the interference of TH signaling with the hallmarks of cancer – is anticipated to inform decision-making and optimize patient selection.
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Affiliation(s)
- Maria V Deligiorgi
- Department of Pharmacology – Clinical Pharmacology Unit, National and Kapodistrian University of Athens, Faculty of Medicine, Building 16, 1st Floor, 75 Mikras Asias, Goudi, Athens, 11527, Greece
| | - Dimitrios T Trafalis
- Department of Pharmacology – Clinical Pharmacology Unit, National and Kapodistrian University of Athens, Faculty of Medicine, Building 16, 1st Floor, 75 Mikras Asias, Goudi, Athens, 11527, Greece
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Xie RT, Li QY, Sun XC, Zhi QJ, Huang XX, Zhu XC, Miao QZ, Zhou DZ, Han DY. Hypomethylation of Thyroid Peroxidase as a Biomarker for Hepatocellular Carcinoma with Tumor Thrombosis. Curr Med Sci 2022; 42:1248-1255. [PMID: 36542322 DOI: 10.1007/s11596-022-2643-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 12/31/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Thyroid hormones (THs) regulate multiple physiological activities in the liver, including cellular metabolism, differentiation, and cell growth, and play important roles in the pathogenesis of hepatocellular carcinoma (HCC). Thyroid peroxidase (TPO) is a key molecule involved in the THs synthesis and signaling pathway. As an epigenetic modification, DNA methylation has a critical role in tumorigenesis with diagnostic potential. However, the connection between THs and DNA methylation has been rarely investigated. METHODS The methylation of key TH-related genes was analyzed by in-house epigenome-wide scanning, and we further analyzed the methylation levels of the TPO promotor in 164 sample pairs of HCC and adjacent non-cancerous tissues by Sequenom EpiTYPER assays, and evaluated their clinical implications. RESULTS We identified that the methylation of the TPO promoter was downregulated in the HCC tissues (P<0.0001) with a mean difference ranging from 18.5% to 22.3%. This methylation pattern correlated with several clinical factors, including a multi-satellite tumor, fibrous capsule, and the presence of tumor thrombus. The receiver operator characteristic (ROC) curve analysis further confirmed that the percent methylated reference (PMR) values for TPO were predictive of the tumor [the area under the curve (AUC) ranged from 0.755 to 0.818] and the thrombosis in the HCC patients (the AUC ranged from 0.706 to 0.777). CONCLUSION These findings demonstrated that epigenetic alterations of TPO, as indicated by the PMR values, were a potential biomarker for HCC patients with tumor thrombosis.
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Affiliation(s)
- Ru-Ting Xie
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Qian-Yu Li
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Xue-Chen Sun
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Qing-Jun Zhi
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Xiang-Xiang Huang
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Xing-Chen Zhu
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Qi-Zeng Miao
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Dai-Zhan Zhou
- Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200000, China.
| | - Dong-Yan Han
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
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Guo X, Jiao H, Cao L, Meng F. Biological implications and clinical potential of invasion and migration related miRNAs in glioma. Front Integr Neurosci 2022; 16:989029. [PMID: 36479040 PMCID: PMC9720134 DOI: 10.3389/fnint.2022.989029] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 11/07/2022] [Indexed: 12/01/2024] Open
Abstract
Gliomas are the most common primary malignant brain tumors and are highly aggressive. Invasion and migration are the main causes of poor prognosis and treatment resistance in gliomas. As migration and invasion occur, patient survival and prognosis decline dramatically. MicroRNAs (miRNAs) are small, non-coding 21-23 nucleotides involved in regulating the malignant phenotype of gliomas, including migration and invasion. Numerous studies have demonstrated the mechanism and function of some miRNAs in glioma migration and invasion. However, the biological and clinical significance (including diagnosis, prognosis, and targeted therapy) of glioma migration and invasion-related miRNAs have not been systematically discussed. This paper reviews the progress of miRNAs-mediated migration and invasion studies in glioma and discusses the clinical value of migration and invasion-related miRNAs as potential biomarkers or targeted therapies for glioma. In addition, these findings are expected to translate into future directions and challenges for clinical applications. Although many biomarkers and their biological roles in glioma invasion and migration have been identified, none have been specific so far, and further exploration of clinical treatment is still in progress; therefore, we aimed to further identify specific markers that may guide clinical treatment and improve the quality of patient survival.
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Affiliation(s)
| | | | | | - Facai Meng
- Department of Neurosurgery, Shaanxi Provincial People's Hospital, Xi'an, China
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Deligiorgi MV, Trafalis DT. The Clinical Relevance of Hypothyroidism in Patients with Solid Non-Thyroid Cancer: A Tantalizing Conundrum. J Clin Med 2022; 11:3417. [PMID: 35743483 PMCID: PMC9224934 DOI: 10.3390/jcm11123417] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/06/2022] [Accepted: 06/08/2022] [Indexed: 02/06/2023] Open
Abstract
Hypothyroidism in patients with solid non-thyroid cancer is a tantalizing entity, integrating an intriguing thyroid hormones (THs)-cancer association with the complexity of hypothyroidism itself. The present narrative review provides a comprehensive overview of the clinical relevance of hypothyroidism in solid non-thyroid cancer. Hypothyroidism in patients with solid non-thyroid cancer is reminiscent of hypothyroidism in the general population, yet also poses distinct challenges due to the dual role of THs in cancer: promoting versus inhibitory. Close collaboration between oncologists and endocrinologists will enable the prompt and personalized diagnosis and treatment of hypothyroidism in patients with solid non-thyroid cancer. Clinical data indicate that hypothyroidism is a predictor of a decreased or increased risk of solid non-thyroid cancer and is a prognostic factor of favorable or unfavorable prognosis in solid non-thyroid cancer. However, the impact of hypothyroidism with respect to the risk and/or prognosis of solid non-thyroid cancer is not a consistent finding. To harness hypothyroidism, or THs replacement, as a personalized anticancer strategy for solid non-thyroid cancer, four prerequisites need to be fulfilled, namely: (i) deciphering the dual THs actions in cancer; (ii) identifying interventions in THs status and developing agents that block tumor-promoting THs actions and/or mimic anticancer THs actions; (iii) appropriate patient selection; and (iv) counteracting current methodological limitations.
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Affiliation(s)
- Maria V. Deligiorgi
- Department of Pharmacology—Clinical Pharmacology Unit, Faculty of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias Str., Goudi, 11527 Athens, Greece;
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Tang Q, Zeng M, Chen L, Fu N. Targeting Thyroid Hormone/Thyroid Hormone Receptor Axis: An Attractive Therapy Strategy in Liver Diseases. Front Pharmacol 2022; 13:871100. [PMID: 35721201 PMCID: PMC9201453 DOI: 10.3389/fphar.2022.871100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 04/19/2022] [Indexed: 12/24/2022] Open
Abstract
Thyroid hormone/thyroid hormone receptor (TH/TR) axis is characterized by TH with the assistance of plasma membrane transporters to combine with TR and mediate biological activities. Growing evidence suggests that TH/TR participates in plenty of hepatic metabolism. Thus, this review focuses on the role of the TH/TR axis in the liver diseases. To be specific, the TH/TR axis may improve metabolic-associated fatty liver disease, hepatitis, liver fibrosis, and liver injury while exacerbating the progression of acute liver failure and alcoholic liver disease. Also, the TH/TR axis has paradoxical roles in hepatocellular carcinoma. The TH/TR axis may be a prospecting target to cure hepatic diseases.
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Affiliation(s)
- Qianyu Tang
- Department of Gastroenterology, The Affiliated Nanhua Hospital, Hunan Provincial Clinical Research Center of Metabolic Associated Fatty Liver Disease, Hengyang Medical School, University of South China, Hengyang, China
| | - Min Zeng
- Department of Gastroenterology, Liuyang Hospital of Chinese Medicine, Changsha, China
| | - Linxi Chen
- Department of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Basic Medical Science, Hengyang Medical School, University of South China, Hengyang, China
| | - Nian Fu
- Department of Gastroenterology, The Affiliated Nanhua Hospital, Hunan Provincial Clinical Research Center of Metabolic Associated Fatty Liver Disease, Hengyang Medical School, University of South China, Hengyang, China
- The Affiliated Nanhua Hospital, Laboratory of Liver Disease, Institute of Clinical Research, Hengyang Medical School, University of South China, Hengyang, China
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Zhang B, Zhou J. CircSEC24A (hsa_circ_0003528) interference suppresses epithelial-mesenchymal transition of hepatocellular carcinoma cells via miR-421/MMP3 axis. Bioengineered 2022; 13:9049-9062. [PMID: 35400271 PMCID: PMC9161912 DOI: 10.1080/21655979.2022.2057761] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Accumulating evidence indicates that circular RNAs (circRNAs) function as conclusive modulators in diverse tumors, including in hepatocellular carcinoma (HCC). Nonetheless, knowledge of the latent mechanisms involving circRNAs in HCC development is insufficient. circSEC24A (hsa_circ_0003528) was discovered by microarray analysis of patients with HCC. Binding sites between circSEC24A, miR-421, miR-421 and matrix metalloproteinase 3 (MMP3) were predicted using online bioinformatics tools. Interactions involving miRNA and target genes or circRNAs were verified by luciferase reporter-gene and RNA pull-down assays. Two HCC cell lines (HCCLM3 and Hep3B) and normal THLE-2 liver cells were used for in vitro experiments. miRNA and mRNA expression levels were detected by RT-qPCR, and protein expression was measured by western blotting. Cell proliferation was evaluated using Cell Counting Kit 8 (CCK-8) assays along with colony formation assays. Cell invasion and migration were determined using the Transwell and wound healing migration assays. A xenograft model was used to evaluate the role of circSEC24A in vivo. circSEC24A expression was significantly upregulated in HCCLM3 and Hep3B cells. Silencing circSEC24A mitigated the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells, which was abrogated by downregulation of miR-421. Meanwhile, MMP3 could bind to miR-421 to decrease the functional effects of miR-421 and induce tumor metastasis. Knockdown of cicSEC24A suppressed tumor growth in vivo. circSEC24A interference suppressed HCC cell EMT by sponging miR-421, further regulating MMP3, and inhibiting tumor growth in vivo. Therefore, circSEC24A could represent a potential target for HCC patient treatment.
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Affiliation(s)
- Bo Zhang
- Department of Basic Medicine, Chongqing Medical and Pharmaceutical College, Chongqing, China
| | - Jian Zhou
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Department of Pathology, the First Affiliated Hospital of ChengDu Medical College, Chengdu, Sichuan, China
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Deligiorgi MV, Trafalis DT. The Intriguing Thyroid Hormones-Lung Cancer Association as Exemplification of the Thyroid Hormones-Cancer Association: Three Decades of Evolving Research. Int J Mol Sci 2021; 23:436. [PMID: 35008863 PMCID: PMC8745569 DOI: 10.3390/ijms23010436] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/22/2021] [Accepted: 12/28/2021] [Indexed: 12/21/2022] Open
Abstract
Exemplifying the long-pursued thyroid hormones (TH)-cancer association, the TH-lung cancer association is a compelling, yet elusive, issue. The present narrative review provides background knowledge on the molecular aspects of TH actions, with focus on the contribution of TH to hallmarks of cancer. Then, it provides a comprehensive overview of data pertinent to the TH-lung cancer association garnered over the last three decades and identifies obstacles that need to be overcome to enable harnessing this association in the clinical setting. TH contribute to all hallmarks of cancer through integration of diverse actions, currently classified according to molecular background. Despite the increasingly recognized implication of TH in lung cancer, three pending queries need to be resolved to empower a tailored approach: (1) How to stratify patients with TH-sensitive lung tumors? (2) How is determined whether TH promote or inhibit lung cancer progression? (3) How to mimic the antitumor and/or abrogate the tumor-promoting TH actions in lung cancer? To address these queries, research should prioritize the elucidation of the crosstalk between TH signaling and oncogenic signaling implicated in lung cancer initiation and progression, and the development of efficient, safe, and feasible strategies leveraging this crosstalk in therapeutics.
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Affiliation(s)
- Maria V. Deligiorgi
- Department of Pharmacology—Clinical Pharmacology Unit, Faculty of Medicine, National and Kapodistrian University of Athens, Building 16, 1st Floor, 75 Mikras Asias Str, 11527 Athens, Greece;
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Low thyroid hormone receptor alpha-2 (THRα-2) tumor expression is associated with unfavorable tumor characteristics and high breast cancer mortality. Breast Cancer Res 2021; 23:117. [PMID: 34930399 PMCID: PMC8691018 DOI: 10.1186/s13058-021-01496-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 12/13/2021] [Indexed: 11/10/2022] Open
Abstract
Background The active thyroid hormone triiodothyronine (T3) has been found to have an estrogen-like effect on breast cancer cells. Thyroid hormone receptor alpha-2 (THRα-2) acts as an antagonist for triiodothyronine (T3) signaling, and a low expression has been associated with unfavorable tumor characteristics and a higher mortality in breast cancer. However, the evidence are not conclusive. The present study evaluates tumor-specific THRα-2 expression in invasive breast cancers and its association with tumor characteristics and long-term mortality in a large population. Method The Malmö Diet and Cancer Study (MDCS), a population-based cohort in Sweden that included 17,035 women from 1991 to 1996, was used. Women diagnosed with breast cancer during 1991–2010 were eligible for inclusion. A tissue micro array was constructed from stored tumor material and stained for THRα-2 using immunohistochemistry. Tumors from 654 patients were scored regarding the intensity and the fraction of cells stained, then dichotomized into low or high expression. Date and cause of death were collected up until 2018-12-31. Tumor- and patient characteristics were available from the MDCS. Missing data was imputed using chained equations. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for low vs high expression of THRα-2 related to specific tumor factors. Mortality was evaluated with Kaplan–Meier curves and Cox regression, rendering hazard ratios (HRs). Analyses were also stratified for estrogen receptor (ER) status. Results We found strong evidence of an association between low THRα-2 and unfavorable tumor characteristics, including estrogen receptor negativity: OR 4.04 (95% CI 2.28–7.15) and tumor size > 20–50 mm: OR 2.20 (95% CI 1.39–3.49). We found evidence of increased breast cancer-specific mortality for women with low THRα-2, HR 1.38 (95% CI 0.96–1.99), which remained after adjusting for age at diagnosis, HR 1.48 (95% CI 1.03–2.14), but not after adjusting for relevant prognostic factors, HR 0.98 (95% CI 0.66–1.45). THRα-2 expression in ER-negative tumors had an inverse correlation with overall mortality, HR 0.27 (95% CI 0.11–0.65). Conclusion Low tumor-specific THRα-2 expression was in this study associated with prognostically unfavorable tumor characteristics and a higher mortality in breast cancer, but not independent from other prognostic factors. Supplementary Information The online version contains supplementary material available at 10.1186/s13058-021-01496-7.
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Huang PS, Chang CC, Wang CS, Lin KH. Functional roles of non-coding RNAs regulated by thyroid hormones in liver cancer. Biomed J 2021; 44:272-284. [PMID: 33077406 PMCID: PMC8358202 DOI: 10.1016/j.bj.2020.08.009] [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: 07/08/2020] [Revised: 08/19/2020] [Accepted: 08/24/2020] [Indexed: 02/06/2023] Open
Abstract
Recent reports have shown the important role of the non-coding part of human genome RNA (ncRNA) in cancer formation and progression. Among several kinds of ncRNAs, microRNAs (miRNA) play a pivotal role in cancer biology. Accumulating researches have been focused on the importance of non-coding genes in various diseases. In addition to miRNAs, long non-coding RNAs (lncRNAs) have also been extensively documented. Recently, the study of human liver cancer has gradually shifted to these non-coding RNAs that were originally considered "junk". Notably, dysregulated ncRNAs maybe influence on cell proliferation, angiogenesis, anti-apoptosis, and metastasis. Thyroid hormones play critical roles in human development and abnormalities in thyroid hormone levels are associated with various diseases, such as liver cancer. Thyroid hormone receptors (TR) act as ligand-activated nuclear transcription factors to affect multiple functions through the gene-level regulation in the cells and several studies have revealed that thyroid hormone associated with ncRNAs expression. TR actions are complex and tissue- and time-specific, aberrant expression of the various TR isoforms have different effects and are associated with different types of tumor or stages of development. In this review, we discuss various aspects of the research on the thyroid hormones modulated ncRNAs to affect the functions of human liver cells.
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Affiliation(s)
- Po-Shuan Huang
- Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Chih Chang
- Department of General Surgery, Chang Gung Memorial Hospital at Chia yi, Chia yi, Taiwan
| | - Chia-Siu Wang
- Department of General Surgery, Chang Gung Memorial Hospital at Chia yi, Chia yi, Taiwan
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan; Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
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Wu J, Nagy LE, Liangpunsakul S, Wang L. Non-coding RNA crosstalk with nuclear receptors in liver disease. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166083. [PMID: 33497819 PMCID: PMC7987766 DOI: 10.1016/j.bbadis.2021.166083] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 12/28/2020] [Accepted: 01/16/2021] [Indexed: 02/06/2023]
Abstract
The dysregulation of nuclear receptors (NRs) underlies the pathogenesis of a variety of liver disorders. Non-coding RNAs (ncRNAs) are defined as RNA molecules transcribed from DNA but not translated into proteins. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are two types of ncRNAs that have been extensively studied for regulating gene expression during diverse cellular processes. NRs as therapeutic targets in liver disease have been exemplified by the successful application of their pharmacological ligands in clinics. MiRNA-based reagents or drugs are emerging as flagship products in clinical trials. Advancing our understanding of the crosstalk between NRs and ncRNAs is critical to the development of diagnostic and therapeutic strategies. This review summarizes recent findings on the reciprocal regulation between NRs and ncRNAs (mainly on miRNAs and lncRNAs) and their implication in liver pathophysiology, which might be informative to the translational medicine of targeting NRs and ncRNAs in liver disease.
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Affiliation(s)
- Jianguo Wu
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America; Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, United States of America.
| | - Laura E Nagy
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America; Department of Gastroenterology and Hepatology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America; Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, United States of America
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America; Roudebush Veterans Administration Medical Center, Indianapolis, IN, United States of America; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States of America
| | - Li Wang
- Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT, United States of America
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14
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Aranda A. MicroRNAs and thyroid hormone action. Mol Cell Endocrinol 2021; 525:111175. [PMID: 33515639 DOI: 10.1016/j.mce.2021.111175] [Citation(s) in RCA: 12] [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: 11/06/2020] [Revised: 12/29/2020] [Accepted: 01/21/2021] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally repress gene expression by binding generally to the 3'-untranslated regions of their target mRNAs. miRNAs regulate a large fraction of the genome, playing a key role in most physiological and pathological processes. The thyroid hormones (T4 and T3) are major regulators of development, metabolism and cell growth. The thyroid hormones (THs) are synthetized in the thyroid gland and enter the cells through transporter proteins. In the cells, T4 and T3 are metabolized by deiodinase enzymes and bind to nuclear receptors (TRs), which have a higher affinity by T3. TRs act as hormone dependent transcription factors by binding to thyroid hormone response elements (TREs) in the target genes and recruiting transcriptional coregulators. There is increasing evidence that a variety of miRNAs target deiodinases and the receptor, thus regulating TH signaling is different tissues. In turn, the THs have been shown to modulate the expression of specific miRNAs and their mRNA targets in different cell types and organs. In many cases, the existence of TREs in the regulatory regions of these miRNAs has been identified, and the hormone bound receptors transcriptionally regulate expression of these molecules. Changes in the levels of miRNAs have been demonstrated to mediate some of the important actions of the THs in processes such as muscle and heart function, lipid liver metabolism or skin physiology. In addition, miRNA regulation is involved in the effects of TRs on cell proliferation and cancer.
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Affiliation(s)
- Ana Aranda
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
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15
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De Luca R, Davis PJ, Lin HY, Gionfra F, Percario ZA, Affabris E, Pedersen JZ, Marchese C, Trivedi P, Anastasiadou E, Negro R, Incerpi S. Thyroid Hormones Interaction With Immune Response, Inflammation and Non-thyroidal Illness Syndrome. Front Cell Dev Biol 2021; 8:614030. [PMID: 33553149 PMCID: PMC7859329 DOI: 10.3389/fcell.2020.614030] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 12/14/2020] [Indexed: 12/14/2022] Open
Abstract
The interdependence between thyroid hormones (THs), namely, thyroxine and triiodothyronine, and immune system is nowadays well-recognized, although not yet fully explored. Synthesis, conversion to a bioactive form, and release of THs in the circulation are events tightly supervised by the hypothalamic-pituitary-thyroid (HPT) axis. Newly synthesized THs induce leukocyte proliferation, migration, release of cytokines, and antibody production, triggering an immune response against either sterile or microbial insults. However, chronic patho-physiological alterations of the immune system, such as infection and inflammation, affect HPT axis and, as a direct consequence, THs mechanism of action. Herein, we revise the bidirectional crosstalk between THs and immune cells, required for the proper immune system feedback response among diverse circumstances. Available circulating THs do traffic in two distinct ways depending on the metabolic condition. Mechanistically, internalized THs form a stable complex with their specific receptors, which, upon direct or indirect binding to DNA, triggers a genomic response by activating transcriptional factors, such as those belonging to the Wnt/β-catenin pathway. Alternatively, THs engage integrin αvβ3 receptor on cell membrane and trigger a non-genomic response, which can also signal to the nucleus. In addition, we highlight THs-dependent inflammasome complex modulation and describe new crucial pathways involved in microRNA regulation by THs, in physiological and patho-physiological conditions, which modify the HPT axis and THs performances. Finally, we focus on the non-thyroidal illness syndrome in which the HPT axis is altered and, in turn, affects circulating levels of active THs as reported in viral infections, particularly in immunocompromised patients infected with human immunodeficiency virus.
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Affiliation(s)
- Roberto De Luca
- Department of Neurology, Center for Life Science, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Paul J. Davis
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, United States
- Albany Medical College, Albany, NY, United States
| | - Hung-Yun Lin
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, United States
- Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
| | - Fabio Gionfra
- Department of Sciences, University “Roma Tre,” Rome, Italy
| | | | | | - Jens Z. Pedersen
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Cinzia Marchese
- Department of Experimental Medicine, University “La Sapienza,” Rome, Italy
| | - Pankaj Trivedi
- Department of Experimental Medicine, University “La Sapienza,” Rome, Italy
| | - Eleni Anastasiadou
- Department of Experimental Medicine, University “La Sapienza,” Rome, Italy
| | - Roberto Negro
- National Institute of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “S. de Bellis” Research Hospital, Castellana Grotte, Italy
| | - Sandra Incerpi
- Department of Sciences, University “Roma Tre,” Rome, Italy
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16
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Grzywa TM, Klicka K, Włodarski PK. Regulators at Every Step-How microRNAs Drive Tumor Cell Invasiveness and Metastasis. Cancers (Basel) 2020; 12:E3709. [PMID: 33321819 PMCID: PMC7763175 DOI: 10.3390/cancers12123709] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/03/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023] Open
Abstract
Tumor cell invasiveness and metastasis are the main causes of mortality in cancer. Tumor progression is composed of many steps, including primary tumor growth, local invasion, intravasation, survival in the circulation, pre-metastatic niche formation, and metastasis. All these steps are strictly controlled by microRNAs (miRNAs), small non-coding RNA that regulate gene expression at the post-transcriptional level. miRNAs can act as oncomiRs that promote tumor cell invasion and metastasis or as tumor suppressor miRNAs that inhibit tumor progression. These miRNAs regulate the actin cytoskeleton, the expression of extracellular matrix (ECM) receptors including integrins and ECM-remodeling enzymes comprising matrix metalloproteinases (MMPs), and regulate epithelial-mesenchymal transition (EMT), hence modulating cell migration and invasiveness. Moreover, miRNAs regulate angiogenesis, the formation of a pre-metastatic niche, and metastasis. Thus, miRNAs are biomarkers of metastases as well as promising targets of therapy. In this review, we comprehensively describe the role of various miRNAs in tumor cell migration, invasion, and metastasis.
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Affiliation(s)
- Tomasz M. Grzywa
- Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland; (T.M.G.); (K.K.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
- Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Klaudia Klicka
- Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland; (T.M.G.); (K.K.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Paweł K. Włodarski
- Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland; (T.M.G.); (K.K.)
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17
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Liu DL, Lu LL, Dong LL, Liu Y, Bian XY, Lian BF, Xie L, Wen D, Gao DM, Ke AW, Fan J, Wu WZ. miR-17-5p and miR-20a-5p suppress postoperative metastasis of hepatocellular carcinoma via blocking HGF/ERBB3-NF-κB positive feedback loop. Theranostics 2020; 10:3668-3683. [PMID: 32206115 PMCID: PMC7069088 DOI: 10.7150/thno.41365] [Citation(s) in RCA: 39] [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: 10/21/2019] [Accepted: 02/07/2020] [Indexed: 12/14/2022] Open
Abstract
Dysregulation of microRNA (miRNA) is a frequent event in hepatocellular carcinoma (HCC), but little is known whether it is a bystander or an actual player on residual HCC metastasis during liver microenvironment remodeling initiated by hepatectomy. Methods: The differently expressed miRNAs and mRNAs were identified from RNA-seq data. Western blot, qRT-PCR, fluorescence in situ hybridization, immunofluorescence and immunohistochemical were used to detect the expression of miRNA and mRNA in cell lines and patient tissues. The biological functions were investigated in vitro and in vivo. Chromatin immunoprecipitation, proximity ligation and luciferase reporter assay were used to explore the specific binding of target genes. The expression of HGF/ERBB3 signaling was detected by Western blot. Results: In this study, HGF induced by hepatectomy was shown to promote metastasis of residual HCC cells. miR-17-5p and miR-20a-5p were confirmed to play inhibitory roles on HCC metastasis. And ERBB3 was found to be the common target of miR-17-5p and miR-20a-5p. HCC cells with lower levels of miR-17-5p and miR-20a-5p or higher level of ERBB3 were often more sensitive to response HGF stimuli and to facilitate metastatic colonization both in vitro and in vivo experimental systems. Furthermore, HGF reinforced ERBB3 expression by NF-κB transcriptional activity in a positive feedback loop. Of particular importance, HCC patients with lower levels of miR-17-5p and miR-20a-5p or higher level of ERBB3 had significantly shorter OS and PFS survivals after surgical resection. Conclusion: miR-17-5p and miR-20a-5p could suppress postoperative metastasis of hepatocellular carcinoma via blocking HGF/ERBB3-NF-κB positive feedback loop and offer a new probable strategy for metastasis prevention after HCC resection.
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Affiliation(s)
- Dong-Li Liu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Li-Li Lu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Li-Li Dong
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Yang Liu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Xin-Yu Bian
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Bao-Feng Lian
- Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai 201203, China
| | - Lu Xie
- Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai 201203, China
| | - Duo Wen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Dong-Mei Gao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Ai-Wu Ke
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
- Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Wei-Zhong Wu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
- Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
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18
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Ma Y, Cang S, Li G, Su Y, Zhang H, Wang L, Yang J, Shi X, Qin G, Yuan H. Integrated analysis of transcriptome data revealed MMP3 and MMP13 as critical genes in anaplastic thyroid cancer progression. J Cell Physiol 2019; 234:22260-22271. [PMID: 31081124 DOI: 10.1002/jcp.28793] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 03/30/2019] [Accepted: 04/24/2019] [Indexed: 02/06/2023]
Abstract
To better understand the molecular mechanisms of anaplastic thyroid carcinoma (ATC), we aimed to identify the hub genes specifically involved in ATC by integrated bioinformatics analysis. In this study, using three Gene Expression Omnibus data sets with the same platform GPL570, we screened hub genes involved in ATC progression. In vitro experiments, such as western blot analysis, Transwell assays, and coimmunoprecipitation, was performed to verify our findings. By comparing three subtypes of thyroid cancer with normal tissue, we found ATC harbored more changed genes than well and poorly differentiated thyroid cancer. Using specifically differentially expressed genes between ATC and normal thyroid tissues to perform Gene ontology (GO) analysis, ATC showed enrichments of GO terms involved in lymphocyte migration and activation, collagen catabolic and metabolic process, thyroid hormone synthesis, and embolism. Using genes involved in extracellular matrix, coexpression network analysis and protein-protein interaction analysis were performed to identify matrix metalloproteinase 3 (MMP3) and MMP13 as two hub genes. Our experimental data indicated that both MMP3 and MMP13 were upregulated in ATC and knockdown of either of them could notably suppress ATC cell invasion and migration. Mechanistically, Gene Set Enrichment Analysis, coimmunoprecipitation, and rescue experiments revealed MMP3 and MMP13 not only interacted with each other, but also regulated each other through the janus kinase/signal transducer and activator of transcription 3 and mammalian target of rapamycin pathways. In conclusion, we identified a specific molecular mechanisms for the development of ATC by integrated analysis of transcriptome and in vitro experiments, which suggested that MMP3 and MMP13 might be developed as novel therapeutic targets for ATC.
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Affiliation(s)
- Yuehua Ma
- Department of Endocrinology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China
| | - Shundong Cang
- Department of Oncology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China
| | - Guoqing Li
- Department of Breast Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China
| | - Yong Su
- Department of Endocrinology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China
| | - Huifeng Zhang
- Department of Endocrinology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China
| | - Limin Wang
- Department of Endocrinology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China
| | - Junpeng Yang
- Department of Endocrinology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China
| | - Xiaoyang Shi
- Department of Endocrinology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China
| | - Guijun Qin
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Huijuan Yuan
- Department of Endocrinology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China
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19
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Huang PS, Wang CS, Yeh CT, Lin KH. Roles of Thyroid Hormone-Associated microRNAs Affecting Oxidative Stress in Human Hepatocellular Carcinoma. Int J Mol Sci 2019; 20:E5220. [PMID: 31640265 PMCID: PMC6834183 DOI: 10.3390/ijms20205220] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 10/17/2019] [Accepted: 10/18/2019] [Indexed: 02/07/2023] Open
Abstract
Oxidative stress occurs as a result of imbalance between the generation of reactive oxygen species (ROS) and antioxidant genes in cells, causing damage to lipids, proteins, and DNA. Accumulating damage of cellular components can trigger various diseases, including metabolic syndrome and cancer. Over the past few years, the physiological significance of microRNAs (miRNA) in cancer has been a focus of comprehensive research. In view of the extensive level of miRNA interference in biological processes, the roles of miRNAs in oxidative stress and their relevance in physiological processes have recently become a subject of interest. In-depth research is underway to specifically address the direct or indirect relationships of oxidative stress-induced miRNAs in liver cancer and the potential involvement of the thyroid hormone in these processes. While studies on thyroid hormone in liver cancer are abundantly documented, no conclusive information on the potential relationships among thyroid hormone, specific miRNAs, and oxidative stress in liver cancer is available. In this review, we discuss the effects of thyroid hormone on oxidative stress-related miRNAs that potentially have a positive or negative impact on liver cancer. Additionally, supporting evidence from clinical and animal experiments is provided.
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Affiliation(s)
- Po-Shuan Huang
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan.
- Department of Biomedical Sciences, College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan.
| | - Chia-Siu Wang
- Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan.
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 33302, Taiwan.
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan.
- Department of Biomedical Sciences, College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan.
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 33302, Taiwan.
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33302, Taiwan.
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20
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Chen CY, Wu SM, Lin YH, Chi HC, Lin SL, Yeh CT, Chuang WY, Lin KH. Induction of nuclear protein-1 by thyroid hormone enhances platelet-derived growth factor A mediated angiogenesis in liver cancer. Am J Cancer Res 2019; 9:2361-2379. [PMID: 31149049 PMCID: PMC6531305 DOI: 10.7150/thno.29628] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 02/24/2019] [Indexed: 01/03/2023] Open
Abstract
Background & Aims: Hepatocellular carcinoma (HCC) is among the leading causes of cancer deaths worldwide. Many studies indicate that disruption of cellular thyroid hormone signaling promotes HCC progression. However, the mechanisms underlying the regulation of genes downstream of thyroid hormone actions in HCC have remained elusive. In the current study, we identified NUPR1 (nuclear protein-1), a stress-induced protein that overexpresses in various neoplasia, is upregulated by triiodothyronine/thyroid hormone receptor (T3/TR) signaling and aimed to elucidate its role in angiogenesis in cancer progression. Methods: Quantitative reverse transcription-PCR, luciferase promoter and chromatin immunoprecipitation assays were performed to identify the NUPR1 regulatory mechanism by T3/TR. In vitro and In vivo vascular formations were performed to detect the angiogenic function of NUPR1. Human angiogenesis arrays were performed to identify the downstream angiogenic pathway. The sorafenib resistant ability of TR/NUPR1 was further examined in vitro and in vivo. Clinical relevance of TR, NUPR1 and platelet-derived growth factor A (PDGFA) were investigate in HCC samples using qRT-PCR and western blot. Results: Our experiments disclosed positive regulation of NUPR1 expression by T3/TR through direct binding to the -2066 to -1910 region of the NUPR1 promoter. Elevated NUPR1 and TR expression link to poor survival in clinical HCC specimens. An analysis of clinicopathological parameters showed that expression of NUPR1 is associated with vascular invasion and pathology stage. Functional studies revealed that NUPR1 induced endothelial cell angiogenesis in vitro and in vivo. Using a human angiogenesis array, we identified PDGFA as a target of NUPR1 in the downstream angiogenic pathway. NUPR1 induced transcription of PDGFA through direct binding to the corresponding promoter region, and inhibition of the PDGFA signaling pathway impaired angiogenesis in human umbilical vein endothelial cells (HUVECs). Notably, the angiogenic effects of NUPR1/PDGFA were mediated by the MEK/ERK signaling pathway. TR/NUPR1 expression increased cell viability and resistance to sorafenib treatment. Moreover NUPR1 expression was positively correlated with TRα, TRβ, and PDGFA expression. Conclusions: We propose that the T3/TR/NUPR1/PDGFA/MEK/ERK axis has a vital role in hepatocarcinogenesis and suggest NUPR1 as a potential therapeutic target in HCC.
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21
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Singh BK, Sinha RA, Yen PM. Novel Transcriptional Mechanisms for Regulating Metabolism by Thyroid Hormone. Int J Mol Sci 2018; 19:3284. [PMID: 30360449 PMCID: PMC6214012 DOI: 10.3390/ijms19103284] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 10/11/2018] [Accepted: 10/18/2018] [Indexed: 12/14/2022] Open
Abstract
The thyroid hormone plays a key role in energy and nutrient metabolisms in many tissues and regulates the transcription of key genes in metabolic pathways. It has long been believed that thyroid hormones (THs) exerted their effects primarily by binding to nuclear TH receptors (THRs) that are associated with conserved thyroid hormone response elements (TREs) located on the promoters of target genes. However, recent transcriptome and ChIP-Seq studies have challenged this conventional view as discordance was observed between TH-responsive genes and THR binding to DNA. While THR association with other transcription factors bound to DNA, TH activation of THRs to mediate effects that do not involve DNA-binding, or TH binding to proteins other than THRs have been invoked as potential mechanisms to explain this discrepancy, it appears that additional novel mechanisms may enable TH to regulate the mRNA expression. These include activation of transcription factors by SIRT1 via metabolic actions by TH, the post-translational modification of THR, the THR co-regulation of transcription with other nuclear receptors and transcription factors, and the microRNA (miR) control of RNA transcript expression to encode proteins involved in the cellular metabolism. Together, these novel mechanisms enlarge and diversify the panoply of metabolic genes that can be regulated by TH.
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Affiliation(s)
- Brijesh Kumar Singh
- Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore 169857, Singapore.
| | - Rohit Anthony Sinha
- Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, Uttar Pradesh, India.
| | - Paul Michael Yen
- Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore 169857, Singapore.
- Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA.
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22
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An automated screening method for detecting compounds with goitrogenic activity using transgenic zebrafish embryos. PLoS One 2018; 13:e0203087. [PMID: 30157258 PMCID: PMC6114901 DOI: 10.1371/journal.pone.0203087] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 08/14/2018] [Indexed: 12/30/2022] Open
Abstract
The knowledge on environmentally relevant chemicals that may interfere with thyroid signaling is scarce. Here, we present a method for the screening of goitrogens, compounds that disrupt the thyroid gland function, based on the automatic orientation of zebrafish in a glass capillary and a subsequent imaging of reporter gene fluorescence in the thyroid gland of embryos of the transgenic zebrafish line tg(tg:mCherry). The tg(tg:mCherry) reporter gene indicates a compensatory upregulation of thyroglobulin, the thyroid hormone precursor, in response to inhibition of thyroid hormone synthesis. Fish embryos were exposed to a negative control compound (3,4-dichloroaniline), or a concentration series of known goitrogenic compounds (resorcinol, methimazole, potassium perchlorate, 6-propyl-2-thiouracil, ethylenethiourea, phloroglucinol, pyrazole) with maximum exposure concentration selected based on mortality and/or solubility. Exposure to 3,4-dichloroaniline decreased the fluorescence signal. All goitrogenic compounds exhibited clear concentration-dependent inductions of reporter fluorescence 1.4 to 2.6 fold above control levels. Concentration-response modelling was used to calculate goitrogenic potencies based on EC50 values. The new automated method offers an efficient screening approach for goitrogenic activity.
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23
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Noruzi S, Azizian M, Mohammadi R, Hosseini SA, Rashidi B, Mohamadi Y, Nesaei A, Seiri P, Sahebkar A, Salarinia R, Aghdam AM, Mirzaei H. Micro-RNAs as critical regulators of matrix metalloproteinases in cancer. J Cell Biochem 2018; 119:8694-8712. [PMID: 30132957 DOI: 10.1002/jcb.27182] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Accepted: 05/24/2018] [Indexed: 12/25/2022]
Abstract
Metastasis is known to be one of the important factors associated with cancer-related deaths worldwide. Several cellular and molecular targets are involved in the metastasis process. Among these targets, matrix metalloproteinases (MMPs) play central roles in promoting cancer metastasis. MMPs could contribute toward tumor growth, angiogenesis, migration, and invasion via degradation of the extracellular matrix and activation of pre-pro-growth factors. Therefore, identification of various cellular and molecular pathways that affect MMPs could contribute toward a better understanding of the metastatic pathways involved in various tumors. Micro-RNAs are important targets that could affect MMPs. Multiple lines of evidence have indicated that deregulation of various micro-RNAs, including miR-9, Let-7, miR-10b, and miR-15b, affects metastasis of tumor cells via targeting MMPs.
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Affiliation(s)
- Somaye Noruzi
- Department of Medical Biotechnology and Molecular Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnourd, Iran
| | - Mitra Azizian
- Department of Clinical Biochemistry, Ftabaculty of Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Rezvan Mohammadi
- Department of Medical Biotechnology and Molecular Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnourd, Iran
| | - Seyede Atefe Hosseini
- Department of Medical Biotechnology and Molecular Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnourd, Iran
| | - Bahman Rashidi
- Department of Anatomical Sciences, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yousef Mohamadi
- Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Department of Anatomy, Faculty of medicine, Qom University of Medical Sciences, Qom, Iran
| | - Abolfazl Nesaei
- Department of Basic Sciences, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Parvaneh Seiri
- Department of Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Salarinia
- Department of Medical Biotechnology and Molecular Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnourd, Iran
| | - Arad Mobasher Aghdam
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Department of Biomaterials, Tissue Engineering and Nanotechnology, School of Advanced Technologies in Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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24
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Anyetei-Anum CS, Roggero VR, Allison LA. Thyroid hormone receptor localization in target tissues. J Endocrinol 2018; 237:R19-R34. [PMID: 29440347 PMCID: PMC5843491 DOI: 10.1530/joe-17-0708] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 02/12/2018] [Indexed: 12/28/2022]
Abstract
The thyroid hormone receptors, TRα1, TRβ1 and other subtypes, are members of the nuclear receptor superfamily that mediate the action of thyroid hormone signaling in numerous tissues to regulate important physiological and developmental processes. Their most well-characterized role is as ligand-dependent transcription factors; TRs bind thyroid hormone response elements in the presence or absence of thyroid hormone to facilitate the expression of target genes. Although primarily residing in the nucleus, TRα1 and TRβ1 shuttle rapidly between the nucleus and cytoplasm. We have identified multiple nuclear localization signals and nuclear export signals within TRα1 and TRβ1 that interact with importins and exportins, respectively, to mediate translocation across the nuclear envelope. More recently, enigmatic cytoplasmic functions have been ascribed to other TR subtypes, expanding the diversity of the cellular response to thyroid hormone. By integrating data on localization signal motifs, this review provides an overview of the complex interplay between TR's dynamic transport pathways and thyroid hormone signaling activities. We examine the variation in TR subtype response to thyroid hormone signaling, and what is currently known about regulation of the variety of tissue-specific localization patterns, including targeting to the nucleus, the mitochondria and the inner surface of the plasma membrane.
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Affiliation(s)
| | - Vincent R Roggero
- Department of BiologyCollege of William and Mary, Williamsburg, Virginia, USA
| | - Lizabeth A Allison
- Department of BiologyCollege of William and Mary, Williamsburg, Virginia, USA
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25
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Non-coding RNAs in hepatocellular carcinoma: molecular functions and pathological implications. Nat Rev Gastroenterol Hepatol 2018; 15:137-151. [PMID: 29317776 DOI: 10.1038/nrgastro.2017.169] [Citation(s) in RCA: 340] [Impact Index Per Article: 48.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is a leading lethal malignancy worldwide. However, the molecular mechanisms underlying liver carcinogenesis remain poorly understood. Over the past two decades, overwhelming evidence has demonstrated the regulatory roles of different classes of non-coding RNAs (ncRNAs) in liver carcinogenesis related to a number of aetiologies, including HBV, HCV and NAFLD. Among the ncRNAs, microRNAs, which belong to a distinct class of small ncRNAs, have been proven to play a crucial role in the post-transcriptional regulation of gene expression. Deregulation of microRNAs has been broadly implicated in the inactivation of tumour-suppressor genes and activation of oncogenes in HCC. Modern high-throughput sequencing analyses have unprecedentedly identified a very large number of non-coding transcripts. Divergent groups of long ncRNAs have been implicated in liver carcinogenesis through interactions with DNA, RNA or proteins. Overall, ncRNAs represent a burgeoning field of cancer research, and we are only beginning to understand the importance and complicity of the ncRNAs in liver carcinogenesis. In this Review, we summarize the common deregulation of small and long ncRNAs in human HCC. We also comprehensively review the pathological roles of ncRNAs in liver carcinogenesis, epithelial-to-mesenchymal transition and HCC metastasis and discuss the potential applications of ncRNAs as diagnostic tools and therapeutic targets in human HCC.
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26
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Singh BK, Sinha RA, Ohba K, Yen PM. Role of thyroid hormone in hepatic gene regulation, chromatin remodeling, and autophagy. Mol Cell Endocrinol 2017; 458:160-168. [PMID: 28216439 DOI: 10.1016/j.mce.2017.02.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Revised: 02/09/2017] [Accepted: 02/10/2017] [Indexed: 01/21/2023]
Abstract
Thyroid hormone (TH) actions on development and metabolism have been studied ever since the discovery of thyroxine almost a century ago. Initial studies focused on the physiological and biochemical actions of TH. Later, the cloning of the thyroid hormone receptor (THR) isoforms and the development of techniques enabled the study of TH regulation of complex cellular processes (such as gene transcription). Recently we found that TH activates secondary transcription factors such as FOXO1, to amplify gene transcription; and also is a potent inducer of autophagy that was critical for fatty acid β-oxidation in the liver. This review summarizes the recent advancements in our understanding of TH regulation of gene expression of metabolic genes (via co-regulators/transcription factors and epigenetic control) and autophagy in the liver. Our deeper understanding of TH action recently has led to the development of tissue- and THR isoform-specific TH mimetics that may be useful for the treatment of metabolic disorders.
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Affiliation(s)
- Brijesh Kumar Singh
- Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 169857, Singapore
| | - Rohit Anthony Sinha
- Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 169857, Singapore
| | - Kenji Ohba
- Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 169857, Singapore; Department of Internal Medicine, Enshu Hospital, Hamamatsu, Shizuoka 430-0929, Japan
| | - Paul Michael Yen
- Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 169857, Singapore.
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27
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Chung IH, Wu TI, Liao CJ, Hu JY, Lin YH, Tai PJ, Lai CH, Lin KH. Overexpression of lipocalin 2 in human cervical cancer enhances tumor invasion. Oncotarget 2017; 7:11113-26. [PMID: 26840566 PMCID: PMC4905461 DOI: 10.18632/oncotarget.7096] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 01/17/2016] [Indexed: 02/06/2023] Open
Abstract
Cervical carcinoma is the third-most common cause of cancer-related deaths in women worldwide. However, the molecular mechanisms underlying the metastasis of cervical cancer are still unclear. Oligonucleotide microarrays coupled with bioinformatics analysis show that cytoskeletal remodeling and epithelial-to- mesenchymal transition (EMT) are significant pathways in clinical specimens of cervical cancer. In accord with clinical observations demonstrating ectopic expression of lipocalin 2 (LCN2), an oncogenic protein associated with EMT, in malignant tumors, was significantly upregulated in cervical cancer and correlated with lymph node metastasis. Overexpression of LCN2 enhanced tumor cell migration and invasion both in vitro and in vivo. Conversely, knockdown or neutralization of LCN2 reduced tumor cell migration and invasion. LCN2-induced migration was stimulated by activation of the EMT-associated proteins, Snail, Twist, N-cadherin, fibronectin, and MMP-9. Our findings collectively support a potential role of LCN2 in cancer cell invasion through the EMT pathway and suggest that LCN2 could be effectively utilized as a lymph node metastasis marker in cervical cancer.
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Affiliation(s)
- I-Hsiao Chung
- Department of Biochemistry, School of Medicine, Chang-Gung University and Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan 333
| | - Tzu-I Wu
- Department of Biochemistry, School of Medicine, Chang-Gung University and Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan 333.,Department of Obstetrics and Gynecology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 116
| | - Chia-Jung Liao
- Department of Biochemistry, School of Medicine, Chang-Gung University and Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan 333
| | - Jin-Yo Hu
- Department of Biochemistry, School of Medicine, Chang-Gung University and Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan 333
| | - Yang-Hsiang Lin
- Department of Biochemistry, School of Medicine, Chang-Gung University and Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan 333
| | - Pei-Ju Tai
- Department of Biochemistry, School of Medicine, Chang-Gung University and Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan 333
| | - Chyong-Huey Lai
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan 333.,Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan 333
| | - Kwang-Huei Lin
- Department of Biochemistry, School of Medicine, Chang-Gung University and Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan 333
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28
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Goemann IM, Romitti M, Meyer ELS, Wajner SM, Maia AL. Role of thyroid hormones in the neoplastic process: an overview. Endocr Relat Cancer 2017; 24:R367-R385. [PMID: 28928142 DOI: 10.1530/erc-17-0192] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 08/24/2017] [Indexed: 12/13/2022]
Abstract
Thyroid hormones (TH) are critical regulators of several physiological processes, which include development, differentiation and growth in virtually all tissues. In past decades, several studies have shown that changes in TH levels caused by thyroid dysfunction, disruption of deiodinases and/or thyroid hormone receptor (TR) expression in tumor cells, influence cell proliferation, differentiation, survival and invasion in a variety of neoplasms in a cell type-specific manner. The function of THs and TRs in neoplastic cell proliferation involves complex mechanisms that seem to be cell specific, exerting effects via genomic and nongenomic pathways, repressing or stimulating transcription factors, influencing angiogenesis and promoting invasiveness. Taken together, these observations indicate an important role of TH status in the pathogenesis and/or development of human neoplasia. Here, we aim to present an updated and comprehensive picture of the accumulated knowledge and the current understanding of the potential role of TH status on the different hallmarks of the neoplastic process.
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Affiliation(s)
- Iuri Martin Goemann
- Thyroid SectionEndocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Mirian Romitti
- Thyroid SectionEndocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Erika L Souza Meyer
- Department of Internal MedicineUniversidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil
| | - Simone Magagnin Wajner
- Thyroid SectionEndocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Ana Luiza Maia
- Thyroid SectionEndocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
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29
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Zhang J, Roggero VR, Allison LA. Nuclear Import and Export of the Thyroid Hormone Receptor. VITAMINS AND HORMONES 2017; 106:45-66. [PMID: 29407444 DOI: 10.1016/bs.vh.2017.04.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The thyroid hormone receptors, TRα1 and TRβ1, are members of the nuclear receptor superfamily that forms one of the most abundant classes of transcription factors in multicellular organisms. Although primarily localized to the nucleus, TRα1 and TRβ1 shuttle rapidly between the nucleus and cytoplasm. The fine balance between nuclear import and export of TRs has emerged as a critical control point for modulating thyroid hormone-responsive gene expression. Mutagenesis studies have defined two nuclear localization signal (NLS) motifs that direct nuclear import of TRα1: NLS-1 in the hinge domain and NLS-2 in the N-terminal A/B domain. Three nuclear export signal (NES) motifs reside in the ligand-binding domain. A combined approach of shRNA-mediated knockdown and coimmunoprecipitation assays revealed that nuclear entry of TRα1 is facilitated by importin 7, likely through interactions with NLS-2, and importin β1 and the adapter importin α1 interacting with both NLS-1 and NLS-2. Interestingly, TRβ1 lacks NLS-2 and nuclear import depends solely on the importin α1/β1 heterodimer. Heterokaryon and fluorescence recovery after photobleaching shuttling assays identified multiple exportins that play a role in nuclear export of TRα1, including CRM1 (exportin 1), and exportins 4, 5, and 7. Even single amino acid changes in TRs dramatically alter their intracellular distribution patterns. We conclude that mutations within NLS and NES motifs affect nuclear shuttling activity, and propose that TR mislocalization contributes to the development of some types of cancer and Resistance to Thyroid Hormone syndrome.
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Affiliation(s)
- Jibo Zhang
- College of William and Mary, Williamsburg, VA, United States
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30
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Differential Maturation of miR-17 ~ 92 Cluster Members in Human Cancer Cell Lines. Appl Biochem Biotechnol 2017; 182:1540-1547. [DOI: 10.1007/s12010-017-2416-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 01/16/2017] [Indexed: 12/13/2022]
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31
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Barbato S, Solaini G, Fabbri M. MicroRNAs in Oncogenesis and Tumor Suppression. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2017; 333:229-268. [PMID: 28729026 DOI: 10.1016/bs.ircmb.2017.05.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
MicroRNAs (MiRNAs) have emerged in the last 15 years as central players in the biology of cancer. Increasing lines of evidence have supported their regulatory role in the expression of both oncogenes and tumor-suppressor genes, progressively clarifying which genes are modulated by specific MiRNAs dysregulated in cancer. Intriguingly, a "target-specific" understanding of MiRNA function in oncology has been replaced by a more "pathway-specific" vision of their involvement in cancer biology. This work provides a state-of-the-art knowledge of the role of MiRNAs in the most frequently altered signaling pathways in cancer cells and provides an updated overview on some of the most relevant findings trying to decode the complex molecular mechanisms of cancer.
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Affiliation(s)
- Simona Barbato
- Laboratory of Biochemistry and Mitochondrial Pathophysiology, University of Bologna, Bologna, Italy
| | - Giancarlo Solaini
- Laboratory of Biochemistry and Mitochondrial Pathophysiology, University of Bologna, Bologna, Italy
| | - Muller Fabbri
- Children's Center for Cancer and Blood Diseases and The Saban Research Institute, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Children's Hospital Los Angeles, Los Angeles, CA, United States.
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32
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Akhtar N, Singh AK, Ahmed S. MicroRNA-17 Suppresses TNF-α Signaling by Interfering with TRAF2 and cIAP2 Association in Rheumatoid Arthritis Synovial Fibroblasts. THE JOURNAL OF IMMUNOLOGY 2016; 197:2219-28. [PMID: 27534557 DOI: 10.4049/jimmunol.1600360] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 07/18/2016] [Indexed: 12/23/2022]
Abstract
TNF-α is a major cytokine implicated in rheumatoid arthritis (RA), and its expression is regulated at the transcriptional and posttranscriptional levels. However, the impact of changes in microRNA expression on posttranslational processes involved in TNF-α signaling networks is not well defined in RA. In this study, we evaluated the effect of miR-17, a member of the miR-17-92 cluster, on the TNF-α signaling pathway in human RA synovial fibroblasts (SFs). We demonstrated that miR-17 expression was significantly low in RA serum, SFs, and synovial tissues, as well as in the serum and joints of adjuvant-induced arthritis rats. RNA-sequencing analysis showed modulation of 664 genes by pre-miR-17 in human RA SFs. Ingenuity pathway analysis of RNA-sequencing data identified the ubiquitin proteasome system in the TNF-α signaling pathway as a primary target of miR-17. Western blot analysis confirmed the reduction in TRAF2, cIAP1, cIAP2, USP2, and PSMD13 expression by miR-17 in TNF-α-stimulated RA SFs. Immunoprecipitation assays showed that miR-17 restoration increased the K48-linked polyubiquitination of TRAF2, cIAP1, and cIAP2 in TNF-α-stimulated RA SFs. Thus, destabilization of TRAF2 by miR-17 reduced the ability of TRAF2 to associate with cIAP2, resulting in the downregulation of TNF-α-induced NF-κBp65, c-Jun, and STAT3 nuclear translocation and the production of IL-6, IL-8, MMP-1, and MMP-13 in human RA SFs. In conclusion, this study provides evidence for the role of miR-17 as a negative regulator of TNF-α signaling by modulating the protein ubiquitin processes in RA SFs.
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Affiliation(s)
- Nahid Akhtar
- Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA 99210
| | - Anil Kumar Singh
- Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA 99210
| | - Salahuddin Ahmed
- Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA 99210
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33
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Qiao J, Fang CY, Chen SX, Wang XQ, Cui SJ, Liu XH, Jiang YH, Wang J, Zhang Y, Yang PY, Liu F. Stroma derived COL6A3 is a potential prognosis marker of colorectal carcinoma revealed by quantitative proteomics. Oncotarget 2016; 6:29929-46. [PMID: 26338966 PMCID: PMC4745773 DOI: 10.18632/oncotarget.4966] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 08/04/2015] [Indexed: 12/22/2022] Open
Abstract
Colorectal cancer (CRC) represents the third most common cancer in males and second in females worldwide. Here, we performed a quantitative 8-plex iTRAQ proteomics analysis of the secreted proteins from five colonic fibroblast cultures and three colon cancer epithelial cell lines. We identified 1114 proteins at 0% FDR, including 587 potential secreted proteins. We further recognized 116 fibroblast-enriched proteins which were significantly associated with cell movement, angiogenesis, proliferation and wound healing, and 44 epithelial cell-enriched proteins. By interrogation of Oncomine database, we found that 20 and 8 fibroblast-enriched proteins were up- and downregulated in CRC, respectively. Western blots confirmed the fibroblast-specific secretion of filamin C, COL6A3, COL4A1 and spondin-2. Upregulated mRNA and stroma expression of COL6A3 in CRC, which were revealed by Oncomine analyses and tissue-microarray-immunohistochemistry, indicated poor prognosis. COL6A3 expression was significantly associated with Dukes stage, T stage, stage, recurrence and smoking status. Circulating plasma COL6A3 in CRC patients was upregulated significantly comparing with healthy peoples. Receiver operating characteristic curve analysis revealed that COL6A3 has better predictive performance for CRC with an area under the curve of 0.885 and the best sensitivity/specificity of 92.9%/81.3%. Thus we demonstrated that COL6A3 was a potential diagnosis and prognosis marker of CRC.
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Affiliation(s)
- Jie Qiao
- Department of Medical Systems Biology, School of Basic Medical Sciences, Shanghai, China.,Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Cai-Yun Fang
- Department of Chemistry, Fudan University, Shanghai, China
| | - Sun-Xia Chen
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Xiao-Qing Wang
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Shu-Jian Cui
- College of Bioscience and Biotechnology, Key Laboratory of Crop Genetics and Physiology of Jiangsu Province, Yangzhou University, Yangzhou, China
| | - Xiao-Hui Liu
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Ying-Hua Jiang
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jie Wang
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yang Zhang
- Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Peng-Yuan Yang
- Department of Medical Systems Biology, School of Basic Medical Sciences, Shanghai, China.,Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,Department of Chemistry, Fudan University, Shanghai, China
| | - Feng Liu
- Department of Medical Systems Biology, School of Basic Medical Sciences, Shanghai, China.,Institutes of Biomedical Sciences, Fudan University, Shanghai, China
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34
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Perra A, Plateroti M, Columbano A. T3/TRs axis in hepatocellular carcinoma: new concepts for an old pair. Endocr Relat Cancer 2016; 23:R353-69. [PMID: 27353037 DOI: 10.1530/erc-16-0152] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 06/27/2016] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and its burden is expected to further increase in the next years. Chronic inflammation, induced by multiple viruses or metabolic alterations, and epigenetic and genetic modifications, cooperate in cancer development via a combination of common and distinct aetiology-specific pathways. In spite of the advances of classical therapies, the prognosis of this neoplasm has not considerably improved over the past few years. The advent of targeted therapies and the approval of the systemic treatment of advanced HCC with the kinase inhibitor sorafenib have provided some hope for the future. However, the benefits obtained from this treatment are still disappointing, as it extends the median life expectancy of patients by only few months. It is thus mandatory to find alternative effective treatments. Although the role played by thyroid hormones (THs) and their nuclear receptors (TRs) in human cancer is still unclear, mounting evidence indicates that they behave as oncosuppressors in HCC. However, the molecular mechanisms by which they exert this effect and the consequence of their activation following ligand binding on HCC progression remain elusive. In this review, we re-evaluate the existing evidence of the role of TH/TRs in HCC development; we will also discuss how TR alterations could affect fundamental biological processes, such as hepatocyte proliferation and differentiation, and consequently HCC progression. Finally, we will discuss if and how TRs can be foreseen as therapeutic targets in HCC and whether selective TR modulation by TH analogues may hold promise for HCC treatment.
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Affiliation(s)
- Andrea Perra
- Department of Biomedical SciencesUniversity of Cagliari, Cagliari, Italy
| | - Michelina Plateroti
- Cancer Research Center of Lyon INSERM U1052CNRS UMR5286, Université de Lyon, Université Lyon 1, Centre Léon Bérard, Département de la Recherche, Lyon, France
| | - Amedeo Columbano
- Department of Biomedical SciencesUniversity of Cagliari, Cagliari, Italy
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35
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Mihailovich M, Bremang M, Spadotto V, Musiani D, Vitale E, Varano G, Zambelli F, Mancuso FM, Cairns DA, Pavesi G, Casola S, Bonaldi T. miR-17-92 fine-tunes MYC expression and function to ensure optimal B cell lymphoma growth. Nat Commun 2015; 6:8725. [PMID: 26555894 PMCID: PMC4667639 DOI: 10.1038/ncomms9725] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 09/22/2015] [Indexed: 01/07/2023] Open
Abstract
The synergism between c-MYC and miR-17-19b, a truncated version of the miR-17-92 cluster, is well-documented during tumor initiation. However, little is known about miR-17-19b function in established cancers. Here we investigate the role of miR-17-19b in c-MYC-driven lymphomas by integrating SILAC-based quantitative proteomics, transcriptomics and 3′ untranslated region (UTR) analysis upon miR-17-19b overexpression. We identify over one hundred miR-17-19b targets, of which 40% are co-regulated by c-MYC. Downregulation of a new miR-17/20 target, checkpoint kinase 2 (Chek2), increases the recruitment of HuR to c-MYC transcripts, resulting in the inhibition of c-MYC translation and thus interfering with in vivo tumor growth. Hence, in established lymphomas, miR-17-19b fine-tunes c-MYC activity through a tight control of its function and expression, ultimately ensuring cancer cell homeostasis. Our data highlight the plasticity of miRNA function, reflecting changes in the mRNA landscape and 3′ UTR shortening at different stages of tumorigenesis. The synergism between c-MYC and miR-17-19b plays an important role in lymphoma initiation. In this study, the authors identify a panel of targets co-regulated by miR-17-19b and in MYC-driven lymphoma and unravel the molecular mechanism through which miR-17-19b inhibits MYC translation.
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Affiliation(s)
- Marija Mihailovich
- Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy
| | - Michael Bremang
- Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy
| | - Valeria Spadotto
- Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy
| | - Daniele Musiani
- Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy
| | - Elena Vitale
- Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy
| | - Gabriele Varano
- Units of Genetics of B cells and lymphomas, IFOM, FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy
| | | | - Francesco M Mancuso
- Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy
| | - David A Cairns
- Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy
| | - Giulio Pavesi
- Department of Biosciences, Milan University, Milan 20133, Italy
| | - Stefano Casola
- Units of Genetics of B cells and lymphomas, IFOM, FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy
| | - Tiziana Bonaldi
- Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy
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36
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Heublein S, Mayr D, Meindl A, Angele M, Gallwas J, Jeschke U, Ditsch N. Thyroid Hormone Receptors Predict Prognosis in BRCA1 Associated Breast Cancer in Opposing Ways. PLoS One 2015; 10:e0127072. [PMID: 26029931 PMCID: PMC4451081 DOI: 10.1371/journal.pone.0127072] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 04/11/2015] [Indexed: 12/02/2022] Open
Abstract
Since BRCA1 associated breast cancers are frequently classified as hormone receptor negative or even triple negative, the application of endocrine therapies is rather limited in these patients. Like hormone receptors that bind to estrogen or progesterone, thyroid hormone receptors (TRs) are members of the nuclear hormone receptor superfamily. TRs might be interesting biomarkers - especially in the absence of classical hormone receptors. The current study aimed to investigate whether TRs may be specifically expressed in BRCA1 associated cancer cases and whether they are of prognostic significance in these patients as compared to sporadic breast cancer cases. This study analyzed TRα and TRβ immunopositivity in BRCA1 associated (n = 38) and sporadic breast cancer (n = 86). Further, TRs were studied in MCF7 (BRCA1 wildtype) and HCC3153 (BRCA1 mutated) cells. TRβ positivity rate was significantly higher in BRCA1 associated as compared to sporadic breast cancers (p = 0.001). The latter observation remained to be significant when cases that had been matched for clinicopathological criteria were compared (p = 0.037). Regarding BRCA1 associated breast cancer cases TRβ positivity turned out to be a positive prognostic factor for five-year (p = 0.007) and overall survival (p = 0.026) while TRα positivity predicted reduced five-year survival (p = 0.030). Activation of TRβ resulted in down-modulation of CTNNB1 while TRα inhibition reduced cell viability in HCC3153. However, only BRCA1 wildtype MCF7 cells were capable of rapidly degrading TRα1 in response to T3 stimulation. Significantly, this study identified TRβ to be up-regulated in BRCA1 associated breast cancer and revealed TRs to be associated with patients’ prognosis. TRs were also found to be expressed in triple negative BRCA1 associated breast cancer. Further studies need to be done in order to evaluate whether TRs may become interesting targets of endocrine therapeutic approaches, especially when tumors are triple-negative.
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Affiliation(s)
- Sabine Heublein
- Department of Obstetrics and Gynecology, Ludwig-Maximilians-University of Munich, Munich, Germany
- * E-mail:
| | - Doris Mayr
- Department of Pathology, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Alfons Meindl
- Department of Obstetrics and Gynecology, Technical University of Munich, Munich, Germany
| | - Martin Angele
- Department of Surgery, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Julia Gallwas
- Department of Obstetrics and Gynecology, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Udo Jeschke
- Department of Obstetrics and Gynecology, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Nina Ditsch
- Department of Obstetrics and Gynecology, Ludwig-Maximilians-University of Munich, Munich, Germany
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Lin YH, Wu MH, Liao CJ, Huang YH, Chi HC, Wu SM, Chen CY, Tseng YH, Tsai CY, Chung IH, Tsai MM, Chen CY, Lin TP, Yeh YH, Chen WJ, Lin KH. Repression of microRNA-130b by thyroid hormone enhances cell motility. J Hepatol 2015; 62:1328-40. [PMID: 25617495 DOI: 10.1016/j.jhep.2014.12.035] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Revised: 12/02/2014] [Accepted: 12/23/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Thyroid hormone (T3) and its receptor (TR) are involved in cell growth and cancer progression. Although deregulation of microRNA (miRNA) expression has been detected in many tumor types, the mechanisms underlying functional impairment and specific involvement of miRNAs in tumor metastasis remain unclear. In the current study, we aimed to elucidate the involvement of deregulated miRNA-130b (miR-130b) and its target genes mediated by T3/TR in cancer progression. METHODS Quantitative reverse transcription-PCR, luciferase and chromatin immunoprecipitation assays were performed to identify the miR-130b transcript and the mechanisms implicated in its regulation. The effects of miR-130b on hepatocellular carcinoma (HCC) invasion were further examined in vitro and in vivo. Clinical correlations among miR-130b, TRs and interferon regulatory factor 1 (IRF1) were examined in HCC samples using Spearman correlation analysis. RESULTS Our experiments disclosed negative regulation of miR-130b expression by T3/TR. Overexpression of miR-130b led to marked inhibition of cell migration and invasion, which was mediated via suppression of IRF1. Cell migration ability was promoted by T3, but partially suppressed upon miR-130b overexpression. Furthermore, miR-130b suppressed expression of epithelial-mesenchymal transition (EMT)-related genes, matrix metalloproteinase-9, phosphorylated mammalian target of rapamycin (mTOR), p-ERK1/2, p-AKT and p-signal transducer and activator of transcription (STAT)-3. Notably, miR-130b was downregulated in hepatoma samples and its expression patterns were inversely correlated with those of TRα1 and IRF1. CONCLUSIONS Our data collectively highlight a novel pathway interlinking T3/TR, miR-130b, IRF1, the EMT-related genes, p-mTOR, p-STAT3 and the p-AKT cascade, which regulates the motility and invasion of hepatoma cells.
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Affiliation(s)
- Yang-Hsiang Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
| | - Meng-Han Wu
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
| | - Chia-Jung Liao
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
| | - Ya-Hui Huang
- Liver Research Center, Department of Hepato-Gastroenterology, Chang-Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan
| | - Hsiang-Cheng Chi
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
| | - Sheng-Ming Wu
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
| | - Cheng-Yi Chen
- Department of Medical Research, Mackay Memorial Hospital, Taipei 251, Taiwan
| | - Yi-Hsin Tseng
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
| | - Chung-Ying Tsai
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
| | - I-Hsiao Chung
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
| | - Ming-Ming Tsai
- Department of Nursing, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
| | - Ching-Ying Chen
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
| | - Tina P Lin
- Pre-med Program, Pacific Union College, Angwin 94508, USA
| | - Yung-Hsin Yeh
- Division of Cardiology, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan 333, Taiwan
| | - Wei-Jan Chen
- Division of Cardiology, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan 333, Taiwan
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
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Decock J, Hendrickx W, Thirkettle S, Gutiérrez-Fernández A, Robinson SD, Edwards DR. Pleiotropic functions of the tumor- and metastasis-suppressing matrix metalloproteinase-8 in mammary cancer in MMTV-PyMT transgenic mice. Breast Cancer Res 2015; 17:38. [PMID: 25848906 PMCID: PMC4380014 DOI: 10.1186/s13058-015-0545-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Accepted: 03/03/2015] [Indexed: 12/26/2022] Open
Abstract
INTRODUCTION Matrix metalloproteinase-8 (MMP-8; neutrophil collagenase) is an important regulator of innate immunity that has oncosuppressive actions in numerous tumor types. METHODS We have intercrossed Mmp8-null mice with the Polyoma virus middle T oncogene-driven (MMTV-PyMT) mouse model of mammary cancer to explore the effects of loss of MMP-8 on the incidence and progression of mammary carcinomas. RESULTS In this aggressive mouse model of breast cancer, loss of MMP-8 accelerated tumor onset even further, such that 90% of MMTV-PyMT; Mmp8-null female mice were tumor-bearing at the time of weaning. Throughout the 14 weeks of the model, tumor burden increased in homozygous Mmp8-null mice compared to Mmp8-wild-type and -heterozygote animals. Likewise, lung metastasis dramatically increased in the MMTV-PyMT; Mmp8-null mice. Immunohistochemistry revealed that tumors in wild-type, Mmp8-heterozygotes and -null animals had similar vascular density at 8 weeks, but at 10 weeks Mmp8-wild-type tumors had a lower vascularity than their heterozygote and null counterparts. No differences in macrophage infiltration were apparent throughout primary tumor development, though at 10 weeks a drop in neutrophil infiltrates was observed in Mmp8-wild-type tumors. Using quantitative real-time RT-PCR, we tracked the expression of the entire Mmp and Timp gene families, observing a significant decrease in Mmp3 expression in Mmp8-null tumors compared to wild-type and heterozygotes throughout the time course of the model, which was confirmed at the protein level. CONCLUSIONS These findings provide novel insight into the suppressive action of MMP-8 on mammary tumorigenesis and metastasis, and indicate that the loss of MMP-8 likely has pleiotropic effects on innate immunity and angiogenesis that are reflected in changes in the protease web.
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Affiliation(s)
- Julie Decock
- />School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ UK
- />Cancer Research Center, Qatar Biomedical Research Institute, Qatar Foundation, Doha, Qatar
| | - Wouter Hendrickx
- />School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ UK
- />Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar
| | - Sally Thirkettle
- />School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ UK
| | - Ana Gutiérrez-Fernández
- />Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Av. Julián Clavería, s/n, Oviedo, 33006 Spain
| | - Stephen D Robinson
- />School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ UK
| | - Dylan R Edwards
- />School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ UK
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Davis PJ, Hercbergs A, Luidens MK, Lin HY. Recurrence of differentiated thyroid carcinoma during full TSH suppression: is the tumor now thyroid hormone dependent? Discov Oncol 2014; 6:7-12. [PMID: 25292307 PMCID: PMC4309911 DOI: 10.1007/s12672-014-0204-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Accepted: 09/29/2014] [Indexed: 01/09/2023] Open
Abstract
Well-standardized primary treatment and long-term management of differentiated thyroid carcinoma (DTC) include lowering or suppression of host thyrotropin (TSH) with exogenous L-thyroxine (T4). This treatment recognizes the trophic action of TSH on DTC cells. Suppression of endogenous TSH with T4 is continued in recurrent disease. However, T4 can induce proliferation of follicular and papillary thyroid carcinoma cell lines and of other human carcinoma cells. The proliferative mechanism is initiated at a cell surface receptor for T4 on integrin αvβ3, a receptor by which the hormone also inhibits p53-dependent apoptosis in tumor cells. In recurrent DTC with satisfactory suppression of endogenous TSH, we discuss here the possibility that the tumor is no longer TSH dependent and that T4 has become a critical growth factor for the cancer.
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Affiliation(s)
- Paul J Davis
- Department of Medicine, Albany Medical College, Albany, NY, USA,
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40
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Jiang H, Wang P, Li X, Wang Q, Deng ZB, Zhuang X, Mu J, Zhang L, Wang B, Yan J, Miller D, Zhang HG. Restoration of miR17/20a in solid tumor cells enhances the natural killer cell antitumor activity by targeting Mekk2. Cancer Immunol Res 2014; 2:789-99. [PMID: 24801835 PMCID: PMC4396632 DOI: 10.1158/2326-6066.cir-13-0162] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Aberrant microRNA (miRNA) expression has been identified in various human solid cancers. However, whether the levels of miRNA expression in tumor cells have any effect on tumor progression has not been determined. In this proof-of-concept study, the restoration of high-level expression of the miR17-92 cluster of miRNAs reveals its function as a tumor suppressor in murine solid cancer cells. Specifically, genetically engineered expression of higher levels of miR17/20a in the miR17-92 cluster in both murine breast cancer and colon cancer cells triggered natural killer (NK)-cell recognition by inhibiting the expression of MHC class I (H-2D) through the Mekk2-Mek5-Erk5 pathway. Results from the mouse tumor studies were recapitulated using samples of human solid tumors. Together, these data indicate that miR17/20a miRNAs function as tumor suppressors by reprogramming tumor cells for NK cell-mediated cytotoxicity.
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Affiliation(s)
- Hong Jiang
- Louisville Veterans Administration Medical Center; James Graham Brown Cancer Center;
| | - Ping Wang
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei; and
| | - Xiaohua Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | | | | | | | | | | | | | - Jun Yan
- James Graham Brown Cancer Center
| | | | - Huang-Ge Zhang
- Louisville Veterans Administration Medical Center; James Graham Brown Cancer Center; Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky;
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Dong Q, Cai N, Tao T, Zhang R, Yan W, Li R, Zhang J, Luo H, Shi Y, Luan W, Zhang Y, You Y, Wang Y, Liu N. An axis involving SNAI1, microRNA-128 and SP1 modulates glioma progression. PLoS One 2014; 9:e98651. [PMID: 24959930 PMCID: PMC4068992 DOI: 10.1371/journal.pone.0098651] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 05/05/2014] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND Glioblastoma is an extraordinarily aggressive disease that requires more effective therapeutic options. Snail family zinc finger 1, dysregulated in many neoplasms, has been reported to be involved in gliomas. However, the biological mechanisms underlying SNAI1 function in gliomas need further investigation. METHODS Quantitative real-time PCR was used to measure microRNA-128 (miR-128) expression level and western blot was performed to detect protein expression in U87 and U251 cells and human brain tissues. Cell cycle, CCK-8, transwell and wound-healing assays were performed. Dual-luciferase reporter assay was used for identifying the mechanism of SNAI1 and miR-128b regulation. The mechanism of miR-128 targeting SP1 was also tested by luciferase reporter assay. Immunohistochemistry and in situ hybridisation staining were used for quantifying SNAI1, SP1 and miR-128 expression levels in human glioma samples. RESULTS The Chinese Glioma Genome Atlas (CGGA) data revealed that SNAI1 was up-regulated in glioma and we confirmed the findings in normal and glioma tissues. SNAI1 depletion by shRNA retarded the cell cycle and suppressed proliferation and invasion in glioma cell lines. The CGGA data showed that the Pearson correlation index between SNAI1 and miR-128 was negatively correlated. SNAI1 suppressed miR-128b expression by binding to the miR-128b specific promoter motif, and miR-128 targeted SP1 via binding to the 3'-untranslated region of SP1. Moreover, introduction of miR-128 anti-sense oligonucleotide alleviated the cell cycle retardation, proliferation and invasion inhibition induced by SNAI1 shRNA. Immunohistochemistry and in situ hybridisation analysis of SNAI1, SP1 and miR-128 unraveled their expression levels and correlations in glioma samples. CONCLUSIONS We propose that the SNAI1/miR-128/SP1 axis, which plays a vital role in glioma progression, may come to be a clinically relevant therapeutic target.
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Affiliation(s)
- Qingsheng Dong
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ning Cai
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Tao Tao
- Department of Urology, Affiliated Zhongda Hospital, Southeast University, Nanjing, China
| | - Rui Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Yan
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Rui Li
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Junxia Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hui Luo
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yan Shi
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wenkang Luan
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yaxuan Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yongping You
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yingyi Wang
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ning Liu
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Tan W, Li Y, Lim SG, Tan TMC. miR-106b-25/miR-17-92 clusters: Polycistrons with oncogenic roles in hepatocellular carcinoma. World J Gastroenterol 2014; 20:5962-5972. [PMID: 24876719 PMCID: PMC4033436 DOI: 10.3748/wjg.v20.i20.5962] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 01/11/2014] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs are small endogenously expressed RNA molecules which are involved in the process of silencing gene expression through translational regulation. The polycistronic miR-17-92 cluster is the first microRNA cluster shown to play a role in tumorigenesis. It has two other paralogs in the human genome, the miR-106b-25 cluster and the miR-106a-363 cluster. Collectively, the microRNAs encoded by these clusters can be further grouped based on the seed sequences into four families, namely the miR-17, the miR-92, the miR-18 and the miR-19 families. Over-expression of the miR-106b-25 and miR-17-92 clusters has been reported not only during the development of cirrhosis but also subsequently during the development of hepatocellular carcinoma. Members of these clusters have also been shown to affect the replication of hepatitis B and hepatitis C viruses. Various targets of these microRNAs have been identified, and these targets are involved in tumor growth, cell survival and metastasis. In this review, we first describe the regulation of these clusters by c-Myc and E2F1, and how the members of these clusters in turn regulate E2F1 expression forming an auto-regulatory loop. In addition, the roles of the various members of the clusters in affecting relevant target gene expression in the pathogenesis of hepatocellular carcinoma will also be discussed.
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MicroRNAs in the Regulation of MMPs and Metastasis. Cancers (Basel) 2014; 6:625-45. [PMID: 24670365 PMCID: PMC4074795 DOI: 10.3390/cancers6020625] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Revised: 02/21/2014] [Accepted: 03/04/2014] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs are integral molecules in the regulation of numerous physiological cellular processes including cellular differentiation, proliferation, metabolism and apoptosis. Their function transcends normal physiology and extends into several pathological entities including cancer. The matrix metalloproteinases play pivotal roles, not only in tissue remodeling, but also in several physiological and pathological processes, including those supporting cancer progression. Additionally, the contribution of active MMPs in metastatic spread and the establishment of secondary metastasis, via the targeting of several substrates, are also well established. This review focuses on the important miRNAs that have been found to impact cancer progression and metastasis through direct and indirect interactions with the matrix metalloproteinases.
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UVA and UVB irradiation differentially regulate microRNA expression in human primary keratinocytes. PLoS One 2013; 8:e83392. [PMID: 24391759 PMCID: PMC3877020 DOI: 10.1371/journal.pone.0083392] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Accepted: 10/29/2013] [Indexed: 12/22/2022] Open
Abstract
MicroRNA (miRNA)-mediated regulation of the cellular transcriptome is an important epigenetic mechanism for fine-tuning regulatory pathways. These include processes related to skin cancer development, progression and metastasis. However, little is known about the role of microRNA as an intermediary in the carcinogenic processes following exposure to UV-radiation. We now show that UV irradiation of human primary keratinocytes modulates the expression of several cellular miRNAs. A common set of miRNAs was influenced by exposure to both UVA and UVB. However, each wavelength band also activated a distinct subset of miRNAs. Common sets of UVA- and UVB-regulated miRNAs harbor the regulatory elements GLYCA-nTRE, GATA-1-undefined-site-13 or Hox-2.3-undefined-site-2 in their promoters. In silico analysis indicates that the differentially expressed miRNAs responding to UV have potential functions in the cellular pathways of cell growth and proliferation. Interestingly, the expression of miR-23b, which is a differentiation marker of human keratinocytes, is remarkably up-regulated after UVA irradiation. Studying the interaction between miR-23b and its putative skin-relevant targets using a Luciferase reporter assay revealed that RRAS2 (related RAS viral oncogene homolog 2), which is strongly expressed in highly aggressive malignant skin cancer, to be a direct target of miR-23b. This study demonstrates for the first time a differential miRNA response to UVA and UVB in human primary keratinocytes. This suggests that selective regulation of signaling pathways occurs in response to different UV energies. This may shed new light on miRNA-regulated carcinogenic processes involved in UV-induced skin carcinogenesis.
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