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1
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Wang Z, Liu Y, Asemi Z. Quercetin and microRNA Interplay in Apoptosis Regulation: A New Therapeutic Strategy for Cancer? Curr Med Chem 2025; 32:939-957. [PMID: 38018191 DOI: 10.2174/0109298673259466231031050437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 07/06/2023] [Accepted: 10/09/2023] [Indexed: 11/30/2023]
Abstract
Cancer is known as a global problem for the health and economy. Following cancer onset, apoptosis is the primary mechanism countering the tumor cells' growth. Most anticancer agents initiate apoptosis to remove tumor cells. Phytochemicals have appeared as a beneficial treatment option according to their less adverse effects. In recent decades, quercetin has been highlighted due to its high pharmacological benefits, and various literature has suggested it as a potential anti-proliferative agent against different kinds of cancers. The microRNAs (miRNAs) play key roles in cancer treatment, progression, and apoptosis. This review reviewed the effect of quercetin on miRNAs contributing to the induction or inhibition of apoptosis in cancers.
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Affiliation(s)
- Zicheng Wang
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210000, Jiangsu, China
- Department of Pharmacology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, Jiangsu, China
| | - Yanqing Liu
- Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210000, Jiangsu, China
- Department of Pharmacology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, Jiangsu, China
| | - Zatollah Asemi
- Department of Nutrition, Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, I.R. Iran
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2
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Aberrant transcription factors in the cancers of the pancreas. Semin Cancer Biol 2022; 86:28-45. [PMID: 36058426 DOI: 10.1016/j.semcancer.2022.08.011] [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: 06/13/2022] [Revised: 08/15/2022] [Accepted: 08/29/2022] [Indexed: 11/21/2022]
Abstract
Transcription factors (TFs) are essential for proper activation of gene set during the process of organogenesis, differentiation, lineage specificity. Reactivation or dysregulation of TFs regulatory networks could lead to deformation of organs, diseases including various malignancies. Currently, understanding the mechanism of oncogenesis became necessity for the development of targeted therapeutic strategy for different cancer types. It is evident that many TFs go awry in cancers of the pancreas such as pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine neoplasms (PanNENs). These mutated or dysregulated TFs abnormally controls various signaling pathways in PDAC and PanNENs including RTK, PI3K-PTEN-AKT-mTOR, JNK, TGF-β/SMAD, WNT/β-catenin, SHH, NOTCH and VEGF which in turn regulate different hallmarks of cancer. Aberrant regulation of such pathways have been linked to the initiation, progression, metastasis, and resistance in pancreatic cancer. As of today, a number of TFs has been identified as crucial regulators of pancreatic cancer and a handful of them shown to have potential as therapeutic targets in pre-clinical and clinical settings. In this review, we have summarized the current knowledge on the role and therapeutic usefulness of TFs in PDAC and PanNENs.
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3
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Quatannens D, Verhoeven Y, Van Dam P, Lardon F, Prenen H, Roeyen G, Peeters M, Smits ELJ, Van Audenaerde J. Targeting hedgehog signaling in pancreatic ductal adenocarcinoma. Pharmacol Ther 2022; 236:108107. [PMID: 34999181 DOI: 10.1016/j.pharmthera.2022.108107] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 12/27/2021] [Accepted: 01/03/2022] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer related death. The urgent need for effective therapies is highlighted by the lack of adequate targeting. In PDAC, hedgehog (Hh) signaling is known to be aberrantly activated, which prompted the pathway as a possible target for effective treatment for PDAC patients. Unfortunately, specific targeting of upstream molecules within the Hh signaling pathway failed to bring clinical benefit. This led to the ongoing debate on Hh targeting as a therapeutic treatment for PDAC patients. Additionally, concurrent non-canonical activation routes also result in translocation of Gli transcription factors into the nucleus. Therefore, different downstream targets of the Hh signaling pathway were identified and evaluated in preclinical and clinical research. In this review we summarize the variety of Hh signaling antagonists in different preclinical models of PDAC. Furthermore, we discuss published and ongoing clinical trials that evaluated Hh antagonists and point out the current hurdles and future perspectives in the light of redesigning Hh-targeting therapies for the treatment of PDAC patients.
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Affiliation(s)
- Delphine Quatannens
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
| | - Yannick Verhoeven
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
| | - Peter Van Dam
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Unit of Gynecologic Oncology, University Hospital Antwerp (UZA), Antwerp, Belgium.
| | - Filip Lardon
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
| | - Hans Prenen
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Department of Oncology, University Hospital Antwerp (UZA), Antwerp, Belgium.
| | - Geert Roeyen
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Department of Hepatobiliary Transplantation and Endocrine Surgery, University Hospital Antwerp (UZA), Antwerp, Belgium.
| | - Marc Peeters
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Department of Oncology, University Hospital Antwerp (UZA), Antwerp, Belgium.
| | - Evelien L J Smits
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
| | - Jonas Van Audenaerde
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
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Di Fiore R, Suleiman S, Pentimalli F, O’Toole SA, O’Leary JJ, Ward MP, Conlon NT, Sabol M, Ozretić P, Erson-Bensan AE, Reed N, Giordano A, Herrington CS, Calleja-Agius J. Could MicroRNAs Be Useful Tools to Improve the Diagnosis and Treatment of Rare Gynecological Cancers? A Brief Overview. Int J Mol Sci 2021; 22:3822. [PMID: 33917022 PMCID: PMC8067678 DOI: 10.3390/ijms22083822] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/01/2021] [Accepted: 04/05/2021] [Indexed: 02/07/2023] Open
Abstract
Gynecological cancers pose an important public health issue, with a high incidence among women of all ages. Gynecological cancers such as malignant germ-cell tumors, sex-cord-stromal tumors, uterine sarcomas and carcinosarcomas, gestational trophoblastic neoplasia, vulvar carcinoma and melanoma of the female genital tract, are defined as rare with an annual incidence of <6 per 100,000 women. Rare gynecological cancers (RGCs) are associated with poor prognosis, and given the low incidence of each entity, there is the risk of delayed diagnosis due to clinical inexperience and limited therapeutic options. There has been a growing interest in the field of microRNAs (miRNAs), a class of small non-coding RNAs of ∼22 nucleotides in length, because of their potential to regulate diverse biological processes. miRNAs usually induce mRNA degradation and translational repression by interacting with the 3' untranslated region (3'-UTR) of target mRNAs, as well as other regions and gene promoters, as well as activating translation or regulating transcription under certain conditions. Recent research has revealed the enormous promise of miRNAs for improving the diagnosis, therapy and prognosis of all major gynecological cancers. However, to date, only a few studies have been performed on RGCs. In this review, we summarize the data currently available regarding RGCs.
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Affiliation(s)
- Riccardo Di Fiore
- Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, MSD 2080 Msida, Malta;
- Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA;
| | - Sherif Suleiman
- Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, MSD 2080 Msida, Malta;
| | - Francesca Pentimalli
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, I-80131 Napoli, Italy;
| | - Sharon A. O’Toole
- Departments of Obstetrics and Gynaecology and Histopathology, Trinity St James’s Cancer Institute, Trinity College Dublin, 8 Dublin, Ireland;
| | - John J. O’Leary
- Department of Histopathology, Trinity St James’s Cancer Institute, Trinity College Dublin, 8 Dublin, Ireland; (J.J.O.); (M.P.W.)
| | - Mark P. Ward
- Department of Histopathology, Trinity St James’s Cancer Institute, Trinity College Dublin, 8 Dublin, Ireland; (J.J.O.); (M.P.W.)
| | - Neil T. Conlon
- National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, 9 Dublin, Ireland;
| | - Maja Sabol
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (M.S.); (P.O.)
| | - Petar Ozretić
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (M.S.); (P.O.)
| | - Ayse Elif Erson-Bensan
- Department of Biological Sciences, Middle East Technical University, Ankara 06810, Turkey;
| | - Nicholas Reed
- Beatson Oncology Centre, Gartnavel General Hospital, 1053 Great Western Road, Glasgow G12 0YN, UK;
| | - Antonio Giordano
- Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA;
- Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy
| | - C. Simon Herrington
- Cancer Research UK Edinburgh Centre, Western General Hospital, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK;
| | - Jean Calleja-Agius
- Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, MSD 2080 Msida, Malta;
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5
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Fu J, Shrivastava A, Shrivastava SK, Srivastava RK, Shankar S. Triacetyl resveratrol upregulates miRNA‑200 and suppresses the Shh pathway in pancreatic cancer: A potential therapeutic agent. Int J Oncol 2019; 54:1306-1316. [PMID: 30720134 DOI: 10.3892/ijo.2019.4700] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 01/07/2019] [Indexed: 11/06/2022] Open
Abstract
Trans‑3,4',5‑trihydroxystilbene (resveratrol) is a naturally occurring polyphenolic phytoalexin with marked anticancer activities, and is mainly found in grapes, berries and peanuts. However, due to a low bioavailability, it has not progressed to clinical practice for cancer treatment. Therefore, the aims of the present study were to examine the anticancer activities of the resveratrol derivative, triacetyl resveratrol (TCRV), in pancreatic cancer cells. Apoptosis was measured by fluorescence‑activated cell sorting and terminal deoxynucleotidyl transferase (TdT)‑mediated dUTP nick‑end labeling assays. Gene expression was measured by reverse transcription‑quantitative polymerase chain reaction. TCRV inhibited colony formation and induced apoptosis through caspase‑3 activation in human pancreatic cancer AsPC‑1 and PANC‑1 cells, whereas it exerted no effect on human pancreatic normal ductal epithelial cells (HPNE). TCRV inhibited epithelial‑mesenchymal transition (EMT) by upregulating the expression of E‑cadherin and suppressing the expression of N‑cadherin and the transcription factors, Snail, Slug and Zeb1. TCRV inhibited Zeb1 3'UTR‑luciferase activity through the upregulation of microRNA (miR)‑200 family members. The inhibitory effects of TCRV on pancreatic cancer cell migration and invasion were counteracted by anti‑miR‑200 family members. The inhibitory effects of TCRV on EMT and the induction of apoptosis were exerted through the suppression of the sonic hedgehog (Shh) pathway, and through the modulation of cyclin D1 and Bcl‑2 expression. The hyperactivation of the Shh pathway by either Shh protein or Gli1 overexpression abrogated the biological effects of TCRV. Taken together, the results of this study demonstrate that TCRV inhibits pancreatic cancer growth and EMT by targeting the Shh pathway and its downstream signaling mediators. TCRV inhibited EMT through the upregulation of miR‑200 family members. Since TCRV effectively inhibited the growth of human pancreatic cancer cells by modulating the Shh pathway, without affecting the growth of HPNE cells, our findings suggest the possible use of TCRV as a promising candidate for the treatment and/or prevention of pancreatic cancer.
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Affiliation(s)
- Junsheng Fu
- College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, P.R. China
| | - Anju Shrivastava
- St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Sushant K Shrivastava
- Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India
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Werner JH, Rosenberg JH, Um JY, Moulton MJ, Agrawal DK. Molecular discoveries and treatment strategies by direct reprogramming in cardiac regeneration. Transl Res 2019; 203:73-87. [PMID: 30142308 PMCID: PMC6289806 DOI: 10.1016/j.trsl.2018.07.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 06/27/2018] [Accepted: 07/25/2018] [Indexed: 12/14/2022]
Abstract
Cardiac tissue has minimal endogenous regenerative capacity in response to injury. Treatment options are limited following tissue damage after events such as myocardial infarction. Current strategies are aimed primarily at injury prevention, but attention has been increasingly targeted toward the development of regenerative therapies. This review focuses on recent developments in the field of cardiac fibroblast reprogramming into induced cardiomyocytes. Early efforts to produce cardiac regeneration centered around induced pluripotent stem cells, but clinical translation has proved elusive. Currently, techniques are being developed to directly transdifferentiate cardiac fibroblasts into induced cardiomyocytes. Viral vector-driven expression of a combination of transcription factors including Gata4, Mef2c, and Tbx5 induced cardiomyocyte development in mice. Subsequent combinational modifications have extended these results to human cell lines and increased efficacy. The miRNAs including combinations of miR-1, miR-133, miR-208, and miR-499 can improve or independently drive regeneration of cardiomyocytes. Similar results could be obtained by combinations of small molecules with or without transcription factor or miRNA expression. The local tissue environment greatly impacts favorability for reprogramming. Modulation of signaling pathways, especially those mediated by VEGF and TGF-β, enhance differentiation to cardiomyocytes. Current reprogramming strategies are not ready for clinical application, but recent breakthroughs promise regenerative cardiac therapies in the near future.
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Affiliation(s)
- John H Werner
- Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, Nebraska
| | - John H Rosenberg
- Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, Nebraska
| | - John Y Um
- Department of Cardiothoracic Surgery, University of Nebraska Medical Center, Omaha, Nebraska
| | - Michael J Moulton
- Department of Cardiothoracic Surgery, University of Nebraska Medical Center, Omaha, Nebraska
| | - Devendra K Agrawal
- Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, Nebraska.
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7
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MicroRNA in pancreatic adenocarcinoma: predictive/prognostic biomarkers or therapeutic targets? Oncotarget 2016; 6:23323-41. [PMID: 26259238 PMCID: PMC4695121 DOI: 10.18632/oncotarget.4492] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 07/03/2015] [Indexed: 12/19/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a poor prognosis, short overall survival and few chemotherapeutic choices. MicroRNAs (miRNAs) are non-coding, single-stranded RNAs of around 22 nucleotides involved in the pathogenic mechanisms of carcinogenesis and metastasis. They have been studied in many tumors in order to identify potential diagnostic, prognostic or therapeutic targets. In the current literature, many studies have analyzed the role of miRNAs in PDAC. In fact, the absence of appropriate biomarkers, the difficultly of early detection of this tumor, and the lack of effective chemotherapy in patients with unresectable disease have focused attention on miRNAs as new, interesting advance in this malignancy. In this review we analyzed the role of miRNAs in PDAC in order to understand the mechanisms of action and the difference between the onco-miRNA and the tumor suppressor miRNA. We also reviewed all the data related to the use of these molecules as predictive as well as prognostic biomarkers in the course of the disease. Finally, the possible therapeutic use of miRNAs or anti-miRNAs in PDAC is also discussed. In conclusion, although there is still no clinical application for these molecules in PDAC, it is our opinion that the preclinical evidence of the role of specific miRNAs in carcinogenesis, the possibility of using miRNAs as diagnostic or prognostic biomarkers, and their potential therapeutic role, warrant future studies in PDAC.
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8
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Hyun J, Jung Y. MicroRNAs in liver fibrosis: Focusing on the interaction with hedgehog signaling. World J Gastroenterol 2016; 22:6652-6662. [PMID: 27547008 PMCID: PMC4970468 DOI: 10.3748/wjg.v22.i29.6652] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 06/08/2016] [Accepted: 06/29/2016] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a repair process in response to damage in the liver; however, severe and chronic injury promotes the accumulation of fibrous matrix, destroying the normal functions and architecture of liver. Hepatic stellate cells (HSCs) are quiescent in normal livers, but in damaged livers, they transdifferentiate into myofibroblastic HSCs, which produce extracellular matrix proteins. Hedgehog (Hh) signaling orchestrates tissue reconstruction in damaged livers and contributes to liver fibrogenesis by regulating HSC activation. MicroRNAs (miRNAs), endogenous small non-coding RNAs interfering with RNA post-transcriptionally, regulate various cellular processes in healthy organisms. The dysregulation of miRNAs is closely associated with diseases, including liver diseases. Thus, miRNAs are good targets in the diagnosis and treatment of various diseases, including liver fibrosis; however, the regulatory mechanisms of miRNAs that interact with Hh signaling in liver fibrosis remain unclear. We review growing evidence showing the association of miRNAs with Hh signaling. Recent studies suggest that Hh-regulating miRNAs induce inactivation of HSCs, leading to decreased hepatic fibrosis. Although miRNA-delivery systems and further knowledge of interacting miRNAs with Hh signaling need to be improved for the clinical usage of miRNAs, recent findings indicate that the miRNAs regulating Hh signaling are promising therapeutic agents for treating liver fibrosis.
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9
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Hawa Z, Haque I, Ghosh A, Banerjee S, Harris L, Banerjee SK. The miRacle in Pancreatic Cancer by miRNAs: Tiny Angels or Devils in Disease Progression. Int J Mol Sci 2016; 17:E809. [PMID: 27240340 PMCID: PMC4926343 DOI: 10.3390/ijms17060809] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 05/04/2016] [Accepted: 05/19/2016] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with increasing incidence and high mortality. Surgical resection is the only potentially curative treatment of patients with PDAC. Because of the late presentation of the disease, about 20 percent of patients are candidates for this treatment. The average survival of resected patients is between 12 and 20 months, with a high probability of relapse. Standard chemo and radiation therapies do not offer significant improvement of the survival of these patients. Furthermore, novel treatment options aimed at targeting oncogenes or growth factors in pancreatic cancer have proved unsuccessful. Thereby, identifying new biomarkers that can detect early stages of this disease is of critical importance. Among these biomarkers, microRNAs (miRNAs) have supplied a profitable recourse and become an attractive focus of research in PDAC. MiRNAs regulate many genes involved in the development of PDAC through mRNA degradation or translation inhibition. The possibility of intervention in the molecular mechanisms of miRNAs regulation could begin a new generation of PDAC therapies. This review summarizes the reports describing miRNAs involvement in cellular processes involving pancreatic carcinogenesis and their utility in diagnosis, survival and therapeutic potential in pancreatic cancer.
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Affiliation(s)
- Zuhair Hawa
- Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA.
| | - Inamul Haque
- Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA.
- Division of Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66205, USA.
| | - Arnab Ghosh
- Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA.
- Division of Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66205, USA.
| | - Snigdha Banerjee
- Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA.
- Division of Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66205, USA.
| | - LaCoiya Harris
- Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA.
| | - Sushanta K Banerjee
- Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA.
- Division of Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66205, USA.
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66205, USA.
- Department of Pathology, University of Kansas Medical Center, Kansas City, KS 66205, USA.
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Karandish F, Mallik S. Biomarkers and Targeted Therapy in Pancreatic Cancer. BIOMARKERS IN CANCER 2016; 8:27-35. [PMID: 27147897 PMCID: PMC4847554 DOI: 10.4137/bic.s34414] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 03/06/2016] [Accepted: 03/11/2016] [Indexed: 12/18/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) constitutes 90% of pancreatic cancers. PDAC is a complex and devastating disease with only 1%-3% survival rate in five years after the second stage. Treatment of PDAC is complicated due to the tumor microenvironment, changing cell behaviors to the mesenchymal type, altered drug delivery, and drug resistance. Considering that pancreatic cancer shows early invasion and metastasis, critical research is needed to explore different aspects of the disease, such as elaboration of biomarkers, specific signaling pathways, and gene aberration. In this review, we highlight the biomarkers, the fundamental signaling pathways, and their importance in targeted drug delivery for pancreatic cancers.
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Affiliation(s)
- Fataneh Karandish
- Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND, USA
| | - Sanku Mallik
- Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND, USA
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11
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Voelter-Mahlknecht S. Epigenetic associations in relation to cardiovascular prevention and therapeutics. Clin Epigenetics 2016; 8:4. [PMID: 26779291 PMCID: PMC4714496 DOI: 10.1186/s13148-016-0170-0] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 01/06/2016] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular diseases (CVD) increasingly burden societies with vast financial and health care problems. Therefore, the importance of improving preventive and therapeutic measures against cardiovascular diseases is continually growing. To accomplish such improvements, research must focus particularly on understanding the underlying mechanisms of such diseases, as in the field of epigenetics, and pay more attention to strengthening primary prevention. To date, preliminary research has found a connection between DNA methylation, histone modifications, RNA-based mechanisms and the development of CVD like atherosclerosis, cardiac hypertrophy, myocardial infarction, and heart failure. Several therapeutic agents based on the findings of such research projects are currently being tested for use in clinical practice. Although these tests have produced promising data so far, no epigenetically active agents or drugs targeting histone acetylation and/or methylation have actually entered clinical trials for CVDs, nor have they been approved by the FDA. To ensure the most effective prevention and treatment possible, further studies are required to understand the complex relationship between epigenetic regulation and the development of CVD. Similarly, several classes of RNA therapeutics are currently under development. The use of miRNAs and their targets as diagnostic or prognostic markers for CVDs is promising, but has not yet been realized. Further studies are necessary to improve our understanding of the involvement of lncRNA in regulating gene expression changes underlying heart failure. Through the data obtained from such studies, specific therapeutic strategies to avoid heart failure based on interference with incRNA pathways could be developed. Together, research and testing findings raise hope for enhancing the therapeutic armamentarium. This review presents the currently available data concerning epigenetic mechanisms and compounds involved in cardiovascular diseases, as well as preventive and therapeutic approaches against them.
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Affiliation(s)
- Susanne Voelter-Mahlknecht
- University Hospital of Tuebingen, Institute of Occupational and Social Medicine and Health Services Research, Wilhelmstr. 27, 72074 Tuebingen, Germany
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12
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Sun L, Chua CYX, Tian W, Zhang Z, Chiao PJ, Zhang W. MicroRNA Signaling Pathway Network in Pancreatic Ductal Adenocarcinoma. J Genet Genomics 2015; 42:563-577. [PMID: 26554910 DOI: 10.1016/j.jgg.2015.07.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Revised: 07/16/2015] [Accepted: 07/22/2015] [Indexed: 01/15/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is considered to be the most lethal and aggressive malignancy with high mortality and poor prognosis. Their responses to current multimodal therapeutic regimens are limited. It is urgently needed to identify the molecular mechanism underlying pancreatic oncogenesis. Twelve core signaling cascades have been established critical in PDAC tumorigenesis by governing a wide variety of cellular processes. MicroRNAs (miRNAs) are aberrantly expressed in different types of tumors and play pivotal roles as post-transcriptional regulators of gene expression. Here, we will describe how miRNAs regulate different signaling pathways that contribute to pancreatic oncogenesis and progression.
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Affiliation(s)
- Longhao Sun
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA; Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Corrine Ying Xuan Chua
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston 77030, USA
| | - Weijun Tian
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Zhixiang Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Paul J Chiao
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston 77030, USA
| | - Wei Zhang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston 77030, USA; Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China.
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13
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You J, Zhao J, Wen X, Wu C, Huang Q, Guan F, Wu R, Liang D, Li C. Chemoradiation therapy using cyclopamine-loaded liquid-lipid nanoparticles and lutetium-177-labeled core-crosslinked polymeric micelles. J Control Release 2015; 202:40-8. [PMID: 25637565 DOI: 10.1016/j.jconrel.2015.01.031] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 01/16/2015] [Accepted: 01/26/2015] [Indexed: 12/12/2022]
Abstract
Cyclopamine (CPA), a potent inhibitor of the Hedgehog pathway, has produced promising anticancer results in a number of preclinical studies. CPA has also been found to enhance tumor response to radiation therapy. However, CPA is water insoluble. A drug delivery system suitable for systemic administration of CPA is needed before CPA can be considered for clinical translation. We hypothesized that CPA solubilized in a liquid-lipid nanoparticle system (CPA-LLP) for intravenous injection would have desirable pharmacokinetic properties and increased anticancer efficacy. We further hypothesized that CPA-LLP would enhance the response of tumor cells to targeted radiotherapy delivered selectively through intratumoral injection of lutetium-177 bound to core-crosslinked polymeric micelles (CCPM-(177)Lu). We tested the combination therapy in 4T1 murine breast cancer and Miapaca-2 human pancreatic adenocarcinoma models. The results showed that CPA-LLP had higher antitumor cytotoxicity than free CPA (IC50 values [mean±SEM]: 2.7±0.2μM vs. 11.3±1.2μM against 4T1 cells; 1.8±0.2 vs. 17.1±1.26μM against Miapaca-2 cells; p<0.0001). In both cell lines, CPA-LLP resulted in significantly lower clonogenicity than free CPA (p<0.05). Moreover, in both cell lines, CPA-LLP significantly enhanced the cell response to CCPM-(177)Lu radiotherapy as measured by clonogenic assay (p<0.05). In 4T1 and Miapaca-2 mouse xenograft models, the combination of CPA-LLP and CCPM-(177)Lu delayed tumor growth more than either monotherapy did alone. In the 4T1 tumor model, tumor size at 16days after treatment was significantly smaller with the combination therapy than with all the other treatments. In the Miapaca-2 model, the combination therapy resulted in the highest rate of mouse survival and prevented tumor relapse. In conclusion, the combination of CPA-LLP and CCPM-(177)Lu was an effective strategy for treating breast and pancreatic cancer and deserves further investigation.
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Affiliation(s)
- Jian You
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Jun Zhao
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Xiaoxia Wen
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Chunhui Wu
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Qian Huang
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Fada Guan
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Richard Wu
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Dong Liang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, 3100 Cleburne Street, Houston, TX 77004, USA
| | - Chun Li
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
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14
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Clinical implications of miRNAs in the pathogenesis, diagnosis and therapy of pancreatic cancer. Adv Drug Deliv Rev 2015; 81:16-33. [PMID: 25453266 DOI: 10.1016/j.addr.2014.10.020] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Revised: 10/12/2014] [Accepted: 10/15/2014] [Indexed: 02/06/2023]
Abstract
Despite considerable progress being made in understanding pancreatic cancer (PC) pathogenesis, it still remains the 10th most often diagnosed malignancy in the world and 4th leading cause of cancer related deaths in the United States with a five year survival rate of only 6%. The aggressive nature, lack of early diagnostic and prognostic markers, late clinical presentation, and limited efficacy of existing treatment regimens make PC a lethal cancer with high mortality and poor prognosis. Therefore, novel reliable biomarkers and molecular targets are urgently needed to combat this deadly disease. MicroRNAs (miRNAs) are short (19-24 nucleotides) non-coding RNA molecules implicated in the regulation of gene expression at post-transcriptional level and play significant roles in various physiological and pathological conditions. Aberrant expression of miRNAs has been reported in several cancers including PC and is implicated in PC pathogenesis and progression, suggesting their utility in diagnosis, prognosis and therapy. In this review, we summarize the role of several miRNAs that regulate various oncogenes (KRAS) and tumor suppressor genes (p53, p16, SMAD4, etc.) involved in PC development, their prospective roles as diagnostic and prognostic markers and as a therapeutic targets.
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15
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Chitkara D, Mittal A, Mahato RI. miRNAs in pancreatic cancer: therapeutic potential, delivery challenges and strategies. Adv Drug Deliv Rev 2015; 81:34-52. [PMID: 25252098 DOI: 10.1016/j.addr.2014.09.006] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Revised: 08/18/2014] [Accepted: 09/15/2014] [Indexed: 02/08/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a severe pancreatic malignancy and is predicted to victimize 1.5% of men and women during their lifetime (Cancer statistics: SEER stat fact sheet, National Cancer Institute, 2014). miRNAs have emerged as a promising prognostic, diagnostic and therapeutic tool to fight against pancreatic cancer. miRNAs could modulate gene expression by imperfect base-pairing with target mRNA and hence provide means to fine-tune multiple genes simultaneously and alter various signaling pathways associated with the disease. This exceptional miRNA feature has provided a paradigm shift from the conventional one drug one target concept to one drug multiple target theory. However, in vivo miRNA delivery is not fully realized due to challenges posed by this special class of therapeutic molecules, which involves thorough understanding of the biogenesis and physicochemical properties of miRNA and delivery carriers along with the pathophysiology of the PDAC. This review highlights the delivery strategies of miRNA modulators (mimic/inhibitor) in cancer with special emphasis on PDAC since successful delivery of miRNA in vivo constitutes the major challenge in clinical translation of this promising class of therapeutics.
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Khan MA, Zubair H, Srivastava SK, Singh S, Singh AP. Insights into the Role of microRNAs in Pancreatic Cancer Pathogenesis: Potential for Diagnosis, Prognosis, and Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 889:71-87. [PMID: 26658997 DOI: 10.1007/978-3-319-23730-5_5] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is a highly lethal malignancy and a fourth leading cause of cancer-related death in the United States. Poor survival of pancreatic cancer patients is largely because of its asymptomatic progression to advanced stage against which no effective therapy is currently available. Over the years, we have developed significant knowledge of molecular progression of pancreatic cancer and identified several genetic and epigenetic aberrations to be involved in its etiology and aggressive behavior. In that regard, recent lines of evidence have suggested important roles of microRNAs (miRNAs/miRs) in pancreatic cancer pathogenesis. microRNAs belonging to a family of small, noncoding RNAs are able to control diverse biological processes due to their ability to regulate gene expression at the posttranscriptional level. Accordingly, dysregulation of miRNAs can lead to several disease conditions, including cancer. There is a long list of microRNAs that exhibit aberrant expression in pancreatic cancer and serve as key microplayers in its initiation, progression, metastasis, and chemoresistance. These findings have suggested that microRNAs could be exploited as novel biomarkers for diagnostic and prognostic assessments of pancreatic cancer and as targets for therapy. This book chapter describes clinical problems associated with pancreatic cancer, roles that microRNAs play in various aspects of pancreatic cancer pathogenesis, and envision opportunities for potential use of microRNAs in pancreatic cancer management.
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Affiliation(s)
- Mohammad Aslam Khan
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, AL, 36604-1405, USA
| | - Haseeb Zubair
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, AL, 36604-1405, USA
| | - Sanjeev Kumar Srivastava
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, AL, 36604-1405, USA
| | - Seema Singh
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, AL, 36604-1405, USA
| | - Ajay Pratap Singh
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, AL, 36604-1405, USA. .,Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, USA.
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17
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Aberrant MicroRNAs in Pancreatic Cancer: Researches and Clinical Implications. Gastroenterol Res Pract 2014; 2014:386561. [PMID: 24899890 PMCID: PMC4034662 DOI: 10.1155/2014/386561] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Revised: 03/11/2014] [Accepted: 03/24/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a high rate of mortality and poor prognosis. Numerous studies have proved that microRNA (miRNA) may play a vital role in a wide range of malignancies, including PDAC, and dysregulated miRNAs, including circulating miRNAs, are associated with PDAC proliferation, invasion, chemosensitivity, and radiosensitivity, as well as prognosis. Greater understanding of the roles of miRNAs in PDAC could provide insights into this disease and identify potential diagnostic markers and therapeutic targets. The current review focuses on recent advances with respect to the roles of miRNAs in PDAC and their practical value.
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18
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miRNAs for the detection of multidrug resistance: overview and perspectives. Molecules 2014; 19:5611-23. [PMID: 24786846 PMCID: PMC6270919 DOI: 10.3390/molecules19055611] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Revised: 04/23/2014] [Accepted: 04/25/2014] [Indexed: 12/29/2022] Open
Abstract
The goal of the present paper is to establish and validate the link between cancer diagnosis and therapy by microRNAs detection. The induction in vitro of some specific microRNAs after treatment with MDR ligands has been outlined. Starting from the results obtained by in vitro induction of MDCK and MDCK-MDR1 cells treated by a MDR1 ligand, a new scenario in the early diagnosis and chemotherapy could be disclosed. To corroborate this perspective a short overview on pancreatic cancer diagnosis and chemotherapeutic treatment has been reported.
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19
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Sethi S, Li Y, Sarkar FH. Regulating miRNA by natural agents as a new strategy for cancer treatment. Curr Drug Targets 2014; 14:1167-74. [PMID: 23834152 DOI: 10.2174/13894501113149990189] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Accepted: 07/01/2013] [Indexed: 12/19/2022]
Abstract
MicroRNAs (miRNAs) are small single-strand non-coding endogenous RNAs that regulate gene expression by multiple mechanisms. Recent evidence suggests that miRNAs are critically involved in the pathogenesis, evolution, and progression of cancer. The miRNAs are also crucial for the regulation of cancer stem cells (CSCs). In addition, miRNAs are known to control the processes of Epithelial-to-Mesenchymal Transition (EMT) of cancer cells. This evidence suggests that miRNAs could serve as targets in cancer treatment, and as such manipulating miRNAs could be useful for the killing CSCs or reversal of EMT phenotype of cancer cells. Hence, targeting miRNAs, which are deregulated in cancer, could be a promising strategy for cancer therapy. Recently, the regulation of miRNAs by natural, nontoxic chemopreventive agents including curcumin, resveratrol, isoflavones, (-)-epigallocatechin-3-gallate (EGCG), lycopene, 3,3'- diindolylmethane (DIM), and indole-3-carbinol (I3C) has been described. Therefore, natural agents could inhibit cancer progression, increase drug sensitivity, reverse EMT, and prevent metastasis though modulation of miRNAs, which will provide a newer therapeutic approach for cancer treatment especially when combined with conventional therapeutics.
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Affiliation(s)
- Sajiv Sethi
- Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
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20
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Gnoni A, Licchetta A, Scarpa A, Azzariti A, Brunetti AE, Simone G, Nardulli P, Santini D, Aieta M, Delcuratolo S, Silvestris N. Carcinogenesis of pancreatic adenocarcinoma: precursor lesions. Int J Mol Sci 2013; 14:19731-62. [PMID: 24084722 PMCID: PMC3821583 DOI: 10.3390/ijms141019731] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Revised: 09/04/2013] [Accepted: 09/10/2013] [Indexed: 02/06/2023] Open
Abstract
Pancreatic adenocarcinoma displays a variety of molecular changes that evolve exponentially with time and lead cancer cells not only to survive, but also to invade the surrounding tissues and metastasise to distant sites. These changes include: genetic alterations in oncogenes and cancer suppressor genes; changes in the cell cycle and pathways leading to apoptosis; and also changes in epithelial to mesenchymal transition. The most common alterations involve the epidermal growth factor receptor (EGFR) gene, the HER2 gene, and the K-ras gene. In particular, the loss of function of tumor-suppressor genes has been documented in this tumor, especially in CDKN2a, p53, DPC4 and BRCA2 genes. However, other molecular events involved in pancreatic adenocarcinoma pathogenesis contribute to its development and maintenance, specifically epigenetic events. In fact, key tumor suppressors that are well established to play a role in pancreatic adenocarcinoma may be altered through hypermethylation, and oncogenes can be upregulated secondary to permissive histone modifications. Indeed, factors involved in tumor invasiveness can be aberrantly expressed through dysregulated microRNAs. This review summarizes current knowledge of pancreatic carcinogenesis from its initiation within a normal cell until the time that it has disseminated to distant organs. In this scenario, highlighting these molecular alterations could provide new clinical tools for early diagnosis and new effective therapies for this malignancy.
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Affiliation(s)
- Antonio Gnoni
- Medical Oncology Unit, Hospital Vito Fazzi, Lecce 73100, Italy; E-Mails: (A.G.); (A.L.)
| | - Antonella Licchetta
- Medical Oncology Unit, Hospital Vito Fazzi, Lecce 73100, Italy; E-Mails: (A.G.); (A.L.)
| | - Aldo Scarpa
- Department of Pathology and Diagnostics, University of Verona, Verona 37121, Italy; E-Mail:
| | - Amalia Azzariti
- Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre Istituto Tumori “Giovanni Paolo II”, Bari 70124, Italy; E-Mail:
| | - Anna Elisabetta Brunetti
- Scientific Direction, National Cancer Research Centre Istituto Tumori “Giovanni Paolo II”, Bari 70124, Italy; E-Mail: (A.E.B.); (S.D.)
| | - Gianni Simone
- Histopathology Unit, National Cancer Research Centre Istituto Tumori “Giovanni Paolo II”, Bari 70124, Italy; E-Mail:
| | - Patrizia Nardulli
- Hospital Pharmacy Unit - National Cancer Research Centre Istituto Tumori “Giovanni Paolo II”, Bari 70124, Italy; E-Mail:
| | - Daniele Santini
- Medical Oncology Department, University Campus Bio-Medico, Rome 00199, Italy; E-Mail:
| | - Michele Aieta
- Medical Oncology Unit - CROB-IRCCS, 85028, Rionero in Vulture, Potenza 85100, Italy; E-Mail:
| | - Sabina Delcuratolo
- Scientific Direction, National Cancer Research Centre Istituto Tumori “Giovanni Paolo II”, Bari 70124, Italy; E-Mail: (A.E.B.); (S.D.)
| | - Nicola Silvestris
- Medical Oncology Unit, National Cancer Research Centre Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, Bari 70124, Italy
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21
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Du Y, Liu M, Gao J, Li Z. Aberrant MicroRNAs Expression Patterns in Pancreatic Cancer and Their Clinical Translation. Cancer Biother Radiopharm 2013; 28:361-9. [PMID: 23621126 DOI: 10.1089/cbr.2012.1389] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Affiliation(s)
- Yiqi Du
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
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22
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Tumor suppressor protein VHL inhibits Hedgehog-Gli activation through suppression of Gli1 nuclear localization. FEBS Lett 2013; 587:826-32. [DOI: 10.1016/j.febslet.2013.01.050] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2012] [Revised: 01/19/2013] [Accepted: 01/23/2013] [Indexed: 11/20/2022]
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23
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Cheng H, Shi S, Cai X, Long J, Xu J, Liu C, Yu X. microRNA signature for human pancreatic cancer invasion and metastasis. Exp Ther Med 2012; 4:181-187. [PMID: 22970025 DOI: 10.3892/etm.2012.585] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Accepted: 05/14/2012] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer has the poorest prognosis among all human malignant solid tumors, mainly due to its high invasive and metastatic biological features. microRNAs (miRNAs) are a group of endogenous and small non-coding RNA molecules 18-25 nucleotides in length, functioning as either tumor-suppressor genes or oncogenes. Evidence has shown that regulation of miRNAs in pancreatic cancer is associated with tumor growth, invasion, metastasis and resistance to therapy. Over the last decade, many studies have also found that there is a close relationship between miRNAs and biological characteristics of pancreatic cancer invasion and metastasis, such as the presence of cancer stem cells, epithelial-mesenchymal transition (EMT) phenotype, DNA methylation or epigenetic alteration, and the activation of some specific signaling pathways. Therefore, better understanding of the complex role of miRNAs in the development and progression of pancreatic cancer metastasis may provide new insights that could be of therapeutic consequence. In this brief review, we discuss the literature concerning the correlation between miRNAs and pancreatic cancer, focusing on miRNAs that contribute to pancreatic cancer invasion and metastasis, particularly on cancer stem cell characteristics, the EMT process, epigenetic modifications and tumor-associated signaling pathways.
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Affiliation(s)
- He Cheng
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University, Shanghai Cancer Center
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24
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Pignot G, Vieillefond A, Vacher S, Zerbib M, Debre B, Lidereau R, Amsellem-Ouazana D, Bieche I. Hedgehog pathway activation in human transitional cell carcinoma of the bladder. Br J Cancer 2012; 106:1177-86. [PMID: 22361633 PMCID: PMC3304423 DOI: 10.1038/bjc.2012.55] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2011] [Revised: 01/27/2012] [Accepted: 02/03/2012] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The Hedgehog (Hh) signalling pathway functions as an organiser in embryonic development. Recent studies have shown constitutive activation of this pathway in various malignancies, but its role in bladder cancer remains poorly studied. METHODS Expression levels of 31 genes and 9 microRNAs (miRNAs) involved in the Hh pathway were determined by quantitative real-time RT-PCR in 71 bladder tumour samples (21 muscle-invasive (MIBC) and 50 non-muscle-invasive (NMIBC) bladder cancers), as well as in 6 bladder cancer cell lines. RESULTS The SHH ligand gene and Gli-inducible target genes (FOXM1, IGF2, OSF2, H19, and SPP1) were overexpressed in tumour samples as compared with normal bladder tissue. SHH overexpression was found in 96% of NMIBC and 52% of MIBC samples, as well as in two bladder cancer cell lines. Altered expression of miRNAs supported their oncogene or tumour-suppressor gene status. In univariate analysis, high expression levels of PTCH2, miRNA-92A, miRNA-19A, and miRNA-20A were associated with poorer overall survival in MIBC (P=0.02, P=0.012, P=0.047, and P=0.036, respectively). CONCLUSION We observed constitutive activation of the Hh pathway in most NMIBC and about 50% of MIBC. We also found that some protein-coding genes and miRNAs involved in the Hh pathway may have prognostic value at the individual level.
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Affiliation(s)
- G Pignot
- Department of Urology, Service d'Urologie, Université Paris Descartes, Sorbonne Paris Cité, 27 rue du Faubourg Saint Jaques, Paris F-75014, France.
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25
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Iovanna J, Mallmann MC, Gonçalves A, Turrini O, Dagorn JC. Current knowledge on pancreatic cancer. Front Oncol 2012; 2:6. [PMID: 22655256 PMCID: PMC3356035 DOI: 10.3389/fonc.2012.00006] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2011] [Accepted: 01/11/2012] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer is the fourth leading cause of cancer death with a median survival of 6 months and a dismal 5-year survival rate of 3-5%. The development and progression of pancreatic cancer are caused by the activation of oncogenes, the inactivation of tumor suppressor genes, and the deregulation of many signaling pathways. Therefore, the strategies targeting these molecules as well as their downstream signaling could be promising for the prevention and treatment of pancreatic cancer. However, although targeted therapies for pancreatic cancer have yielded encouraging results in vitro and in animal models, these findings have not been translated into improved outcomes in clinical trials. This failure is due to an incomplete understanding of the biology of pancreatic cancer and to the selection of poorly efficient or imperfectly targeted agents. In this review, we will critically present the current knowledge regarding the molecular, biochemical, clinical, and therapeutic aspects of pancreatic cancer.
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Affiliation(s)
- Juan Iovanna
- INSERM U624, Stress Cellulaire, Parc Scientifique et Technologique de LuminyMarseille, France
| | | | - Anthony Gonçalves
- Département d’Oncologie Médicale, Institut Paoli-CalmettesMarseille, France
| | - Olivier Turrini
- Département de Chirurgie Oncologique, Institut Paoli-CalmettesMarseille, France
| | - Jean-Charles Dagorn
- INSERM U624, Stress Cellulaire, Parc Scientifique et Technologique de LuminyMarseille, France
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Budhu A, Wang XW. MicroRNAs and Gastroenterological Cancers. DRUG DISCOVERY TODAY. DISEASE MECHANISMS 2011; 8:e95-e102. [PMID: 22582080 PMCID: PMC3349158 DOI: 10.1016/j.ddmec.2011.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
MicroRNAs are small noncoding RNAs that control gene expression. In doing so, they functionally contribute to the maintenance of cellular processes as well as several important features related to cancer development and progression such as cell growth control, differentiation and apoptosis. In fact, recent studies have shown that microRNAs are suitable and effective cancer-related biomarkers since they display altered expression profiles in cancers versus normal tissue. In addition, microRNAs have been associated with cancer progression and outcome. In this review, the current state of knowledge microRNA expression and function in relation to gastroenterological cancers will be addressed. Moreover, the mechanisms to alter their expression and the potential application of microRNAs in clinical settings will also be highlighted. Finally, the challenges involved in translating microRNA research to the clinic will be discussed.
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Affiliation(s)
- Anuradha Budhu
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, U.S.A
| | - Xin W Wang
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, U.S.A
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27
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Serva A, Claas C, Starkuviene V. A Potential of microRNAs for High-Content Screening. J Nucleic Acids 2011; 2011:870903. [PMID: 21922044 PMCID: PMC3172976 DOI: 10.4061/2011/870903] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2010] [Revised: 05/15/2011] [Accepted: 06/03/2011] [Indexed: 12/19/2022] Open
Abstract
In the last years miRNAs have increasingly been recognised as potent posttranscriptional regulators of gene expression. Possibly, miRNAs exert their action on virtually any biological process by simultaneous regulation of numerous genes. The importance of miRNA-based regulation in health and disease has inspired research to investigate diverse aspects of miRNA origin, biogenesis, and function. Despite the recent rapid accumulation of experimental data, and the emergence of functional models, the complexity of miRNA-based regulation is still far from being well understood. In particular, we lack comprehensive knowledge as to which cellular processes are regulated by which miRNAs, and, furthermore, how temporal and spatial interactions of miRNAs to their targets occur. Results from large-scale functional analyses have immense potential to address these questions. In this review, we discuss the latest progress in application of high-content and high-throughput functional analysis for the systematic elucidation of the biological roles of miRNAs.
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Affiliation(s)
- Andrius Serva
- BioQuant, University of Heidelberg, 69120 Heidelberg, Germany
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28
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Henry JC, Azevedo-Pouly ACP, Schmittgen TD. microRNA Replacement Therapy for Cancer. Pharm Res 2011; 28:3030-42. [DOI: 10.1007/s11095-011-0548-9] [Citation(s) in RCA: 106] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2011] [Accepted: 07/22/2011] [Indexed: 12/19/2022]
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29
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Vandenboom Ii TG, Li Y, Philip PA, Sarkar FH. MicroRNA and Cancer: Tiny Molecules with Major Implications. Curr Genomics 2011; 9:97-109. [PMID: 19440450 PMCID: PMC2674802 DOI: 10.2174/138920208784139555] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2008] [Revised: 03/21/2008] [Accepted: 03/26/2008] [Indexed: 12/19/2022] Open
Abstract
Cancer is currently a major public health problem and, as such, emerging research is making significant progress in identifying major players in its biology. One recent topic of interest involves microRNAs (miRNAs) which are small, non-coding RNA molecules that inhibit gene expression post-transcriptionally. They accomplish this by binding to the 3’ untranslated region (3’UTR) of target messengerRNA (mRNA), resulting in either their degradation or inhibition of translation, depending on the degree of complementary base pairing. They are transcribed by RNA polymerase II and are formed into mature miRNAs via two steps, each catalyzed by a different ribonuclease III (RNaseIII). Cross-species comparisons demonstrate that miRNAs are evolutionarily conserved and play important roles in a wide array of normal biological processes. Importantly, aberrant miRNA expression is correlated with human disease, especially in the development of cancer. Recent research has identified targets and functions of miRNAs, illustrating that some are oncogenic in nature while others show tumor suppressor activity. The miRNAs have also been characterized as having high potential in the clinical arena and, as such, have been a target for exploitation toward cancer therapy. Not only has it been shown that miRNA expression profiles may prove useful as diagnostic and prognostic markers in cancer, various miRNA-based therapies show promise as well. It is anticipated that further research will elucidate the benefits of using miRNAs as clinical agents in the battle against cancer and other chronic diseases.
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Targeted delivery of mutant tolerant anti-coxsackievirus artificial microRNAs using folate conjugated bacteriophage Phi29 pRNA. PLoS One 2011; 6:e21215. [PMID: 21698212 PMCID: PMC3115994 DOI: 10.1371/journal.pone.0021215] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2011] [Accepted: 05/23/2011] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Myocarditis is the major heart disease in infants and young adults. It is very commonly caused by coxsackievirus B3 (CVB3) infection; however, no specific treatment or vaccine is available at present. RNA interference (RNAi)-based anti-viral therapy has shown potential to inhibit viral replication, but this strategy faces two major challenges; viral mutational escape from drug suppression and targeted delivery of the reagents to specific cell populations. METHODOLOGY/PRINCIPAL FINDINGS In this study, we designed artificial microRNAs (AmiRs) targeting the 3'untranslated region (3'UTR) of CVB3 genome with mismatches to the central region of their targeting sites. Antiviral evaluation showed that AmiR-1 and AmiR-2 reduced CVB3 (Kandolf and CG strains) replication approximately 100-fold in both HeLa cells and HL-1 cardiomyocytes. To achieve specific delivery, we linked AmiRs to the folate-conjugated bacterial phage packaging RNA (pRNA) and delivered the complexes into HeLa cells, a folate receptor positive cancer cells widely used as an in vitro model for CVB3 infection, via folate-mediated specific internalization. We found that our designed pRNA-AmiRs conjugates were tolerable to target mutations and have great potential to suppress viral mutational escape with little effect on triggering interferon induction. CONCLUSION/SIGNIFICANCE This study provides important clues for designing AmiRs targeting the 3'UTR of viral genome. It also proves the feasibility of specific deliver of AmiRs using conjugated pRNA vehicles. These small AmiRs combined with pRNA-folate conjugates could form a promising system for antiviral drug development.
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Parvani JG, Taylor MA, Schiemann WP. Noncanonical TGF-β signaling during mammary tumorigenesis. J Mammary Gland Biol Neoplasia 2011; 16:127-46. [PMID: 21448580 PMCID: PMC3723114 DOI: 10.1007/s10911-011-9207-3] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2011] [Accepted: 03/08/2011] [Indexed: 12/16/2022] Open
Abstract
Breast cancer is a heterogeneous disease comprised of at least five major tumor subtypes that coalesce as the second leading cause of cancer death in women in the United States. Although metastasis clearly represents the most lethal characteristic of breast cancer, our understanding of the molecular mechanisms that govern this event remains inadequate. Clinically, ~30% of breast cancer patients diagnosed with early-stage disease undergo metastatic progression, an event that (a) severely limits treatment options, (b) typically results in chemoresistance and low response rates, and (c) greatly contributes to aggressive relapses and dismal survival rates. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that regulates all phases of postnatal mammary gland development, including branching morphogenesis, lactation, and involution. TGF-β also plays a prominent role in suppressing mammary tumorigenesis by preventing mammary epithelial cell (MEC) proliferation, or by inducing MEC apoptosis. Genetic and epigenetic events that transpire during mammary tumorigenesis conspire to circumvent the tumor suppressing activities of TGF-β, thereby permitting late-stage breast cancer cells to acquire invasive and metastatic phenotypes in response to TGF-β. Metastatic progression stimulated by TGF-β also relies on its ability to induce epithelial-mesenchymal transition (EMT) and the expansion of chemoresistant breast cancer stem cells. Precisely how this metamorphosis in TGF-β function comes about remains incompletely understood; however, recent findings indicate that the initiation of oncogenic TGF-β activity is contingent upon imbalances between its canonical and noncanonical signaling systems. Here we review the molecular and cellular contributions of noncanonical TGF-β effectors to mammary tumorigenesis and metastatic progression.
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MESH Headings
- Animals
- Breast Neoplasms/genetics
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Disease Progression
- Epithelial-Mesenchymal Transition
- Female
- Humans
- Mammary Glands, Animal/growth & development
- Mammary Glands, Animal/metabolism
- Mammary Glands, Animal/pathology
- Mammary Glands, Human/growth & development
- Mammary Glands, Human/metabolism
- Mammary Glands, Human/pathology
- Mammary Neoplasms, Experimental/genetics
- Mammary Neoplasms, Experimental/metabolism
- Mammary Neoplasms, Experimental/pathology
- Signal Transduction
- Transforming Growth Factor beta/genetics
- Transforming Growth Factor beta/metabolism
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Affiliation(s)
- Jenny G Parvani
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
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Budhu A, Ji J, Wang XW. The clinical potential of microRNAs. J Hematol Oncol 2010; 3:37. [PMID: 20925959 PMCID: PMC2958878 DOI: 10.1186/1756-8722-3-37] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2010] [Accepted: 10/06/2010] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs are small noncoding RNAs that function to control gene expression. These small RNAs have been shown to contribute to the control of cell growth, differentiation and apoptosis, important features related to cancer development and progression. In fact, recent studies have shown the utility of microRNAs as cancer-related biomarkers. This is due to the finding that microRNAs display altered expression profiles in cancers versus normal tissue. In addition, microRNAs have been associated with cancer progression. In this review, the mechanisms to alter microRNA expression and their relation to cancer will be addressed. Moreover, the potential application of microRNAs in clinical settings will also be highlighted. Finally, the challenges regarding the translation of research involving microRNAs to the clinical realm will be discussed.
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Affiliation(s)
- Anuradha Budhu
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
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Morris JP, Wang SC, Hebrok M. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat Rev Cancer 2010; 10:683-95. [PMID: 20814421 PMCID: PMC4085546 DOI: 10.1038/nrc2899] [Citation(s) in RCA: 451] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by near-universal mutations in KRAS and frequent deregulation of crucial embryonic signalling pathways, including the Hedgehog (Hh) and Wnt-β-catenin cascades. The creation of mouse models that closely resemble the human disease has provided a platform to better understand when and in which cell types these pathways are misregulated during PDAC development. Here we examine the central part that KRAS plays in the biology of PDAC, and how the timing and location of Hh and Wnt-β-catenin signalling dictate the specification and oncogenic properties of PDAC.
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Affiliation(s)
- John P Morris
- Diabetes Center, University of California, San Francisco, 513 Parnassus Ave, San Francisco, California 94143, USA
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Mine T, Matsueda S, Gao H, Li Y, Wong KK, Peoples GE, Ferrone S, Ioannides CG. Created Gli-1 duplex short-RNA (i-Gli-RNA) eliminates CD44 Hi progenitors of taxol-resistant ovarian cancer cells. Oncol Rep 2010; 23:1537-43. [PMID: 20428807 DOI: 10.3892/or_00000793] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Notch and Hedgehog activate cell-cycle progression of adult and cancer stem cells. Notch is activated by DLL and Jag presents on neighboring cells. We investigated the effects of density of the Notch-activating ligand, Jag-1, and targeting Gli-1, in activation of division of paclitaxel/taxol-resistant, (PTX Res) ovarian cancer cells SKOV3 (SKOV3). We used the specific gamma-presenilin inhibitor, DAPT, to identify the specificity of activating signals for Notch-1 and created 'butterfly-duplex-3548-Gli-1-inhibitory RNA' (i-Gli-1.RNA) to inhibit cell division. To accurately quantify kinetics of division, the expression of CD44 and CD24 was determined in each gated population of divided cells. CD44 High proliferated when activated by Jag-1 Low and poorly when activated by Jag-1 High. DAPT inhibited proliferation of cells activated by Jag-1 Low, and increased proliferation of cells activated by Jag-1 High. Only 5-10% of cells activated by Jag-1 High and Jag-1 Low divided fast, polynomial, and symmetric. i-Gli-1.RNA eliminated more than 50% of the small CD44 High/CD24 Neg cells in divisions 3 and 4. This effect appeared specific compared with cells transfected with negative control siRNA. i-Gli-1.RNA had no effect on large CD44 High/CD24 Neg cells, but inhibited the population of CD44 High/CD24 Low cells. Expansion of CD44 High inversely correlated with Jag-1 density on activating autologous tumor and fibrosarcoma cells. Created i-RNAs may decrease the resting CSC pool. Notch and Gli-1 signals play an important role in proliferation/division and survival of cancer stem cells. Targeting Notch-1 through its enhancer Gl-1, should be significant for novel treatments to eliminate taxol-resistant cancer stem cells (CSC). i.Gli-1 RNA should be more effective if used together with Taxol.
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Affiliation(s)
- Takashi Mine
- Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Li Y, Kong D, Wang Z, Sarkar FH. Regulation of microRNAs by natural agents: an emerging field in chemoprevention and chemotherapy research. Pharm Res 2010; 27:1027-41. [PMID: 20306121 PMCID: PMC2974845 DOI: 10.1007/s11095-010-0105-y] [Citation(s) in RCA: 151] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2009] [Accepted: 02/25/2010] [Indexed: 12/11/2022]
Abstract
In recent years, microRNAs have received greater attention in cancer research. These small, non-coding RNAs could inhibit target gene expression by binding to the 3' untranslated region of target mRNA, resulting in either mRNA degradation or inhibition of translation. miRNAs play important roles in many normal biological processes; however, studies have also shown that aberrant miRNA expression is correlated with the development and progression of cancers. The miRNAs could have oncogenic or tumor suppressor activities. Moreover, some miRNAs could regulate formation of cancer stem cells and epithelial-mesenchymal transition phenotype of cancer cells which are typically drug resistant. Furthermore, miRNAs could be used as biomarkers for diagnosis and prognosis, and thus miRNAs are becoming emerging targets for cancer therapy. Recent studies have shown that natural agents including curcumin, isoflavone, indole-3-carbinol, 3,3'-diindolylmethane, (-)-epigallocatechin-3-gallate, resveratrol, etc. could alter miRNA expression profiles, leading to the inhibition of cancer cell growth, induction of apoptosis, reversal of epithelial-mesenchymal transition, or enhancement of efficacy of conventional cancer therapeutics. These emerging results clearly suggest that specific targeting of miRNAs by natural agents could open newer avenues for complete eradication of tumors by killing the drug-resistant cells to improve survival outcome in patients diagnosed with malignancies.
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Affiliation(s)
- Yiwei Li
- Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Dejuan Kong
- Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Zhiwei Wang
- Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Fazlul H. Sarkar
- Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA. Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 740 HWCRC, 4100 John R Street, Detroit, Michigan 48201, USA
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SHP (small heterodimer partner) suppresses the transcriptional activity and nuclear localization of Hedgehog signalling protein Gli1. Biochem J 2010; 427:413-22. [PMID: 20175750 DOI: 10.1042/bj20091445] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Gli (glioma-associated oncogene homologue) proteins act as terminal effectors of the Hedgehog signalling pathway, which is implicated in the development of many human malignancies. Gli activation is important for cell proliferation and anti-apoptosis in various cancers. Several studies have suggested that nuclear receptors have anti-cancer effects by inhibiting the activation of various oncoproteins. However, the involvement of nuclear receptors on the Hedgehog/Gli signalling pathway is poorly defined. In the present study we identified SHP (small heterodimer partner) as a nuclear receptor that decreased the expression of Gli target genes by repressing the transcriptional activity of Gli1. The inhibitory effect of SHP was associated with the inhibition of Gli1 nuclear localization via protein-protein interaction. Finally, SHP overexpression decreased the expression of Gli target genes and SHP knockdown increased the expression of these genes. Taken together, these results suggest that SHP can play a negative role in Hedgehog/Gli1 signalling.
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Torres A, Torres K, Maciejewski R, Harvey WH. MicroRNAs and their role in gynecological tumors. Med Res Rev 2010; 31:895-923. [PMID: 20358579 DOI: 10.1002/med.20205] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
There have been only few events in the history of molecular biology that could be compared to the discovery of microRNAs and their role in cell physiology and pathology. MicroRNAs are small, single-stranded, noncoding RNAs composed of 19-25 nucleotides (∼22 nt), which have been proven to regulate gene expression at the posttranscriptional level. The regulatory function of microRNAs was demonstrated in normal and diseased conditions. In particular, it has been linked to cell cycle regulation, cell proliferation and differentiation, inflammatory response, and apoptosis. Altered expression profiles of microRNA have been observed in many pathologies, including diabetes, rheumatoid arthritis, and several cancers. To date, more than 700 human microRNAs have been identified and in silico-based analyses estimate at least 500 more to be identified. The purpose of this review is to present the current perspective on microRNAs structure and biogenesis as well as their contribution to the etiopathogenesis of gynecological tumors. We discuss results of the recent publications that indicate possibilities of microRNAs use as novel markers for tumors screening, early diagnosis, and treatment monitoring. The possible utilization of microRNAs as prognostic factors and specific therapy targets is also reviewed.
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Affiliation(s)
- Anna Torres
- Laboratory of Biostructure, Human Anatomy Department, Medical University of Lublin, Lublin, Poland.
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Galasso M, Sana ME, Volinia S. Non-coding RNAs: a key to future personalized molecular therapy? Genome Med 2010; 2:12. [PMID: 20236487 PMCID: PMC2847703 DOI: 10.1186/gm133] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Continual discoveries on non-coding RNA (ncRNA) have changed the landscape of human genetics and molecular biology. Over the past ten years it has become clear that ncRNAs are involved in many physiological cellular processes and contribute to molecular alterations in pathological conditions. Several classes of ncRNAs, such as small interfering RNAs, microRNAs, PIWI-associated RNAs, small nucleolar RNAs and transcribed ultra-conserved regions, are implicated in cancer, heart diseases, immune disorders, and neurodegenerative and metabolic diseases. ncRNAs have a fundamental role in gene regulation and, given their molecular nature, they are thus both emerging therapeutic targets and innovative intervention tools. Next-generation sequencing technologies (for example SOLiD or Genome Analyzer) are having a substantial role in the high-throughput detection of ncRNAs. Tools for non-invasive diagnostics now include monitoring body fluid concentrations of ncRNAs, and new clinical opportunities include silencing and inhibition of ncRNAs or their replacement and re-activation. Here we review recent progress on our understanding of the biological functions of human ncRNAs and their clinical potential.
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Affiliation(s)
- Marco Galasso
- Data Mining for Analysis of Microarrays, Department of Morphology and Embryology, Università Degli Studi di Ferrara, 44100 Ferrara, Italy.
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Hirotsu M, Setoguchi T, Sasaki H, Matsunoshita Y, Gao H, Nagao H, Kunigou O, Komiya S. Smoothened as a new therapeutic target for human osteosarcoma. Mol Cancer 2010; 9:5. [PMID: 20067614 PMCID: PMC2818696 DOI: 10.1186/1476-4598-9-5] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2009] [Accepted: 01/12/2010] [Indexed: 12/26/2022] Open
Abstract
Background The Hedgehog signaling pathway functions as an organizer in embryonic development. Recent studies have demonstrated constitutive activation of Hedgehog pathway in various types of malignancies. However, it remains unclear how Hedgehog pathway is involved in the pathogenesis of osteosarcoma. To explore the involvement of aberrant Hedgehog pathway in the pathogenesis of osteosarcoma, we investigated the expression and activation of Hedgehog pathway in osteosarcoma and examined the effect of SMOOTHENED (SMO) inhibition. Results To evaluate the expression of genes of Hedgehog pathway, we performed real-time PCR and immunohistochemistry using osteosarcoma cell lines and osteosarcoma biopsy specimens. To evaluate the effect of SMO inhibition, we did cell viability, colony formation, cell cycle in vitro and xenograft model in vivo. Real-time PCR revealed that osteosarcoma cell lines over-expressed Sonic hedgehog, Indian hedgehog, PTCH1, SMO, and GLI. Real-time PCR revealed over-expression of SMO, PTCH1, and GLI2 in osteosarcoma biopsy specimens. These findings showed that Hedgehog pathway is activated in osteosarcomas. Inhibition of SMO by cyclopamine, a specific inhibitor of SMO, slowed the growth of osteosarcoma in vitro. Cell cycle analysis revealed that cyclopamine promoted G1 arrest. Cyclopamine reduced the expression of accelerators of the cell cycle including cyclin D1, cyclin E1, SKP2, and pRb. On the other hand, p21cip1 wprotein was up-regulated by cyclopamine treatment. In addition, knockdown of SMO by SMO shRNA prevents osteosarcoma growth in vitro and in vivo. Conclusions These findings suggest that inactivation of SMO may be a useful approach to the treatment of patients with osteosarcoma.
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Affiliation(s)
- Masataka Hirotsu
- Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
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Bhardwaj A, Singh S, Singh AP. MicroRNA-based Cancer Therapeutics: Big Hope from Small RNAs. MOLECULAR AND CELLULAR PHARMACOLOGY 2010; 2:213-219. [PMID: 21289871 PMCID: PMC3031298 DOI: 10.4255/mcpharmacol.10.27] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Tremendous progress has been made during the last few years in identification of novel tumor-associated microRNAs and experimental validation of their cancer relevant gene targets. Indeed, these small non-coding RNAs are now known to modulate many biological pathways related to cancer progression, metastasis and therapy-resistance. Therefore, modulating miRNA functions may provide novel therapeutic opportunities for cancer treatment. This article reviews recent literature on the role of miRNAs in cancer with an emphasis on their potential as cancer therapeutics.
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Affiliation(s)
- Arun Bhardwaj
- Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA, 36604
| | - Seema Singh
- Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA, 36604
| | - Ajay P. Singh
- Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA, 36604
- Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, Alabama
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Rachagani S, Kumar S, Batra SK. MicroRNA in pancreatic cancer: pathological, diagnostic and therapeutic implications. Cancer Lett 2009; 292:8-16. [PMID: 20004512 DOI: 10.1016/j.canlet.2009.11.010] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2009] [Revised: 11/10/2009] [Accepted: 11/10/2009] [Indexed: 12/19/2022]
Abstract
MicroRNAs (miRNAs) are a group of small non-coding RNA molecules of 17-25 nucleotides (nt) in length, predicted to control the activity of about 30% of all protein-coding genes in mammals. Altered expressions of miRNAs are reported in various cancers and may associate with cancer pathogenesis, apoptosis, and cell growth, thereby functioning as either tumor suppressors or oncogenes. Recent reports showed that deregulation of miRNA contribute to tumor development and progression and hence, have diagnostic and prognostic value in several human malignancies. This review discusses the current status of miRNA in pancreatic cancer development, progression, diagnosis, and therapy.
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Affiliation(s)
- Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
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Olejniczak M, Galka P, Krzyzosiak WJ. Sequence-non-specific effects of RNA interference triggers and microRNA regulators. Nucleic Acids Res 2009; 38:1-16. [PMID: 19843612 PMCID: PMC2800214 DOI: 10.1093/nar/gkp829] [Citation(s) in RCA: 119] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
RNA reagents of diverse lengths and structures, unmodified or containing various chemical modifications are powerful tools of RNA interference and microRNA technologies. These reagents which are either delivered to cells using appropriate carriers or are expressed in cells from suitable vectors often cause unintended sequence-non-specific immune responses besides triggering intended sequence-specific silencing effects. This article reviews the present state of knowledge regarding the cellular sensors of foreign RNA, the signaling pathways these sensors mobilize and shows which specific features of the RNA reagents set the responsive systems on alert. The representative examples of toxic effects caused in the investigated cell lines and tissues by the RNAs of specific types and structures are collected and may be instructive for further studies of sequence-non-specific responses to foreign RNA in human cells.
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Affiliation(s)
- Marta Olejniczak
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland
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Zhang Y, Li M, Wang H, Fisher WE, Lin PH, Yao Q, Chen C. Profiling of 95 microRNAs in pancreatic cancer cell lines and surgical specimens by real-time PCR analysis. World J Surg 2009; 33:698-709. [PMID: 19030927 PMCID: PMC2933040 DOI: 10.1007/s00268-008-9833-0] [Citation(s) in RCA: 241] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND MicroRNAs (miRNAs) are involved in cancer pathogenesis, apoptosis, and cell growth, thereby functioning as tumor suppressors or oncogenes. However, expression alterations and roles of these miRNAs in pancreatic cancer are largely unknown. We hypothesized that pancreatic cancer may have a unique miRNA profile, which may play a critical role in pancreatic cancer development, progression, diagnosis, and prognosis. METHODS Differential expression of 95 miRNAs was analyzed by real time RT-PCR using the QuantiMir System. All 95 miRNAs chosen for the array are based on their potential functions related to cancer biology, cell development, and apoptosis. The expression of miRNAs for pancreatic cancer tissue samples or cancer cell lines was normalized to U6 RNA and compared with those in relatively normal pancreatic tissues or normal human pancreatic ductal epithelial (HPDE) cells. Human pancreatic tissue with chronic pancreatitis also was included for analysis. RESULTS In the initial analysis, the expression of most 95 miRNAs was substantially changed in pancreatic cancer tissues (n=5) and cell lines (n=3) compared with relatively normal pancreatic tissues and HPDE cells. However, each pancreatic cancer tissue or cell type had a substantially different profiling pattern with other cases or cell types as well as chronic pancreatitis tissue, indicating the individual diversity of pancreatic cancer. Further analysis was performed on 10 pancreatic cancer cell lines and 17 pairs of pancreatic cancer/normal tissues. Eight miRNAs were significantly upregulated in most pancreatic cancer tissues and cell lines, including miR-196a, miR-190, miR-186, miR-221, miR-222, miR-200b, miR-15b, and miR-95. The incidence of upregulation of these eight genes between normal control subjects and tumor cells or tissues ranged from 70-100%. The magnitude of increase of these miRNAs in pancreatic cancer samples ranged from 3- to 2018-fold of normal control subjects. CONCLUSIONS Pancreatic cancer tissues or cell lines have a unique miRNA profiling pattern at the individual basis compared with relatively normal pancreatic tissues or cells as well as pancreatitis tissue. Upregulation of eight miRNAs occurs in most pancreatic cancer tissues and cell types. These miRNAs may share common pathways in pancreatic cancer pathogenesis. This study may provide useful information for further investigations of functional roles of miRNAs in pancreatic cancer development, progression, diagnosis, and prognosis.
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Affiliation(s)
- Yuqing Zhang
- Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine and Michael E. DeBakey VA Medical Center, Houston, Texas
| | - Min Li
- Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine and Michael E. DeBakey VA Medical Center, Houston, Texas
| | - Hao Wang
- Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine and Michael E. DeBakey VA Medical Center, Houston, Texas
| | - William E. Fisher
- Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine and Michael E. DeBakey VA Medical Center, Houston, Texas
| | - Peter H. Lin
- Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine and Michael E. DeBakey VA Medical Center, Houston, Texas
| | - Qizhi Yao
- Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine and Michael E. DeBakey VA Medical Center, Houston, Texas
| | - Changyi Chen
- Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine and Michael E. DeBakey VA Medical Center, Houston, Texas
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Abstract
Cancer is the result of a complex multistep process that involves the accumulation of sequential alterations of several genes, including those encoding microRNAs (miRNAs). miRNAs are a class of 17- to 27-nucleotide single-stranded RNA molecules that regulate gene expression posttranscriptionally. A large body of evidence implicates aberrant miRNA expression patterns in most, if not all, human malignancies. This article reviews our current knowledge about miRNAs, focusing on their involvement in cancer and their potential as diagnostic, prognostic, and therapeutic tools.
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Affiliation(s)
- Rosa Visone
- Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, 460 West, 12th Ave., Columbus, OH 43210, USA
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Zhang S, Zuo H, Yu Z, Huang F, Zhong W. Expression profiles of miRNAs in human pancreatic cancer cell lines. ACTA ACUST UNITED AC 2009. [DOI: 10.1007/s10330-008-0160-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Abstract
The transcription factor glioma-associated antigen-1 (Gli-1) mediates activation of the sonic hedgehog (Shh) pathway, a process that precedes the transformation of tissue stem cells into cancerous stem cells and that is involved in early and late epithelial tumorigenesis. Hypothesizing that targeting the 3'-untranslated region (3'-UTR) of Gli-1 mRNA would effectively inhibit epithelial tumor cell proliferation, we evaluated several complementary miRNA molecules for their ability to do so. The synthetic miRNAs and corresponding duplex/small temporal RNAs were introduced as 3-nucleotide (nt) loops into GU-rich portions of the 3'UTR Gli-1 sequence. One particular miRNA (miRNA Gli-1-3548) and its corresponding duplex (Duplex 3548) significantly inhibited proliferation of Gli-1+ ovarian (SK-OV-3) and pancreatic (MiaPaCa-2) tumor cells by delaying cell division and activating late apoptosis in MiaPaCa-2 cells. Here, we describe the design of effective miRNA sequences and their applications as anti-gene agents.
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Berry NB, Bapat SA. Ovarian cancer plasticity and epigenomics in the acquisition of a stem-like phenotype. J Ovarian Res 2008; 1:8. [PMID: 19025622 PMCID: PMC2612659 DOI: 10.1186/1757-2215-1-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2008] [Accepted: 11/24/2008] [Indexed: 02/07/2023] Open
Abstract
Aggressive epithelial ovarian cancer (EOC) is genetically and epigenetically distinct from normal ovarian surface epithelial cells (OSE) and early neoplasia. Co-expression of epithelial and mesenchymal markers in EOC suggests an involvement of epithelial-mesenchymal transition (EMT) in cancer initiation and progression. This phenomenon is often associated with acquisition of a stem cell-like phenotype and chemoresistance that correlate with the specific gene expression patterns accompanying transformation, revealing a plasticity of the ovarian cancer cell genome during disease progression.Differential gene expressions between normal and transformed cells reflect the varying mechanisms of regulation including genetic changes like rearrangements within the genome, as well as epigenetic changes such as global genomic hypomethylation with localized promoter CpG island hypermethylation. The similarity of gene expression between ovarian cancer cells and the stem-like ovarian cancer initiating cells (OCIC) are surprisingly also correlated with epigenetic mechanisms of gene regulation in normal stem cells. Both normal and cancer stem cells maintain genetic flexibility by co-placement of activating and/or repressive epigenetic modifications on histone H3. The co-occupancy of such opposing histone marks is believed to maintain gene flexibility and such bivalent histones have been described as being poised for transcriptional activation or epigenetic silencing. The involvement of both-microRNA (miRNA) mediated epigenetic regulation, as well as epigenetic-induced changes in miRNA expression further highlight an additional complexity in cancer stem cell epigenomics.Recent advances in array-based whole-genome/epigenome analyses will continue to further unravel the genomes and epigenomes of cancer and cancer stem cells. In order to illuminate phenotypic signatures that delineate ovarian cancer from their associated cancer stem cells, a priority must lie in the expansion of current technologies and further implementation of bioinformatics to handle the complexity of the cancer epigenome and the various networks that coordinate disease initiation and progression. Great potential lies in the translation of these findings into epigenetic-based therapies. Additionally, targeting chemo-resistant cancer stem cells may provide a much needed breakthrough in treatment of advanced ovarian cancer and chemoresistant disease.
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Affiliation(s)
- Nicholas B Berry
- National Centre for Cell Science, NCCS Complex, Pune University Campus, Pune 411007, INDIA
| | - Sharmila A Bapat
- National Centre for Cell Science, NCCS Complex, Pune University Campus, Pune 411007, INDIA
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Love TM, Moffett HF, Novina CD. Not miR-ly small RNAs: big potential for microRNAs in therapy. J Allergy Clin Immunol 2008; 121:309-19. [PMID: 18269923 DOI: 10.1016/j.jaci.2007.12.1167] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2007] [Revised: 12/21/2007] [Accepted: 12/26/2007] [Indexed: 12/19/2022]
Abstract
RNA interference (RNAi) describes a set of natural processes in which genes are silenced by small RNAs. RNAi has been widely used as an experimental tool that has recently become the focus of drug development efforts to treat a variety of diseases and disorders. Like all molecular therapies, in vivo delivery is the major hurdle to realizing therapeutic RNAi. Several strategies have been developed that increase small RNA half-life in the blood, facilitate transduction across biological membranes, and mediate cell-specific delivery. Importantly, these strategies permit targeting of mRNAs as well as microRNAs (miRNAs), a class of small RNAs encoded in the genome. miRNAs are required for multiple developmental and cellular processes. Dysfunction of miRNAs can result in a host of pathologies, suggesting that miRNAs are potential targets of therapy. Recent studies of miRNA function in immune-specific pathways indicate that specific miRNAs might be exploited as therapeutic targets to treat immune disorders, including autoimmunity, allergy, and hematopoietic cancers.
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Affiliation(s)
- Tara M Love
- Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA, USA
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Tili E, Michaille JJ, Gandhi V, Plunkett W, Sampath D, Calin GA. miRNAs and their potential for use against cancer and other diseases. Future Oncol 2008; 3:521-37. [PMID: 17927518 DOI: 10.2217/14796694.3.5.521] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
miRNAs are 19-24 nucleotide long noncoding RNAs found in almost all genetically dissected species, including viruses, plants, nematodes, flies, fish, mice and humans. Rapid advances have been made in understanding their physiological functions, while abnormal patterns of miRNA expression have been found in many disease states, most notably human cancer. It is now clear that miRNAs represent a class of genes with a great potential for use in diagnosis, prognosis and therapy. In this review we will focus on the discoveries that elucidate their crucial role in mammalian diseases, particularly in cancer, and propose that miRNA-based gene therapy might become the potential technology of choice in a wide range of human diseases including cancer.
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Affiliation(s)
- Esmerina Tili
- Ohio State University, Department of Molecular Virology, Immunology & Medical Genetics and Comprehensive Cancer Center, Columbus, OH 43210, USA.
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