|
1
|
Przybyszewski O, Mik M, Nowicki M, Kusiński M, Mikołajczyk-Solińska M, Śliwińska A. Using microRNAs Networks to Understand Pancreatic Cancer-A Literature Review. Biomedicines 2024; 12:1713. [PMID: 39200178 PMCID: PMC11351910 DOI: 10.3390/biomedicines12081713] [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: 05/30/2024] [Revised: 07/26/2024] [Accepted: 07/28/2024] [Indexed: 09/02/2024] Open
Abstract
Pancreatic cancer is a severe disease, challenging to diagnose and treat, and thereby characterized by a poor prognosis and a high mortality rate. Pancreatic ductal adenocarcinoma (PDAC) represents approximately 90% of pancreatic cancer cases, while other cases include neuroendocrine carcinoma. Despite the growing knowledge of the pathophysiology of this cancer, the mortality rate caused by it has not been effectively reduced. Recently, microRNAs have aroused great interest among scientists and clinicians, as they are negative regulators of gene expression, which participate in many processes, including those related to the development of pancreatic cancer. The aim of this review is to show how microRNAs (miRNAs) affect key signaling pathways and related cellular processes in pancreatic cancer development, progression, diagnosis and treatment. We included the results of in vitro studies, animal model of pancreatic cancer and those performed on blood, saliva and tumor tissue isolated from patients suffering from PDAC. Our investigation identified numerous dysregulated miRNAs involved in KRAS, JAK/STAT, PI3/AKT, Wnt/β-catenin and TGF-β signaling pathways participating in cell cycle control, proliferation, differentiation, apoptosis and metastasis. Moreover, some miRNAs (miRNA-23a, miRNA-24, miRNA-29c, miRNA-216a) seem to be engaged in a crosstalk between signaling pathways. Evidence concerning the utility of microRNAs in the diagnosis and therapy of this cancer is poor. Therefore, despite growing knowledge of the involvement of miRNAs in several processes associated with pancreatic cancer, we are beginning to recognize and understand their role and usefulness in clinical practice.
Collapse
Affiliation(s)
- Oskar Przybyszewski
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska St., 92-213 Lodz, Poland
| | - Michał Mik
- Department of General and Colorectal Surgery, Medical University of Lodz, 113 Stefana Żeromskiego St., 90-549 Lodz, Poland; (M.M.); (M.N.)
| | - Michał Nowicki
- Department of General and Colorectal Surgery, Medical University of Lodz, 113 Stefana Żeromskiego St., 90-549 Lodz, Poland; (M.M.); (M.N.)
| | - Michał Kusiński
- Department of Endocrinological, General and Oncological Surgery, Medical University of Lodz, 62 Pabianicka St., 93-513 Lodz, Poland;
| | - Melania Mikołajczyk-Solińska
- Department of Internal Medicine, Diabetology and Clinical Pharmacology, Medical University of Lodz, 251 Pomorska St., 92-213 Lodz, Poland;
| | - Agnieszka Śliwińska
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska St., 92-213 Lodz, Poland
| |
Collapse
|
|
2
|
Khan IA, Saraya A. Circulating MicroRNAs as Noninvasive Diagnostic and Prognostic Biomarkers in Pancreatic Cancer: A Review. J Gastrointest Cancer 2023; 54:720-730. [PMID: 36322366 DOI: 10.1007/s12029-022-00877-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2022] [Indexed: 11/05/2022]
Abstract
Pancreatic cancer (PC) is one of the most lethal human cancers. Currently, most PC cases are diagnosed at an already advanced stage. Early detection of PC is critical to improving survival rates. Therefore, there is an urgent need to identify biomarkers for the early detection of PC. Recently, circulating miRNAs in whole blood and other body fluids have been reported as promising biomarkers for the early detection of various cancers, including PC. Furthermore, due to minimal invasiveness and technical availability, circulating miRNAs hold promise for further wide usage. As a potential novel molecular marker, circulating miRNAs not only represent promising noninvasive diagnostic and prognostic tools but could also improve the evaluation of tumor classification, metastasis, and curative effect. The purpose of this review is to outline the available information regarding circulating miRNAs as biomarkers for the early detection of PC.
Collapse
Affiliation(s)
- Imteyaz Ahmad Khan
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India
| | - Anoop Saraya
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
| |
Collapse
|
|
3
|
Izdebska WM, Daniluk J, Niklinski J. Microbiome and MicroRNA or Long Non-Coding RNA-Two Modern Approaches to Understanding Pancreatic Ductal Adenocarcinoma. J Clin Med 2023; 12:5643. [PMID: 37685710 PMCID: PMC10488817 DOI: 10.3390/jcm12175643] [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: 07/21/2023] [Revised: 08/18/2023] [Accepted: 08/19/2023] [Indexed: 09/10/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of humans' most common and fatal neoplasms. Nowadays, a number of PDAC studies are being conducted in two different fields: non-coding RNA (especially microRNA and long non-coding RNA) and microbiota. It has been recently discovered that not only does miRNA affect particular bacteria in the gut microbiome that can promote carcinogenesis in the pancreas, but the microbiome also has a visible impact on the miRNA. This suggests that it is possible to use the combined impact of the microbiome and noncoding RNA to suppress the development of PDAC. Nevertheless, insufficient research has focused on bounding both approaches to the diagnosis, treatment, and prevention of pancreatic ductal adenocarcinoma. In this article, we summarize the recent literature on the molecular basis of carcinogenesis in the pancreas, the two-sided impact of particular types of non-coding RNA and the pancreatic cancer microbiome, and possible medical implications of the discovered phenomenon.
Collapse
Affiliation(s)
- Wiktoria Maria Izdebska
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Jaroslaw Daniluk
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Jacek Niklinski
- Department of Clinical Molecular Biology, Medical University of Bialystok, 15-089 Bialystok, Poland
| |
Collapse
|
|
4
|
Fukuda K, Seki N, Yasudome R, Mitsueda R, Asai S, Kato M, Idichi T, Kurahara H, Ohtsuka T. Coronin 1C, Regulated by Multiple microRNAs, Facilitates Cancer Cell Aggressiveness in Pancreatic Ductal Adenocarcinoma. Genes (Basel) 2023; 14:genes14050995. [PMID: 37239355 DOI: 10.3390/genes14050995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/18/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023] Open
Abstract
Coronin proteins are actin-related proteins containing WD repeat domains encoded by seven genes (CORO1A, CORO1B, CORO1C, CORO2A, CORO2B, CORO6, and CORO7) in the human genome. Analysis of large cohort data from The Cancer Genome Atlas revealed that expression of CORO1A, CORO1B, CORO1C, CORO2A, and CORO7 was significantly upregulated in pancreatic ductal adenocarcinoma (PDAC) tissues (p < 0.05). Moreover, high expression of CORO1C and CORO2A significantly predicted the 5 year survival rate of patients with PDAC (p = 0.0071 and p = 0.0389, respectively). In this study, we focused on CORO1C and investigated its functional significance and epigenetic regulation in PDAC cells. Knockdown assays using siRNAs targeting CORO1C were performed in PDAC cells. Aggressive cancer cell phenotypes, especially cancer cell migration and invasion, were inhibited by CORO1C knockdown. The involvement of microRNAs (miRNAs) is a molecular mechanism underlying the aberrant expression of cancer-related genes in cancer cells. Our in silico analysis revealed that five miRNAs (miR-26a-5p, miR-29c-3p, miR-130b-5p, miR-148a-5p, and miR-217) are putative candidate miRNAs regulating CORO1C expression in PDAC cells. Importantly, all five miRNAs exhibited tumor-suppressive functions and four miRNAs except miR-130b-5p negatively regulated CORO1C expression in PDAC cells. CORO1C and its downstream signaling molecules are potential therapeutic targets in PDAC.
Collapse
Affiliation(s)
- Kosuke Fukuda
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Naohiko Seki
- Department of Functional Genomics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
| | - Ryutaro Yasudome
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Reiko Mitsueda
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Shunichi Asai
- Department of Functional Genomics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
| | - Mayuko Kato
- Department of Functional Genomics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
| | - Tetsuya Idichi
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Hiroshi Kurahara
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Takao Ohtsuka
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| |
Collapse
|
|
5
|
Di Giorgio C, Bellini R, Lupia A, Massa C, Bordoni M, Marchianò S, Rosselli R, Sepe V, Rapacciuolo P, Moraca F, Morretta E, Ricci P, Urbani G, Monti MC, Biagioli M, Distrutti E, Catalanotti B, Zampella A, Fiorucci S. Discovery of BAR502, as potent steroidal antagonist of leukemia inhibitory factor receptor for the treatment of pancreatic adenocarcinoma. Front Oncol 2023; 13:1140730. [PMID: 36998446 PMCID: PMC10043345 DOI: 10.3389/fonc.2023.1140730] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 02/20/2023] [Indexed: 03/15/2023] Open
Abstract
IntroductionThe leukemia inhibitory factor (LIF), is a cytokine belonging to IL-6 family, whose overexpression correlate with poor prognosis in cancer patients, including pancreatic ductal adenocarcinoma (PDAC). LIF signaling is mediate by its binding to the heterodimeric LIF receptor (LIFR) complex formed by the LIFR receptor and Gp130, leading to JAK1/STAT3 activation. Bile acids are steroid that modulates the expression/activity of membrane and nuclear receptors, including the Farnesoid-X-Receptor (FXR) and G Protein Bile Acid Activated Receptor (GPBAR1).MethodsHerein we have investigated whether ligands to FXR and GPBAR1 modulate LIF/LIFR pathway in PDAC cells and whether these receptors are expressed in human neoplastic tissues. ResultsThe transcriptome analysis of a cohort of PDCA patients revealed that expression of LIF and LIFR is increased in the neoplastic tissue in comparison to paired non-neoplastic tissues. By in vitro assay we found that both primary and secondary bile acids exert a weak antagonistic effect on LIF/LIFR signaling. In contrast, BAR502 a non-bile acid steroidal dual FXR and GPBAR1 ligand, potently inhibits binding of LIF to LIFR with an IC50 of 3.8 µM.DiscussionBAR502 reverses the pattern LIF-induced in a FXR and GPBAR1 independent manner, suggesting a potential role for BAR502 in the treatment of LIFR overexpressing-PDAC.
Collapse
Affiliation(s)
| | - Rachele Bellini
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Antonio Lupia
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
- Net4Science srl, University “Magna Græcia”, Catanzaro, Italy
| | - Carmen Massa
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Martina Bordoni
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Silvia Marchianò
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Valentina Sepe
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | | | - Federica Moraca
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
- Net4Science srl, University “Magna Græcia”, Catanzaro, Italy
| | - Elva Morretta
- Department of Pharmacy, University of Salerno, Salerno, Italy
| | - Patrizia Ricci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Ginevra Urbani
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Michele Biagioli
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Eleonora Distrutti
- Department of Gastroenterology, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Bruno Catalanotti
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
- *Correspondence: Stefano Fiorucci,
| |
Collapse
|
|
6
|
Wang L, Li M, Chen F. microRNA-26a represses pancreatic cancer cell malignant behaviors by targeting E2F7. Discov Oncol 2021; 12:55. [PMID: 35201478 PMCID: PMC8777553 DOI: 10.1007/s12672-021-00448-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 11/10/2021] [Indexed: 01/06/2023] Open
Abstract
Dysregulation of microRNAs (miRNAs) exerts key roles in the development of pancreatic cancer (PCa). miR-26a is reportedly a tumor suppressor in cancers. However, whether miR-26a modulates PCa progression is poorly understood. Here, we found that miR-26a was down-regulated in PCa. Overexpressed miR-26a suppressed PCa cell proliferation, colony formation, and tumor stem cell properties. Mechanically, the transcription factor E2F7 is a downstream target of miR-26a. miR-26a decreased E2F7 expression through binding to the 3'-untranslated region (UTR) of E2F7. Decreased miR-26a in PCa tissues was inversely correlated with E2F7. The inhibitory effects of miR-26a in PCa were reversed by E2F7 overexpression. Consistently, the knockout of E2F7 further significantly inhibited the growth of PCa cells combined with miR-26a overexpression. Further study revealed that E2F7 bound the promoter of vascular endothelial growth factor A (VEGFA), a key factor in angiogenesis, and transcriptionally activated the expression of VEGFA. miR-26a overexpression attenuated the effects of E2F7 on VEGFA promotion. Our results uncovered the novel function of miR-26a/E2F7/VEGFA in PCa, making miR-26a a possible target for PCa treatment.
Collapse
Affiliation(s)
- Liang Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Meijun Li
- Department of Blood, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Fei Chen
- Department of Ultrasound, The First Affiliated Hospital of Jinzhou Medical University, No. 2 of the People Street, Gu Ta district, Jinzhou, 121001, Liao Ning, China.
| |
Collapse
|
|
7
|
Chen S, Gao C, Yu T, Qu Y, Xiao GG, Huang Z. Bioinformatics Analysis of a Prognostic miRNA Signature and Potential Key Genes in Pancreatic Cancer. Front Oncol 2021; 11:641289. [PMID: 34094925 PMCID: PMC8174116 DOI: 10.3389/fonc.2021.641289] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 03/31/2021] [Indexed: 12/11/2022] Open
Abstract
Background In this study, miRNAs and their critical target genes related to the prognosis of pancreatic cancer were screened based on bioinformatics analysis to provide targets for the prognosis and treatment of pancreatic cancer. Methods R software was used to screen differentially expressed miRNAs (DEMs) and genes (DEGs) downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, respectively. A miRNA Cox proportional hazards regression model was constructed based on the miRNAs, and a miRNA prognostic model was generated. The target genes of the prognostic miRNAs were predicted using TargetScan and miRDB and then intersected with the DEGs to obtain common genes. The functions of the common genes were subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses. A protein-protein interaction (PPI) network of the common genes was constructed with the STRING database and visualized with Cytoscape software. Key genes were also screened with the MCODE and cytoHubba plug-ins of Cytoscape. Finally, a prognostic model formed by the key gene was also established to help evaluate the reliability of this screening process. Results A prognostic model containing four downregulated miRNAs (hsa-mir-424, hsa-mir-3613, hsa-mir-4772 and hsa-mir-126) related to the prognosis of pancreatic cancer was constructed. A total of 118 common genes were enriched in two KEGG pathways and 33 GO functional annotations, including extracellular matrix (ECM)-receptor interaction and cell adhesion. Nine key genes related to pancreatic cancer were also obtained: MMP14, ITGA2, THBS2, COL1A1, COL3A1, COL11A1, COL6A3, COL12A1 and COL5A2. The prognostic model formed by nine key genes also possessed good prognostic ability. Conclusions The prognostic model consisting of four miRNAs can reliably predict the prognosis of patients with pancreatic cancer. In addition, the screened nine key genes, which can also form a reliable prognostic model, are significantly related to the occurrence and development of pancreatic cancer. Among them, one novel miRNA (hsa-mir-4772) and two novel genes (COL12A1 and COL5A2) associated with pancreatic cancer have great potential to be used as prognostic factors and therapeutic targets for this tumor.
Collapse
Affiliation(s)
- Shuoling Chen
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, China.,The Second School of Clinical Medicine, Guangdong Medical University, Dongguan, China
| | - Chang Gao
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, China.,Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang, China
| | - Tianyang Yu
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, China.,Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang, China
| | - Yueyang Qu
- School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, China
| | - Gary Guishan Xiao
- School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, China
| | - Zunnan Huang
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, China.,Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang, China
| |
Collapse
|
|
8
|
Lee J, Lee HS, Park SB, Kim C, Kim K, Jung DE, Song SY. Identification of Circulating Serum miRNAs as Novel Biomarkers in Pancreatic Cancer Using a Penalized Algorithm. Int J Mol Sci 2021; 22:1007. [PMID: 33498271 PMCID: PMC7863930 DOI: 10.3390/ijms22031007] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/10/2021] [Accepted: 01/15/2021] [Indexed: 12/16/2022] Open
Abstract
Pancreatic cancer (PC) is difficult to detect in the early stages; thus, identifying specific and sensitive biomarkers for PC diagnosis is crucial, especially in the case of early-stage tumors. Circulating microRNAs are promising non-invasive biomarkers. Therefore, we aimed to identify non-invasive miRNA biomarkers and build a model for PC diagnosis. For the training model, blood serum samples from 63 PC patients and 63 control subjects were used. We selected 39 miRNA markers using a smoothly clipped absolute deviation-based penalized support vector machine and built a PC diagnosis model. From the double cross-validation, the average test AUC was 0.98. We validated the diagnosis model using independent samples from 25 PC patients and 81 patients with intrahepatic cholangiocarcinoma (ICC) and compared the results with those obtained from the diagnosis using carbohydrate antigen 19-9. For the markers miR-155-5p, miR-4284, miR-346, miR-7145-5p, miR-5100, miR-661, miR-22-3p, miR-4486, let-7b-5p, and miR-4703-5p, we conducted quantitative reverse transcription PCR using samples from 17 independent PC patients, 8 ICC patients, and 8 healthy individuals. Differential expression was observed in samples from PC patients. The diagnosis model based on the identified markers showed high sensitivity and specificity for PC detection and is potentially useful for early PC diagnosis.
Collapse
Affiliation(s)
- Jaehoon Lee
- Department of Statistics, Seoul National University, Seoul 08733, Korea;
| | - Hee Seung Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (H.S.L.); (S.B.P.); (C.K.); (K.K.)
| | - Soo Been Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (H.S.L.); (S.B.P.); (C.K.); (K.K.)
| | - Chanyang Kim
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (H.S.L.); (S.B.P.); (C.K.); (K.K.)
| | - Kahee Kim
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (H.S.L.); (S.B.P.); (C.K.); (K.K.)
| | - Dawoon E. Jung
- Institute of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Si Young Song
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (H.S.L.); (S.B.P.); (C.K.); (K.K.)
- Institute of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea
| |
Collapse
|
|
9
|
Nguyen L, Schilling D, Dobiasch S, Raulefs S, Santiago Franco M, Buschmann D, Pfaffl MW, Schmid TE, Combs SE. The Emerging Role of miRNAs for the Radiation Treatment of Pancreatic Cancer. Cancers (Basel) 2020; 12:cancers12123703. [PMID: 33317198 PMCID: PMC7763922 DOI: 10.3390/cancers12123703] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 11/17/2020] [Accepted: 12/04/2020] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Pancreatic cancer is an aggressive disease with a high mortality rate. Radiotherapy is one treatment option within a multimodal therapy approach for patients with locally advanced, non-resectable pancreatic tumors. However, radiotherapy is only effective in about one-third of the patients. Therefore, biomarkers that can predict the response to radiotherapy are of utmost importance. Recently, microRNAs, small non-coding RNAs regulating gene expression, have come into focus as there is growing evidence that microRNAs could serve as diagnostic, predictive and prognostic biomarkers in various cancer entities, including pancreatic cancer. Moreover, their high stability in body fluids such as serum and plasma render them attractive candidates for non-invasive biomarkers. This article describes the role of microRNAs as suitable blood biomarkers and outlines an overview of radiation-induced microRNAs changes and the association with radioresistance in pancreatic cancer. Abstract Today, pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide with a five-year overall survival rate of less than 7%. Only 15–20% of patients are eligible for curative intent surgery at the time of diagnosis. Therefore, neoadjuvant treatment regimens have been introduced in order to downsize the tumor by chemotherapy and radiotherapy. To further increase the efficacy of radiotherapy, novel molecular biomarkers are urgently needed to define the subgroup of pancreatic cancer patients who would benefit most from radiotherapy. MicroRNAs (miRNAs) could have the potential to serve as novel predictive and prognostic biomarkers in patients with pancreatic cancer. In the present article, the role of miRNAs as blood biomarkers, which are associated with either radioresistance or radiation-induced changes of miRNAs in pancreatic cancer, is discussed. Furthermore, the manuscript provides own data of miRNAs identified in a pancreatic cancer mouse model as well as radiation-induced miRNA changes in the plasma of tumor-bearing mice.
Collapse
Affiliation(s)
- Lily Nguyen
- Institute of Radiation Medicine (IRM), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, 85764 Neuherberg, Germany; (L.N.); (D.S.); (S.D.); (S.R.); (M.S.F.); (T.E.S.)
- Department of Radiation Oncology, School of Medicine, Technical University of Munich (TUM), Klinikum rechts der Isar, 81675 Munich, Germany
| | - Daniela Schilling
- Institute of Radiation Medicine (IRM), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, 85764 Neuherberg, Germany; (L.N.); (D.S.); (S.D.); (S.R.); (M.S.F.); (T.E.S.)
- Department of Radiation Oncology, School of Medicine, Technical University of Munich (TUM), Klinikum rechts der Isar, 81675 Munich, Germany
| | - Sophie Dobiasch
- Institute of Radiation Medicine (IRM), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, 85764 Neuherberg, Germany; (L.N.); (D.S.); (S.D.); (S.R.); (M.S.F.); (T.E.S.)
- Department of Radiation Oncology, School of Medicine, Technical University of Munich (TUM), Klinikum rechts der Isar, 81675 Munich, Germany
- Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site Munich, 81675 Munich, Germany
| | - Susanne Raulefs
- Institute of Radiation Medicine (IRM), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, 85764 Neuherberg, Germany; (L.N.); (D.S.); (S.D.); (S.R.); (M.S.F.); (T.E.S.)
- Department of Radiation Oncology, School of Medicine, Technical University of Munich (TUM), Klinikum rechts der Isar, 81675 Munich, Germany
| | - Marina Santiago Franco
- Institute of Radiation Medicine (IRM), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, 85764 Neuherberg, Germany; (L.N.); (D.S.); (S.D.); (S.R.); (M.S.F.); (T.E.S.)
| | - Dominik Buschmann
- Division of Animal Physiology and Immunology, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), 85354 Freising, Germany; (D.B.); (M.W.P.)
| | - Michael W. Pfaffl
- Division of Animal Physiology and Immunology, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), 85354 Freising, Germany; (D.B.); (M.W.P.)
| | - Thomas E. Schmid
- Institute of Radiation Medicine (IRM), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, 85764 Neuherberg, Germany; (L.N.); (D.S.); (S.D.); (S.R.); (M.S.F.); (T.E.S.)
- Department of Radiation Oncology, School of Medicine, Technical University of Munich (TUM), Klinikum rechts der Isar, 81675 Munich, Germany
| | - Stephanie E. Combs
- Institute of Radiation Medicine (IRM), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, 85764 Neuherberg, Germany; (L.N.); (D.S.); (S.D.); (S.R.); (M.S.F.); (T.E.S.)
- Department of Radiation Oncology, School of Medicine, Technical University of Munich (TUM), Klinikum rechts der Isar, 81675 Munich, Germany
- Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site Munich, 81675 Munich, Germany
- Correspondence: ; Tel.: +49-89-4140-4501
| |
Collapse
|
|
10
|
The miRNA Profile in Non-Hodgkin's Lymphoma Patients with Secondary Myelodysplasia. Cells 2020; 9:cells9102318. [PMID: 33086588 PMCID: PMC7656297 DOI: 10.3390/cells9102318] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 10/07/2020] [Accepted: 10/16/2020] [Indexed: 12/15/2022] Open
Abstract
Myelodysplastic syndromes are a group of clonal diseases of hematopoietic stem cells and are characterized by multilineage dysplasia, ineffective hematopoiesis, peripheral blood cytopenias, genetic instability and a risk of transformation to acute myeloid leukemia. Some patients with non-Hodgkin lymphomas (NHLs) may have developed secondary myelodysplasia before therapy. Bone marrow (BM) hematopoiesis is regulated by a spectrum of epigenetic factors, among which microRNAs (miRNAs) are special. The aim of this work is to profile miRNA expression in BM cells in untreated NHL patients with secondary myelodysplasia. A comparative analysis of miRNA expression levels between the NHL and non-cancer blood disorders samples revealed that let-7a-5p was upregulated, and miR-26a-5p, miR-199b-5p, miR-145-5p and miR-150-5p were downregulated in NHL with myelodysplasia (p < 0.05). We for the first time developed a profile of miRNA expression in BM samples in untreated NHL patients with secondary myelodysplasia. It can be assumed that the differential diagnosis for blood cancers and secondary BM conditions based on miRNA expression profiles will improve the accuracy and relevance of the early diagnosis of cancerous and precancerous lesions in BM.
Collapse
|
|
11
|
Valadão de Souza DR, Pessôa R, Nascimento A, Nukui Y, Pereira J, Casseb J, Penalva de Oliveira AC, da Silva Duarte AJ, Clissa PB, Sanabani SS. Small RNA profiles of HTLV-1 asymptomatic carriers with monoclonal and polyclonal rearrangement of the T-cell antigen receptor γ-chain using massively parallel sequencing: A pilot study. Oncol Lett 2020; 20:2311-2321. [PMID: 32782548 PMCID: PMC7400997 DOI: 10.3892/ol.2020.11803] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 05/21/2020] [Indexed: 12/19/2022] Open
Abstract
In the present pilot study, massively parallel sequencing (MPS) technology was used to investigate cellular small RNA (sRNA) levels in the peripheral blood mononuclear cells (PBMCs) of human T-lymphotropic virus type I (HTLV–I) infected asymptomatic carriers with monoclonal (ASM) and polyclonal (ASP) T cell receptor (TCR) γ gene. Blood samples from 15 HTLV–I asymptomatic carriers (seven ASM and eight ASP) were tested for the clonal TCR-γ gene and submitted for sRNA library construction together with blood samples of five healthy controls (HCs) using Illumina sequencing platform. The sRNA-sequencing reads were aligned, annotated and profiled using various bioinformatics tools. Based on these results, possible markers were validated in the study samples by performing reverse transcription-quantitative (RT-q)PCR analysis. A total of 76 known sRNAs and 52 putative novel sRNAs were identified. Among them, 44 known and 34 potential novel sRNAs were differentially expressed in the ASM and ASP libraries compared with HCs. In addition, 10 known sRNAs were exclusively dysregulated in the ASM group and one (transfer RNA 65) was significantly upregulated in the ASP group. Homo sapiens (hsa) microRNA (miRNA/mir)-23a-3p, −28-5p, hsa-let-7e-5p and hsa-mir-28-3p and −361-5p were the most abundantly upregulated mature miRNAs and hsa-mir-363-3p, −532-5p, −106a-5p, −25-3p and −30e-5p were significantly downregulated miRNAs (P<0.05) with a >2-fold difference between the ASM and ASP groups compared with HCs. Based on these results, hsa-mir-23a-3p and −363-3p were selected for additional validation. However, the quantification of these two miRNAs using RT-qPCR did not provide any significant differences. While the present study failed to identify predictive sRNA markers to distinguish between ASM and ASP, the MPS results revealed differential sRNA expression profiles in the PBMCs of HTLV-1 asymptomatic carriers (ASM and ASP) compared with HCs.
Collapse
Affiliation(s)
- Daniela Raguer Valadão de Souza
- Laboratory of Dermatology and Immunodeficiency, Department of Dermatology, Faculty of Medicine, University of São Paulo, São Paulo 05403 000, Brazil
| | - Rodrigo Pessôa
- Laboratory of Dermatology and Immunodeficiency, Department of Dermatology, Faculty of Medicine, University of São Paulo, São Paulo 05403 000, Brazil
| | - Andrezza Nascimento
- Laboratory of Dermatology and Immunodeficiency, Department of Dermatology, Faculty of Medicine, University of São Paulo, São Paulo 05403 000, Brazil
| | - Youko Nukui
- Department of Hematology, Faculty of Medicine, University of São Paulo, São Paulo 05403 000, Brazil
| | - Juliana Pereira
- Department of Hematology, Faculty of Medicine, University of São Paulo, São Paulo 05403 000, Brazil
| | - Jorge Casseb
- Laboratory of Dermatology and Immunodeficiency, Department of Dermatology, Faculty of Medicine, University of São Paulo, São Paulo 05403 000, Brazil
| | | | - Alberto José da Silva Duarte
- Laboratory of Dermatology and Immunodeficiency, Department of Dermatology, Faculty of Medicine, University of São Paulo, São Paulo 05403 000, Brazil
| | | | - Sabri Saeed Sanabani
- Laboratory of Medical Investigation Unit 03,Clinics Hospital, Faculty of Medicine, University of São Paulo, São Paulo 05403 000, Brazil
| |
Collapse
|
|
12
|
Zhang XX, Chen H, Li HY, Chen R, He L, Yang JL, Xiao LL, Chen JL. Long non-coding RNA small nucleolar RNA host gene 6 aggravates pancreatic cancer through upregulation of far upstream element binding protein 1 by sponging microRNA-26a-5p. Chin Med J (Engl) 2020; 133:1211-1220. [PMID: 32433053 PMCID: PMC7249703 DOI: 10.1097/cm9.0000000000000758] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Pancreatic cancer (PC) is a highly deadly malignancy with few effective therapies. We aimed to unmask the role that long non-coding RNA small nucleolar RNA host gene 6 (SNHG6) plays in PC cells by targeting far upstream element binding protein 1 (FUBP1) via microRNA-26a-5p (miR-26a-5p). METHODS SNHG6 expression was predicted by bioinformatics, followed by verification via reverse transcription quantitative polymerase chain reaction. Then, the interactions among SNHG6, miR-26a-5p, and FUBP1 were detected through online software analysis, dual luciferase reporter assay and RNA pull-down. After that, cells were treated with different small interfering RNAs and/or mimic to determine the interactions among SNHG6, miR-26a-5p, and FUBP1 and their roles in PC cells. Finally, the role of SNHG6 in tumor growth in vivo was evaluated by measuring the growth and weight of transplanted tumors in nude mice. A t-test, one-way and two-way analysis of variance were used for data analysis. RESULTS Compared with that in normal tissues, SNHG6 was highly expressed in PC tissues (1.00 ± 0.05 vs. 1.56 ± 0.06, t = 16.03, P < 0.001). Compared with that in human pancreatic duct epithelial cells (HPDE6-C7), SNHG6 showed the highest expression in PANC-1 cells (1.00 ± 0.06 vs. 3.87 ± 0.13, t = 34.72, P < 0.001) and the lowest expression in human pancreatic cancer cells (MIAPaCa-2) (1.00 ± 0.06 vs. 1.41 ± 0.07, t = 7.70, P = 0.0015). Compared with the levels in the si-negative control group, SNHG6 (0.97 ± 0.05 vs. 0.21 ± 0.06, t = 16.85, P < 0.001), N-cadherin (0.74 ± 0.05 vs. 0.41 ± 0.04, t = 8.93, P < 0.001), Vimentin (0.55 ± 0.04 vs. 0.25 ± 0.03, t = 10.39, P < 0.001), and β-catenin (0.62 ± 0.05 vs. 0.32 ± 0.03, t = 8.91, P < 0.001) were decreased, while E-cadherin (0.65 ± 0.06 vs. 1.36 ± 0.07, t = 13.34, P < 0.001) was increased after SNHG6 knockdown or miR-26a-5p overexpression, accompanied by inhibited cell proliferation, migration, and invasion. SNHG6 overexpression exerted the opposite effects. SNHG6 upregulated FUBP1 expression by sponging miR-26a-5p. Silencing SNHG6 blocked the growth of PC in vivo. CONCLUSION Silencing SNHG6 might ameliorate PC through inhibition of FUBP1 by sponging miR-26a-5p, thus providing further supporting evidence for its use in PC treatment.
Collapse
Affiliation(s)
- Xing-Xing Zhang
- Department of Gastroenterology, Shanghai University of Medicine & Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai 201499, China
| | - Hua Chen
- Department of Gastroenterology, Shanghai University of Medicine & Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai 201499, China
| | - Hui-Ying Li
- Department of Gastroenterology, Shanghai University of Medicine & Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai 201499, China
| | - Rui Chen
- Department of Gastroenterology, Shanghai University of Medicine & Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai 201499, China
| | - Lei He
- Department of Gastroenterology, Shanghai University of Medicine & Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai 201499, China
| | - Juan-Li Yang
- Department of Gastroenterology, Shanghai University of Medicine & Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai 201499, China
| | - Lin-Lin Xiao
- Department of Laboratory Medicine, Shanghai University of Medicine & Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai 201499, China
| | - Jin-Lian Chen
- Department of Gastroenterology, Shanghai University of Medicine & Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai 201499, China
| |
Collapse
|
|
13
|
Zhao F, Wei C, Cui MY, Xia QQ, Wang SB, Zhang Y. Prognostic value of microRNAs in pancreatic cancer: a meta-analysis. Aging (Albany NY) 2020; 12:9380-9404. [PMID: 32420903 PMCID: PMC7288910 DOI: 10.18632/aging.103214] [Citation(s) in RCA: 19] [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: 01/14/2020] [Accepted: 04/17/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND The prognostic impact of microRNA (miRNA) expression levels in pancreatic cancer (PC) has been estimated for years, but the outcomes are controversial and heterogeneous. Therefore, we comprehensively reviewed the evidence collected on miRNA expression in PC to determine this effect. RESULTS PC patients with high miR-21 (HR=2.61, 95%CI=1.68-4.04), miR-451a (HR=2.23, 95%CI=1.23-4.04) or miR-1290 (HR=1.43, 95%CI=1.04-1.95) levels in blood had significantly poorer OS (P<0.05). Furthermore, PC patients with high miR-10b (HR=1.73, 95%CI=1.09-2.76), miR-17-5p (HR=1.91, 95%CI=1.30-2.80), miR-21 (HR=1.90, 95%CI=1.61-2.25), miR-23a (HR=2.18, 95%CI=1.52-3.13), miR-155 (HR=2.22, 95%CI=1.27-3.88), miR-203 (HR=1.65, 95%CI=1.14-2.40), miR-221 (HR=1.72, 95%CI=1.08-2.74), miR-222 levels (HR=1.72, 95%CI=1.02-2.91) or low miR-29c (HR=1.39, 95%CI=1.08-1.79), miR-126 (HR=1.55, 95%CI=1.23-1.95), miR-218 (HR=2.62, 95%CI=1.41-4.88) levels in tissues had significantly shorter OS (P<0.05). CONCLUSIONS In summary, blood miR-21, miR-451a, miR-1290 and tissue miR-10b, miR-17-5p, miR-21, miR-23a, miR-29c, miR-126, miR-155, miR-203, miR-218, miR-221, miR-222 had significant prognostic value. METHODS We searched PubMed, EMBASE, Web of Science and Cochrane Database of Systematic Reviews to recognize eligible studies, and 57 studies comprising 5445 PC patients and 15 miRNAs were included to evaluate the associations between miRNA expression levels and overall survival (OS) up to June 1, 2019. Summary hazard ratios (HR) with 95% confidence intervals (CI) were calculated to assess the effect.
Collapse
Affiliation(s)
- Fei Zhao
- , Department of Traditional Chinese Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Chao Wei
- College of Integrated Traditional Chinese and Western Medicine, Jining Medical University, Jining, Shandong, China
| | - Meng-Ying Cui
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Qiang-Qiang Xia
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Shuai-Bin Wang
- Department of Urology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yue Zhang
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35233, USA
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| |
Collapse
|
|
14
|
Pan P, Zhu Z, Oshima K, Aldakkak M, Tsai S, Huang YW, Dong W, Zhang J, Lin CW, Wang Y, Yearsley M, Yu J, Wang LS. Black raspberries suppress pancreatic cancer through modulation of NKp46 +, CD8 +, and CD11b + immune cells. FOOD FRONTIERS 2020; 1:70-82. [PMID: 32368735 DOI: 10.1002/fft2.1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with a low survival rate (9%). Epidemiologic studies show that healthy dietary patterns enriched of fruits and vegetables lower the risk of PDAC. We previously showed that supplementing black raspberries (BRBs) to patients with colorectal cancer increased tumor-infiltrating NK cells and their cytotoxicity. We aimed to determine whether BRBs combat PDAC by modulating cancer immunity. NOD.SCID mice lacking T and B cells were injected with human Panc-1-Luc cells orthotopically, and immunocompetent Kras LSL.G12D/+ -Trp53 LSL.R172H/+ -Pdx-1-Cre mice were fed BRBs. Peripheral blood mononuclear cells (PBMCs) from PDAC patients were treated with butyrate, a microbial metabolite of BRBs. The absence of T and B cells did not dampen BRBs' anti-tumor effects in the NOD.SCID mice. In the Kras LSL.G12D/+ -Trp53 LSL.R172H/+ -Pdx-1-Cre mice, BRBs significantly prolonged survival (189 days versus 154 days). In both models, BRBs decreased tumor-infiltrating CD11b+ cells and the expression of IL-1β, sEH, and Ki67. BRBs also increased tumor-infiltrating NKp46+ cells and the expression of CD107a, a functional marker of cytolytic NK and CD8+ T cells. In Kras LSL.G12D/+ -Trp53 LSL.R172H/+ -Pdx-1-Cre mice, tumor infiltration of CD8+ T cells was increased by BRBs. Further using the PBMCs from PDAC patients, we show that butyrate decreased the population of myeloid-derived suppressor cells (MDSCs). Butyrate also reversed CD11b+ cell-mediated suppression on CD8+ T cells. Interestingly, there is a negative association between MDSC changes and patients' survival, suggesting that the more decrease in MDSC population induced by butyrate treatment, the longer the patient had survived. Our study suggests the immune-modulating potentials of BRBs in PDAC.
Collapse
Affiliation(s)
- Pan Pan
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin
| | - Zheng Zhu
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute
| | | | | | - Susan Tsai
- Department of Surgery, Medical College of Wisconsin
| | - Yi-Wen Huang
- Department of Obstetrics and Gynecology, Medical College of Wisconsin
| | - Wenjuan Dong
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute
| | - Jianying Zhang
- Division of Biostatistics, Department of Science of Informatics, City of Hope National Medical Center and Beckman Research Institute
| | - Chien-Wei Lin
- Division of Biostatistics, Medical College of Wisconsin
| | - Youwei Wang
- The James Cancer Hospital, The Ohio State University
| | | | - Jianhua Yu
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute
| | - Li-Shu Wang
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin
| |
Collapse
|
|
15
|
Chhatriya B, Mukherjee M, Ray S, Sarkar P, Chatterjee S, Nath D, Das K, Goswami S. Comparison of tumour and serum specific microRNA changes dissecting their role in pancreatic ductal adenocarcinoma: a meta-analysis. BMC Cancer 2019; 19:1175. [PMID: 31795960 PMCID: PMC6891989 DOI: 10.1186/s12885-019-6380-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 11/20/2019] [Indexed: 02/07/2023] Open
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is considered as one of the most aggressive cancers lacking efficient early detection biomarkers. Circulating miRNAs are now being considered to have potency to be used as diagnostic and prognostic biomarkers in different diseases as well as cancers. In case of cancer, a fraction of the circulating miRNAs is actually derived from the tumour tissue. This fraction would function as stable biomarker for the disease and also would contribute to the understanding of the disease development. There are not many studies exploring this aspect in pancreatic cancer and even there is not much overlap of results between existing studies. Methods In order to address that gap, we performed a miRNA microarray analysis to identify differentially expressed circulating miRNAs between PDAC patients and normal healthy individuals and also found two more similar datasets to perform a meta-analysis using a total of 182 PDAC patients and 170 normal, identifying a set of miRNAs significantly altered in patient serum. Next, we found five datasets studying miRNA expression profile in tumour tissues of PDAC patients as compared to normal pancreas and performed a second meta-analysis using data from a total of 183 pancreatic tumour and 47 normal pancreas to detect significantly deregulated miRNAs in pancreatic carcinoma. Comparison of these two lists and subsequent search for their target genes which were also deregulated in PDAC in inverse direction to miRNAs was done followed by investigation of their role in disease development. Results We identified 21 miRNAs altered in both pancreatic tumour tissue and serum. While deciphering the functions of their target genes, we characterized key miR-Gene interactions perturbing the biological pathways. We identified important cancer related pathways, pancreas specific pathways, AGE-RAGE signaling, prolactin signaling and insulin resistance signaling pathways among the most affected ones. We also reported the possible involvement of crucial transcription factors in the process. Conclusions Our study identified a unique meta-signature of 21 miRNAs capable of explaining pancreatic carcinogenesis and possibly holding the potential to act as biomarker for the disease detection which could be explored further.
Collapse
Affiliation(s)
| | - Moumita Mukherjee
- National Institute of Biomedical Genomics, Kalyani, West Bengal, India
| | - Sukanta Ray
- School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India
| | - Piyali Sarkar
- Present Address: Tata Medical Centre, Kolkata, West Bengal, India
| | | | - Debashis Nath
- Indira Gandhi Memorial Hospital, Agartala, Tripura, India
| | - Kshaunish Das
- School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India
| | - Srikanta Goswami
- National Institute of Biomedical Genomics, Kalyani, West Bengal, India.
| |
Collapse
|
|
16
|
miR-26a promotes hepatocellular carcinoma invasion and metastasis by inhibiting PTEN and inhibits cell growth by repressing EZH2. J Transl Med 2019; 99:1484-1500. [PMID: 31201367 DOI: 10.1038/s41374-019-0270-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 04/23/2019] [Accepted: 04/28/2019] [Indexed: 12/13/2022] Open
Abstract
A previous study revealed that therapeutic miR-26a delivery suppresses tumorigenesis in a murine liver cancer model, whereas we found that forced miR-26a expression increased hepatocellular carcinoma (HCC) cell migration and invasion, which prompted us to characterize the causes and mechanisms underlying enhanced invasion due to ectopic miR-26a expression. Gain-of-function and loss-of-function experiments demonstrated that miR-26a promoted migration and invasion of BEL-7402 and HepG2 cells in vitro and positively modulated matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, and MMP-10 expression. In addition, exogenous miR-26a expression significantly enhanced the metastatic ability of HepG2 cells in vivo. miR-26a negatively regulated in vitro proliferation of HCC cells, and miR-26a overexpression suppressed HepG2 cell tumor growth in nude mice. Further studies revealed that miR-26a inhibited cell growth by repressing the methyltransferase EZH2 and promoted cell migration and invasion by inhibiting the phosphatase PTEN. Furthermore, PTEN expression negatively correlated with miR-26a expression in HCC specimens from patients with and without metastasis. Thus, our findings suggest for the first time that miR-26a promotes invasion/metastasis by inhibiting PTEN and inhibits cell proliferation by repressing EZH2 in HCC. More importantly, our data also suggest caution if miR-26a is used as a target for cancer therapy in the future.
Collapse
|
|
17
|
Rawat M, Kadian K, Gupta Y, Kumar A, Chain PSG, Kovbasnjuk O, Kumar S, Parasher G. MicroRNA in Pancreatic Cancer: From Biology to Therapeutic Potential. Genes (Basel) 2019; 10:genes10100752. [PMID: 31557962 PMCID: PMC6827136 DOI: 10.3390/genes10100752] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 09/19/2019] [Accepted: 09/20/2019] [Indexed: 12/20/2022] Open
Abstract
Pancreatic cancer is one of the most aggressive malignancies, accounting for more than 45,750 deaths annually in the U.S. alone. The aggressive nature and late diagnosis of pancreatic cancer, coupled with the limitations of existing chemotherapy, present the pressing need for the development of novel therapeutic strategies. Recent reports have demonstrated a critical role of microRNAs (miRNAs) in the initiation, progression, and metastasis of cancer. Furthermore, aberrant expressions of miRNAs have often been associated with the cause and consequence of pancreatic cancer, emphasizing the possible use of miRNAs in the effective management of pancreatic cancer patients. In this review, we provide a brief overview of miRNA biogenesis and its role in fundamental cellular process and miRNA studies in pancreatic cancer patients and animal models. Subsequent sections narrate the role of miRNA in, (i) cell cycle and proliferation; (ii) apoptosis; (iii) invasions and metastasis; and (iv) various cellular signaling pathways. We also describe the role of miRNA's in pancreatic cancer; (i) diagnosis; (ii) prognosis and (iii) therapeutic intervention. Conclusion section describes the gist of review with future directions.
Collapse
Affiliation(s)
- Manmeet Rawat
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
| | - Kavita Kadian
- Department of Biotechnology, Kumaun University, Nainital, Uttarakhand 263001, India.
| | - Yash Gupta
- Department of Internal Medicine, Loyola University Medical Center, Chicago, IL 60153, USA.
| | - Anand Kumar
- Biosecurity and Public Health Group, Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
| | - Patrick S G Chain
- Biosecurity and Public Health Group, Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
| | - Olga Kovbasnjuk
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
| | - Suneel Kumar
- Department of Biomedical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
| | - Gulshan Parasher
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
| |
Collapse
|
|
18
|
Abstract
Objectives: The aim of this research was to study whether plasma microRNAs (miRNA) can be used for early detection of pancreatic cancer (PC) by analyzing prediagnostic plasma samples collected before a PC diagnosis. Background: PC has a poor prognosis due to late presenting symptoms and early metastasis. Circulating miRNAs are altered in PC at diagnosis but have not been evaluated in a prediagnostic setting. Methods: We first performed an initial screen using a panel of 372 miRNAs in a retrospective case-control cohort that included early-stage PC patients and healthy controls. Significantly altered miRNAs at diagnosis were then measured in an early detection case-control cohort wherein plasma samples in the cases are collected before a PC diagnosis. Carbohydrate antigen 19–9 (Ca 19–9) levels were measured in all samples for comparison. Results: Our initial screen, including 23 stage I-II PC cases and 22 controls, revealed 15 candidate miRNAs that were differentially expressed in plasma samples at PC diagnosis. We combined all 15 miRNAs into a multivariate statistical model, which outperformed Ca 19–9 in receiver-operating characteristics analysis. However, none of the candidate miRNAs, individually or in combination, were significantly altered in prediagnostic plasma samples from 67 future PC patients compared with 132 matched controls. In comparison, Ca 19–9 levels were significantly higher in the cases at <5 years before diagnosis. Conclusion: Plasma miRNAs are altered in PC patients at diagnosis, but the candidate miRNAs found in this study appear late in the course of the disease and cannot be used for early detection of the disease.
Collapse
|
|
19
|
Xie Q, Chen C, Li H, Xu J, Wu L, Yu Y, Ren S, Li H, Hua X, Yan H, Rao D, Zhang H, Jin H, Huang H, Huang C. miR-3687 Overexpression Promotes Bladder Cancer Cell Growth by Inhibiting the Negative Effect of FOXP1 on Cyclin E2 Transcription. Mol Ther 2019; 27:1028-1038. [PMID: 30935821 DOI: 10.1016/j.ymthe.2019.03.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 02/07/2019] [Accepted: 03/01/2019] [Indexed: 12/17/2022] Open
Abstract
Cyclin E2, a member of the cyclin family, is a key cell cycle-related protein. This protein plays essential roles in cancer progression, and, as such, an inhibitor of cyclin E2 has been approved to treat several types of cancers. Even so, mechanisms underlying how to regulate cyclin E2 expression in cancer remain largely unknown. In the current study, miR-3687 was upregulated in clinical bladder cancer (BC) tumor tissues, The Cancer Genome Atlas (TCGA) database, and human BC cell lines. Inhibition of miR-3687 expression significantly reduced human BC cell proliferation in vitro and tumor growth in vivo, which coincided with the induction of G0/G1 cell cycle arrest and downregulation of cyclin E2 protein expression. Interestingly, overexpression of cyclin E2 reversed the inhibition of BC proliferation induced by miR-3687. Mechanistic studies suggested that miR-3687 binds to the 3' UTR of foxp1 mRNA, downregulates FOXP1 protein expression, and in turn promotes the transcription of cyclin E2, thereby promoting the growth of BC cells. Collectively, the current study not only establishes a novel regulatory axis of miR-3687/FOXP1 regarding regulation of cyclin E2 expression in BC cells, but also provides strong suggestive evidence that miR-3687 and FOXP1 may be promising targets in therapeutic strategies for human BC.
Collapse
Affiliation(s)
- Qipeng Xie
- Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Caiyi Chen
- Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Haiying Li
- Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jiheng Xu
- Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Lei Wu
- Heze Municipal Hospital, Heze, Shandong, 274031, China
| | - Yuan Yu
- Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Shuwei Ren
- Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Hongyan Li
- Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xiaohui Hua
- Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Huiying Yan
- Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Dapang Rao
- The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Huxiang Zhang
- Biobank of Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Honglei Jin
- Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Haishan Huang
- Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Chuanshu Huang
- Department of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA.
| |
Collapse
|
|
20
|
Yu J, Liu Y, Zhang D, Zhai D, Song L, Cai Z, Yu C. Baicalin inhibits recruitment of GATA1 to the HSD3B2 promoter and reverses hyperandrogenism of PCOS. J Endocrinol 2019; 240:JOE-18-0678.R2. [PMID: 30650063 DOI: 10.1530/joe-18-0678] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 01/15/2019] [Indexed: 01/07/2023]
Abstract
High androgen levels in patients suffering from polycystic ovary syndrome (PCOS) can be effectively reversed if the herb Scutellaria baicalensis is included in traditional Chinese medicine prescriptions. To characterize the effects of baicalin, extracted from S. baicalensis, on androgen biosynthesis in NCI-H295R cells and on hyperandrogenism in PCOS model rats and to elucidate the underlying mechanisms. The optimum concentration and intervention time for baicalin treatment of NCI-H295R cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and enzyme-linked immunosorbent assays. The functional genes affected by baicalin were studied by gene expression profiling (GEP), and the key genes were identified using a dual luciferase assay, RNA interference technique, and genetic mutations. Besides, hyperandrogenic PCOS model rats were induced and confirmed before and after baicalin intervention. As a result, Baicalin decreased the testosterone concentrations in a dose-and time-dependent manner in NCI-H295R cells. GEP revealed that 3β-hydroxysteroid dehydrogenase type II (HSD3B2) was the key enzyme of androgen biosynthesis, and baicalin inhibited the expression of HSD3B2 by regulating the binding of transcription factor GATA-binding factor 1 (GATA1) to the HSD3B2 promoter. Hyperandrogenic PCOS model rats treated with baicalin significantly reversed the high androgen levels of serum and the abnormal ovarian status, restored the estrous cyclicity, and decreased the expression of HSD3B2 in ovarian. In summary , our data revealed that GATA1 is an important transcription factor activating the HSD3B2 promoter in steroidogenesis, and baicalin potentially be an effective therapeutic agent for hyperandrogenism in PCOS by inhibiting the recruitment of GATA1 to the HSD3B2 promoter in ovarian tissue.
Collapse
Affiliation(s)
- Jin Yu
- J Yu, Department of Gynecology of Traditional Chinese Medicine, Changhai hospital, Naval medical university, Shanghai, China
| | - Yuhuan Liu
- Y Yang, Department of Gynecology and Obstetrics, Changhai hospital, Naval medical university, Shanghai, China
| | - Danying Zhang
- D Zhang, Department of Gynecology of Traditional Chinese Medicine, Changhai hospital, Naval medical university, Shanghai, China
| | - Dongxia Zhai
- D Zhai, Department of Gynecology of Traditional Chinese Medicine, Changhai hospital, Naval medical university, Shanghai, China
| | - Linyi Song
- L Song, Department of Gynecology of Traditional Chinese Medicine, Changhai hospital, Naval medical university, Shanghai, China
| | - Zailong Cai
- Z Cai, Department of Biochemistry and Molecular Biology, Naval medical university, Shanghai, China
| | - Chaoqin Yu
- C Yu, Department of Gynecology of Traditional Chinese Medicine, Changhai hospital, Naval medical university, Shanghai, China
| |
Collapse
|
|
21
|
Ding Q, Wang Y, Zuo Z, Gong Y, Krishnamurthy S, Li CW, Lai YJ, Wei W, Wang J, Manyam GC, Diao L, Zhang X, Lin F, Symmans WF, Sun L, Liu CG, Liu X, Debeb BG, Ueno NT, Harano K, Alvarez RH, Wu Y, Cristofanilli M, Huo L. Decreased expression of microRNA-26b in locally advanced and inflammatory breast cancer. Hum Pathol 2018; 77:121-129. [PMID: 29689244 DOI: 10.1016/j.humpath.2018.04.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 04/04/2018] [Accepted: 04/13/2018] [Indexed: 01/23/2023]
Abstract
Advanced-stage breast cancer patients comprise a smaller proportion of breast cancer patients than do early stage patients and are more likely to experience a poor outcome. Understanding the underlying molecular mechanisms and identifying new biomarkers for treatment in this subgroup of patients is paramount. With the aim of identifying microRNAs that are regulated in advanced-stage breast cancer, we found lower expression of miR-26b, a member of the miR-26 family, in inflammatory breast cancer and noninflammatory locally advanced breast cancer tissue than in normal breast tissue, by quantitative real-time polymerase chain reaction and in situ hybridization. Quantitative real-time polymerase chain reaction (but not in situ hybridization) also revealed lower miR-26b expression in inflammatory breast cancer than in noninflammatory locally advanced breast cancer. Furthermore, lower expression of miR-26b was correlated with shorter distant metastasis-free survival and overall survival in univariate analysis, and with shorter overall survival in multivariate analysis. The expression of miRNA-26b was inversely associated with EZH2 protein expression in several breast cancer cell lines, and overexpression and knockdown of miR-26b caused corresponding changes in EZH2 expression. Our study shows that miR-26b may regulate EZH2 expression in breast cancer and may be useful as a therapeutic target for inflammatory breast cancer and noninflammatory locally advanced breast cancer.
Collapse
Affiliation(s)
- Qingqing Ding
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Yan Wang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Zhuang Zuo
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Yun Gong
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX; Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Savitri Krishnamurthy
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX; Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Chia-Wei Li
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Yun-Ju Lai
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Wei Wei
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jing Wang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Ganiraju C Manyam
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Lixia Diao
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Xinna Zhang
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Feng Lin
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - William F Symmans
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Li Sun
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Chang-Gong Liu
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Xiuping Liu
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Bisrat G Debeb
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Naoto T Ueno
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Kenichi Harano
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Ricardo H Alvarez
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Yun Wu
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | - Lei Huo
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX; Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX.
| |
Collapse
|
|
22
|
Chen D, Li J, Li S, Han P, Li N, Wang Y, Du S. miR-184 promotes cell proliferation in tongue squamous cell carcinoma by targeting SOX7. Oncol Lett 2018; 16:2221-2228. [PMID: 30008922 PMCID: PMC6036414 DOI: 10.3892/ol.2018.8906] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 05/14/2018] [Indexed: 12/30/2022] Open
Abstract
The aim of this study was to investigate whether the miR-184 could regulate the proliferation of the tongue squamous cell carcinoma (TSCC) through sex-determining region Y-box 7 (SOX7) gene. miR-184 expression was upregulated in TSCC cell lines and tissues. MTT assay revealed that overexpression of miR-184 significantly promoted the proliferation of the TSCC cells in vitro. SOX7 was the direct target of miR-184 and luciferase reporter assay confirmed that miR-184 downregulated the expression of SOX7. MTT assay verified that knockdown of SOX7 remarkably promoted the proliferation of TSCC cells in vitro. miR-184 promoted the proliferation of TSCC by targeting SOX7. Taken together, our results provided a new potential therapeutic target for TSCC treatment.
Collapse
Affiliation(s)
- Daiyun Chen
- Department of Stomatology, Affiliated Hospital of Taishan Medical University, Taian, Shandong 271000, P.R. China
| | - Junfu Li
- Department of Stomatology, Affiliated Hospital of Taishan Medical University, Taian, Shandong 271000, P.R. China
| | - Shunrong Li
- Department of Critical Care Medicine, People's Hospital of Zhangqiu, Zhangqiu, Shandong 250200, P.R. China
| | - Ping Han
- Department of Respiratory Medicine, People's Hospital of Zhangqiu, Zhangqiu, Shandong 250200, P.R. China
| | - Ning Li
- Department of Pathology, People's Hospital of Zhangqiu, Zhangqiu, Shandong 250200, P.R. China
| | - Yi Wang
- Department of Respiratory Medicine, People's Hospital of Zhangqiu, Zhangqiu, Shandong 250200, P.R. China
| | - Shouqin Du
- Department of Pathology, People's Hospital of Zhangqiu, Zhangqiu, Shandong 250200, P.R. China
| |
Collapse
|
|
23
|
Zhu Y, Chen P, Gao Y, Ta N, Zhang Y, Cai J, Zhao Y, Liu S, Zheng J. MEG3 Activated by Vitamin D Inhibits Colorectal Cancer Cells Proliferation and Migration via Regulating Clusterin. EBioMedicine 2018; 30:148-157. [PMID: 29628342 PMCID: PMC5952405 DOI: 10.1016/j.ebiom.2018.03.032] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 03/27/2018] [Accepted: 03/27/2018] [Indexed: 12/15/2022] Open
Abstract
The long non-coding RNA maternally expressed gene 3 (MEG3) is frequently dysregulated in human cancers; however, its roles in colorectal cancer (CRC) development are largely unknown. Here, we reported that MEG3 was down-regulated in CRC tissues and CRC patients with lower MEG3 showed poorer overall survival and disease-free survival than those with higher MEG3 level. MEG3 over-expression represses CRC cells proliferation and migration in vivo and in vitro, while MEG3 knockdown leads to the enhanced proliferation and metastasis of CRC cells. In CRC cells, MEG3 over-expression is related to decreased Clusterin mRNA and the corresponding protein levels, and it also directly binds to Clusterin protein through its 732–1174 region. In further, Clusterin over-expression rescues the compromised abilities of proliferation and metastasis induced by MEG3 over-expression, suggesting that MEG3 inhibits the CRC progression through regulating the Clusterin activities. Additionally, we found that 1α,25-(OH)2D and vitamin D receptor (VDR) stimulate MEG3 expression in CRC cells through directly binding to its promoter. These results suggested that MEG3 functions as a tumor suppressor in CRC via regulating the Clusterin activities and may underlie the anticancer activities of vitamin D on CRC cells. The VDR/MEG3/Clusterin signaling pathway may serve as potential therapeutic targets and prognosis biomarkers for CRC patients in future.
MEG3 serves as a novel CRC prognosis biomarker and a potential therapeutic target. MEG3 over-expression represses CRC cells proliferation and metastatic features. MEG3 has a role in Clusterin expression and activity down-regulation at transcriptional and post-transcriptional levels. VDR activated MEG3 expression via directly binding to MEG3 promoter.
Collapse
Affiliation(s)
- Yan Zhu
- Department of Pathology, Changhai Hospital, Secondary Military Medical University, Shanghai 200433, PR China
| | - Peizhan Chen
- Translational Medicine Research Center, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai 201821, PR China
| | - Yisha Gao
- Department of Pathology, Changhai Hospital, Secondary Military Medical University, Shanghai 200433, PR China
| | - Na Ta
- Department of Pathology, Changhai Hospital, Secondary Military Medical University, Shanghai 200433, PR China
| | - Yunshuo Zhang
- Department of Pathology, Changhai Hospital, Secondary Military Medical University, Shanghai 200433, PR China
| | - Jialin Cai
- Translational Medicine Research Center, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai 201821, PR China
| | - Yong Zhao
- Office of Shanghai Administrative Committee for Laboratory Animal, Shanghai, Laboratory Animals Research Center, Shanghai, 201203, PR China
| | - Shupeng Liu
- Clinical Research Center, Changhai Hospital, Secondary Military Medical University, Shanghai 200433, PR China.
| | - Jianming Zheng
- Department of Pathology, Changhai Hospital, Secondary Military Medical University, Shanghai 200433, PR China.
| |
Collapse
|
|
24
|
Sun YF, Kan Q, Yang Y, Zhang YH, Shen JX, Zhang C, Zhou XY. Knockout of microRNA‑26a promotes lung development and pulmonary surfactant synthesis. Mol Med Rep 2018; 17:5988-5995. [PMID: 29436664 DOI: 10.3892/mmr.2018.8602] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 01/22/2018] [Indexed: 11/05/2022] Open
Abstract
Normal formation and function of the lungs are essential for the transition of the fetus to an air‑breathing environment at birth. The synthesis of pulmonary surfactant (PS), which is produced by type II alveolar epithelial cells (AECIIs), is required for proper lung development. Previous in vitro studies have suggested that PS synthesis is regulated by microRNA (miR)‑26a in fetal rat AECIIs. The present study explored the potential role of miR‑26a in lung development and PS synthesis by using a miR‑26a‑1/miR‑26a‑2 double knockout mouse model. Hematoxylin and eosin staining and transmission electron microscopy were used to observe the morphology of fetal lungs. Reverse transcription‑quantitative polymerase chain reaction and western blot analysis were performed to examine the mRNA and protein levels of surfactant‑associated proteins. The results demonstrated that the lung formation in the knockout mice was more mature, and that there were more mature lamellar bodies inside AECIIs in miR‑26a knockout mice at late stages of lung development. The findings further demonstrated that knockout of miR‑26a increased surfactant‑associated mRNA and protein expression levels. The results indicated that knockout of miR‑26a promotes lung development and PS synthesis.
Collapse
Affiliation(s)
- Yi-Fan Sun
- Department of Neonatology, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
| | - Qing Kan
- Department of Neonatology, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
| | - Yang Yang
- Department of Neonatology, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
| | - Ying-Hui Zhang
- Department of Neonatology, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
| | - Jin-Xin Shen
- Department of Neonatology, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
| | - Cun Zhang
- Department of Neonatology, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
| | - Xiao-Yu Zhou
- Department of Neonatology, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
| |
Collapse
|
|
25
|
Xu S, Wang T, Yang Z, Li Y, Li W, Wang T, Wang S, Jia L, Zhang S, Li S. miR-26a desensitizes non-small cell lung cancer cells to tyrosine kinase inhibitors by targeting PTPN13. Oncotarget 2018; 7:45687-45701. [PMID: 27285768 PMCID: PMC5216753 DOI: 10.18632/oncotarget.9920] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 05/23/2016] [Indexed: 12/24/2022] Open
Abstract
Epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors (TKIs) have emerged as first-line drugs for non-small cell lung cancers (NSCLCs). However, the resistance to TKIs represents the key limitation for their therapeutic efficacy. We found that miR-26a was upregulated in gefitinib-refractory NSCLCs; miR-26a is downstream of EGFR signaling and directly targets and silences protein tyrosine phosphatase non-receptor type 13 (PTPN13) to maintain the activation of Src, a dephosphorylation substrate of PTPN13, thus reinforcing EGFR pathway in a regulatory circuit. miR-26a inhibition significantly improved NSCLC responses to gefitinib. These data revealed a novel mechanism of NSCLC resistance to TKI treatment.
Collapse
Affiliation(s)
- Shudi Xu
- Department of Respiratory Medicine, Huashan Hospital, Fudan University, Shanghai, China.,Department of Respiratory Medicine, 9th Hospital of Xi'an, Xi'an, China
| | - Tao Wang
- Department of Neurology, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Zhiwei Yang
- Department of Applied Physics, Xi'an Jiaotong University, Xi'an, China
| | - Ying Li
- Department of Respiratory Medicine, Huashan Hospital, Fudan University, Shanghai, China.,Department of Respiratory Medicine, Shaanxi Provincial Second People's Hospital, Xi'an, China
| | - Weijie Li
- Department of Respiratory Medicine, Huashan Hospital, Fudan University, Shanghai, China.,Department of Respiratory Medicine, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Ting Wang
- Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China
| | - Shan Wang
- Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China
| | - Lintao Jia
- Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China
| | - Shengli Zhang
- Department of Applied Physics, Xi'an Jiaotong University, Xi'an, China
| | - Shengqing Li
- Department of Respiratory Medicine, Huashan Hospital, Fudan University, Shanghai, China
| |
Collapse
|
|
26
|
Shao Y, Li P, Zhu ST, Yue JP, Ji XJ, Ma D, Wang L, Wang YJ, Zong Y, Wu YD, Zhang ST. MiR-26a and miR-144 inhibit proliferation and metastasis of esophageal squamous cell cancer by inhibiting cyclooxygenase-2. Oncotarget 2017; 7:15173-86. [PMID: 26959737 PMCID: PMC4924778 DOI: 10.18632/oncotarget.7908] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2015] [Accepted: 01/29/2016] [Indexed: 12/21/2022] Open
Abstract
The altered expression of miRNAs is involved in carcinogenesis of esophageal squamous cell carcinoma (ESCC), but whether miRNAs regulate COX-2 expression in ESCC is not clear. To this end, the expression levels of miR-26a and miR-144 in ESCC clinical tissues and cell lines were investigated by qRT-PCR. COX-2 and PEG2 were quantified by western blot and ELISA. Decrease in miR-26a and miR-144 expression in ESCC was found by a comparison between 30 pairs of ESCC tumor and adjacent normal tissues as well as in 11 ESCC cell lines (P < 0.001). Co-transfection of miR-26a and miR-144 in ESCC cell lines more significantly suppressed cell proliferation, migration, and invasion than did either miR-26a or miR-144 alone (all P < 0.001), as shown by assays of CCK8, migration and invasion and flow cytometry. The inhibitory effect of these two miRNAs in vivo was also verified in nude mice xenograft models. COX-2 was confirmed as a target of miR-26a and miR-144. In conclusion, miR-26a and miR-144 expression is downregulated in ESCC. Co-expression of miR-26a and miR-144 in ESCC cells resulted in inhibition of proliferation and metastasis in vitro and in vivo, suggesting that targeting COX-2 may be the mechanism of these two miRNAs.
Collapse
Affiliation(s)
- Ying Shao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
| | - Sheng-Tao Zhu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
| | - Ji-Ping Yue
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
| | - Xiao-Jun Ji
- Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Dan Ma
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
| | - Li Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
| | - Yong-Jun Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
| | - Ye Zong
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
| | - Yong-Dong Wu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
| | - Shu-Tian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, China
| |
Collapse
|
|
27
|
Wald P, Liu XS, Pettit C, Dillhoff M, Manilchuk A, Schmidt C, Wuthrick E, Chen W, Williams TM. Prognostic value of microRNA expression levels in pancreatic adenocarcinoma: a review of the literature. Oncotarget 2017; 8:73345-73361. [PMID: 29069873 PMCID: PMC5641216 DOI: 10.18632/oncotarget.20277] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 07/23/2017] [Indexed: 01/17/2023] Open
Abstract
Background Clinical and pathologic markers of prognosis and patterns of failure help guide clinicians in selecting patients for adjuvant therapy after surgical resection for pancreatic adenocarcinoma (PDAC). Recent studies have reported the prognostic utility of microRNA profiling in numerous malignancies. Here, we review and summarize the current literature regarding associations between microRNA expression and overall survival in PDAC patients. Materials and Methods We conducted a systematic search in the PubMed database to identify all primary research studies reporting prognostic associations between tumor and/or serum microRNA expression and overall survival in PDAC patients. Eligible articles were reviewed by the authors and relevant findings are summarized below. Results We found 53 publications that fit our search criteria. In total, 23 up-regulated and 49 down-regulated miRNAs have been associated with worse overall survival. MiR-21 is the most commonly reported miRNA, appearing in 19 publications, all of which report aberrant over-expression and association with shorter survival in PDAC. Other miRNAs that appear in multiple publications include miR-10b, −21, −34a, −155, −196a, −198, −200c, −203, −210, −218, −222, and −328. We summarize the preclinical and clinical data implicating these miRNAs in various molecular signaling pathways and cellular functions. Conclusions There is growing evidence that miRNA expression profiles have the potential to provide tumor-specific prognostic information to assist clinicians in more appropriately selecting patients for adjuvant therapy. These molecules are often aberrantly expressed and exhibit oncogenic and/or tumor suppressor functions in PDAC. Additional efforts to develop prognostic and predictive molecular signatures, and further elucidate miRNA mechanisms of action, are warranted.
Collapse
Affiliation(s)
- Patrick Wald
- The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210
| | - X Shawn Liu
- The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210
| | - Cory Pettit
- The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210
| | - Mary Dillhoff
- The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210
| | - Andrei Manilchuk
- The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210
| | - Carl Schmidt
- The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210
| | - Evan Wuthrick
- The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210
| | - Wei Chen
- The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210
| | - Terence M Williams
- The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH 43210
| |
Collapse
|
|
28
|
An aptamer-based targeted delivery of miR-26a protects mice against chemotherapy toxicity while suppressing tumor growth. Blood Adv 2017; 1:1107-1119. [PMID: 29296753 DOI: 10.1182/bloodadvances.2017004705] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 05/25/2017] [Indexed: 12/27/2022] Open
Abstract
The efficacy of traditional chemotherapy is limited by its toxicity, especially with regard to hematopoiesis. Here we show that miR-26a plays a critical role in protecting mice against chemotherapy-induced myeloid suppression by targeting a proapoptotic protein (Bak1) in hematopoietic stem/progenitor cells (HSPCs). Because c-Kit is expressed at high levels in HSPCs, we designed a microRNA-aptamer chimera that contains miR-26a mimic and c-Kit-targeting aptamer and successfully delivered miR-26a into HSPCs to attenuate toxicity of 5' fluorouracil (5-FU) and carboplatin. Meanwhile, our in silico analysis revealed widespread and prognosis-associated downregulation of miR-26a in advanced breast cancer and also showed that KIT is overexpressed among basal-like breast cancer cells and that such expression is associated with poor prognosis. Importantly, the miR-26a aptamer effectively repressed tumor growth in vivo and synergized with 5-FU or carboplatin in cancer therapy in the mouse breast cancer models. Thus, targeted delivery of miR-26a suppresses tumor growth while protecting the host against myelosuppression by chemotherapy.
Collapse
|
|
29
|
Giovannetti E, van der Borden CL, Frampton AE, Ali A, Firuzi O, Peters GJ. Never let it go: Stopping key mechanisms underlying metastasis to fight pancreatic cancer. Semin Cancer Biol 2017; 44:43-59. [PMID: 28438662 DOI: 10.1016/j.semcancer.2017.04.006] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 04/12/2017] [Accepted: 04/18/2017] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive neoplasm, predicted to become the second leading cause of cancer-related deaths before 2030. This dismal trend is mainly due to lack of effective treatments against its metastatic behavior. Therefore, a better understanding of the key mechanisms underlying metastasis should provide new opportunities for therapeutic purposes. Genomic analyses revealed that aberrations that fuel PDAC tumorigenesis and progression, such as SMAD4 loss, are also implicated in metastasis. Recently, microRNAs have been shown to play a regulatory role in the metastatic behavior of many tumors, including PDAC. In particular, miR-10 and miR-21 have appeared as master regulators of the metastatic program, while members of the miR-200 family are involved in the epithelial-to-mesenchymal switch, favoring cell migration and invasiveness. Several studies have also found a close relationship between cancer stem cells (CSCs) and biological features of metastasis, and the CSC markers ALDH1, ABCG2 and c-Met are expressed at high levels in metastatic PDAC cells. Emerging evidence reveals that exosomes are involved in the modulation of the tumor microenvironment and can initiate PDAC pre-metastatic niche formation in the liver and lungs. In this review, we provide an overview of the role of all these pivotal factors in the metastatic behavior of PDAC, and discuss their potential exploitation in the clinic to improve current therapeutics and identify new drug targets.
Collapse
Affiliation(s)
- E Giovannetti
- Lab Medical Oncology, Dept. Medical Oncology, VU University Medical Center (VUmc), Amsterdam, The Netherlands; Cancer Pharmacology Lab, AIRC Start Up Unit, University of Pisa, Pisa, Italy
| | - C L van der Borden
- Lab Medical Oncology, Dept. Medical Oncology, VU University Medical Center (VUmc), Amsterdam, The Netherlands
| | - A E Frampton
- HPB Surgical Unit, Dept. of Surgery & Cancer, Imperial College, Hammersmith Hospital Campus, London, UK
| | - A Ali
- Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, KP, Pakistan; Institute of Cancer Sciences, University of Glasgow, UK
| | - O Firuzi
- Lab Medical Oncology, Dept. Medical Oncology, VU University Medical Center (VUmc), Amsterdam, The Netherlands; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - G J Peters
- Lab Medical Oncology, Dept. Medical Oncology, VU University Medical Center (VUmc), Amsterdam, The Netherlands.
| |
Collapse
|
|
30
|
Li Y, Ren M, Zhao Y, Lu X, Wang M, Hu J, Lu G, He S. MicroRNA-26a inhibits proliferation and metastasis of human hepatocellular carcinoma by regulating DNMT3B-MEG3 axis. Oncol Rep 2017; 37:3527-3535. [PMID: 28440439 DOI: 10.3892/or.2017.5579] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 04/05/2017] [Indexed: 12/14/2022] Open
Abstract
miR-26a is known to play an important oncosuppressive role in HCC. However, its regulatory role and relationship with other non-coding RNAs is less clear. In the present study, we report that the expression levels of miR-26a and long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) were frequently downregulated in HCC tissues compared to matched non-malignant tissues. In addition, the expression levels of miR-26a and MEG3 were negatively correlated with the tumor sizes and TNM clinical stage in HCC patients. Overexpression of miR-26a significantly reduced the capacity of proliferation, invasion and migration of HCC cells. Moreover, we demonstrated that DNA methyltransferase 3b (DNMT3B) was a direct target gene of miR-26a. Overexpression of miR-26a suppressed the expression level of DNMT3B. Inhibited expression of DNMT3B showed similar tumor suppressive effects induced by miR-26a upregulation, and resulted in the upregulation of MEG3. Furthermore, we found that the expression levels of DNMT3B were upregulated in the HCC tissues compared with non-malignant tissues, and it was inversely correlated with miR-26a and MEG3 in HCC tissues. Thus, these results provided a plausible link between the observed reduction of miR-26a and MEG3 in HCCs. Together, the present study added miR-26a/DNMT3B/MEG3 axis to the complex mechanisms of HCC development.
Collapse
Affiliation(s)
- Yarui Li
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Mudan Ren
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yan Zhao
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xinlan Lu
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Mengyao Wang
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Junbi Hu
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Guifang Lu
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Shuixiang He
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| |
Collapse
|
|
31
|
Chen R, Zhang Y, Zhang C, Wu H, Yang S. miR-137 inhibits the proliferation of human non-small cell lung cancer cells by targeting SRC3. Oncol Lett 2017; 13:3905-3911. [PMID: 28521488 DOI: 10.3892/ol.2017.5904] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 01/17/2017] [Indexed: 12/21/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. The results of the present study demonstrate that high expression of microRNA (miR)-137 and low expression of steroid receptor coactivator-3 (SRC3) had a significant negative correlation in 40 NSCLC tissue samples. In addition, cell colony formation and proliferation was significantly reduced in miR-137-transfected A549 and NCI-H838 cells compared with scramble-transfected NSCLC cell lines. miR-137 was identified to induce G1/S cell cycle arrest and dysregulate the mRNA expression of cell cycle-associated proteins (proliferating cell nuclear antigen, cyclin E, cyclin A1, cyclin A2 and p21) in NSCLC cells. Notably, miR-137 could significantly suppress SRC3 3' untranslated region (UTR) luciferase-reporter activity, an effect that was not detectable when the putative 3'-UTR target-site was mutated, further clarifying the molecular mechanisms underlying the role of miR-137 in NSCLC. In conclusion, the results of the present study suggest that miR-137 suppresses NSCLC cell proliferation by partially targeting SRC3.
Collapse
Affiliation(s)
- Ruilin Chen
- Department of Respiratory Medicine, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Yongqing Zhang
- Department of Respiratory Medicine, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Chengcheng Zhang
- Department of Respiratory Medicine, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Hua Wu
- Department of Respiratory Medicine, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Shumei Yang
- Department of Respiratory Medicine, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| |
Collapse
|
|
32
|
MiR-26a inhibits proliferation and migration of HaCaT keratinocytes through regulating PTEN expression. Gene 2016; 594:117-124. [DOI: 10.1016/j.gene.2016.09.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 08/30/2016] [Accepted: 09/05/2016] [Indexed: 01/27/2023]
|
|
33
|
Erdmann K, Kaulke K, Rieger C, Salomo K, Wirth MP, Fuessel S. MiR-26a and miR-138 block the G1/S transition by targeting the cell cycle regulating network in prostate cancer cells. J Cancer Res Clin Oncol 2016; 142:2249-61. [PMID: 27562865 DOI: 10.1007/s00432-016-2222-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 08/20/2016] [Indexed: 11/25/2022]
Abstract
PURPOSE The tumor-suppressive microRNAs miR-26a and miR-138 are significantly down-regulated in prostate cancer (PCa) and have been identified as direct regulators of enhancer of zeste homolog 2 (EZH2), which is a known oncogene in PCa. In the present study, the influence of miR-26a and miR-138 on EZH2 and cellular function including the impact on the cell cycle regulating network was evaluated in PCa cells. METHODS PC-3 and DU-145 PCa cells were transfected with 100 nM of miRNA mimics, siRNA against EZH2 (siR-EZH2) or control constructs for 4 h. Analyses of gene expression and cellular function were conducted 48 h after transfection. RESULTS Both miRNAs influenced the EZH2 expression and activity only marginally, whereas siR-EZH2 led to a notable decrease of the EZH2 expression and activity. Both miRNAs inhibited short- and/or long-term proliferation of PCa cells but showed no effect on viability and apoptosis. In PC-3 cells, miR-26a and miR-138 caused a significant surplus of cells in the G0/G1 phase of 6 and 12 %, respectively, thus blocking the G1/S-phase transition. Treatment with siR-EZH2 was without substantial influence on cellular function and cell cycle. Therefore, alternative target genes involved in cell cycle regulation were identified in silico. MiR-26a significantly diminished the expression of its targets CCNE1, CCNE2 and CDK6, whereas CCND1, CCND3 and CDK6 were suppressed by their regulator miR-138. CONCLUSIONS The present findings suggest an anti-proliferative role for miR-26a and miR-138 in PCa by blocking the G1/S-phase transition independent of EZH2 but via a concerted inhibition of crucial cell cycle regulators.
Collapse
Affiliation(s)
- Kati Erdmann
- Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
| | - Knut Kaulke
- Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Christiane Rieger
- Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Karsten Salomo
- Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Manfred P Wirth
- Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Susanne Fuessel
- Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| |
Collapse
|
|
34
|
Gorjala P, Cairncross JG, Gary RK. p53-dependent up-regulation of CDKN1A and down-regulation of CCNE2 in response to beryllium. Cell Prolif 2016; 49:698-709. [PMID: 27611480 DOI: 10.1111/cpr.12291] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 08/07/2016] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES Beryllium salts (here, beryllium sulphate) can produce a cytostatic effect in some cell types. The basis for this effect may include increased expression of proliferation inhibitors, reduced expression of proliferation promoters, or both. This study sought to determine the role of p53, the tumour-suppressing transcription factor, in mediating beryllium-induced cytostasis. MATERIALS AND METHODS Human A172 glioma cells express wild-type TP53 gene. Activity of p53 was experimentally manipulated using siRNA and related approaches. Key elements of the beryllium-response were compared in normal and p53-knockdown A172 cells using RT-PCR and Western blotting. RESULTS In A172 cells, 10 μm BeSO4 caused 300% increase in CDKN1A (cyclin-dependent kinase inhibitor p21) mRNA and 90% reduction of CCNE2 (cyclin E2) mRNA. The increased p21 mRNA and reduced cyclin E2 mRNA were each dependent on presence of functional p53. For p21, increased mRNA led to commensurately increased protein levels. In contrast, reduction in cyclin E2 mRNA levels did not lead to corresponding reductions in cyclin E2 protein. The proteasomal inhibitor MG-132 caused p53 protein to increase, but it had no effect on cyclin E2 protein levels. Cycloheximide time course studies indicated that the cyclin E2 protein half-life was more than 12 hours in these cells. CONCLUSIONS Beryllium elicited p53-dependent changes in mRNA levels of key determinants of cell proliferation such as p21 and cyclin E2. However, cyclin E2 protein appeared to be aberrantly regulated in this cell type, as its turnover was unexpectedly slow.
Collapse
Affiliation(s)
- P Gorjala
- Department of Chemistry and Biochemistry, University of Nevada Las Vegas, Las Vegas, NV, USA
| | - J G Cairncross
- Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada
| | - R K Gary
- Department of Chemistry and Biochemistry, University of Nevada Las Vegas, Las Vegas, NV, USA.
| |
Collapse
|
|
35
|
Loss of miR-26a-5p promotes proliferation, migration, and invasion in prostate cancer through negatively regulating SERBP1. Tumour Biol 2016; 37:12843-12854. [PMID: 27449037 DOI: 10.1007/s13277-016-5158-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 07/12/2016] [Indexed: 01/07/2023] Open
Abstract
The biological role of miR-26a involved in the carcinogenesis of prostate cancer (PC) has been controversial. Besides, the underlying mechanism by which miR-26a plays a role in PC has been unclear. To investigate the role of miR-26a-5p in the PC, miR-26a-5p was detected and statistically analyzed in clinical PC tissues and a panel of PC cell lines. Using bioinformatics analysis, we found that serpine1 messenger RNA (mRNA) binding protein 1 (SERBP1) was a potential downstream target of miR-26a-5p. Using luciferase reporter and western blot, we identified that miR-26a-5p negatively regulated SERBP1 on the PC cell line level. It was confirmed that miR-26a-5p was markedly downregulated in PC tissues compared with normal controls whose reduced expression was significantly associated with metastasis and poor overall prognosis and found that miR-26a-5p was able to prevent proliferation and motility of PC cells in vitro. Additionally, SERBP1 was identified as a downstream target of miR-26a-5p. Moreover, it was observed that SERBP1 was markedly upregulated in prostate cancer tissues and was significantly associated with tissue metastasis and Gleason score. Taken together, our results for the first time demonstrate that the loss of miR-26a-5p promotes proliferation, migration, and invasion through targeting SERBP1 in PC, supporting the tumor-suppressing role of miR-26a-5p in PC.
Collapse
|
|
36
|
MicroRNA in pancreatic cancer. J Hum Genet 2016; 62:33-40. [DOI: 10.1038/jhg.2016.59] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 04/26/2016] [Accepted: 04/27/2016] [Indexed: 02/07/2023]
|
|
37
|
Berman M, Mattheolabakis G, Suresh M, Amiji M. Reversing epigenetic mechanisms of drug resistance in solid tumors using targeted microRNA delivery. Expert Opin Drug Deliv 2016; 13:987-98. [DOI: 10.1080/17425247.2016.1178236] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Melissa Berman
- Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA
| | - George Mattheolabakis
- Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA
| | - Megha Suresh
- Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA
| | - Mansoor Amiji
- Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA
- Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| |
Collapse
|
|
38
|
Chen J, Zhang K, Xu Y, Gao Y, Li C, Wang R, Chen L. The role of microRNA-26a in human cancer progression and clinical application. Tumour Biol 2016; 37:7095-108. [PMID: 27039398 DOI: 10.1007/s13277-016-5017-y] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 03/18/2016] [Indexed: 12/17/2022] Open
Abstract
MicroRNAs, a class of endogenous, small (18-25 nucleotides) noncoding RNAs, regulate gene expression by directly binding to the 3'-untranslated regions of target messenger RNAs. Evidence has shown that alteration of microRNAs is involved in cancer initial and progression. MicroRNA-26a is commonly dysregulated in diverse cancers and is involved in various biological processes, including proliferation, migration, invasion, angiogenesis, and metabolism by targeting multiple mRNAs. This review summarizes current research on the physiology and pathological functions of miR-26a and its applications for clinical therapy.
Collapse
Affiliation(s)
- Jing Chen
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, 305 Zhong Shan Road East, Nanjing, Jiangsu Province, People's Republic of China
| | - Kai Zhang
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, 305 Zhong Shan Road East, Nanjing, Jiangsu Province, People's Republic of China
| | - Yuejuan Xu
- Department of Medical Oncology, Jiangsu Cancer Hospital, Nanjing, People's Republic of China
| | - Yanping Gao
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, 305 Zhong Shan Road East, Nanjing, Jiangsu Province, People's Republic of China
| | - Chen Li
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, 305 Zhong Shan Road East, Nanjing, Jiangsu Province, People's Republic of China
| | - Rui Wang
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, 305 Zhong Shan Road East, Nanjing, Jiangsu Province, People's Republic of China.
| | - Longbang Chen
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, 305 Zhong Shan Road East, Nanjing, Jiangsu Province, People's Republic of China.
| |
Collapse
|
|
39
|
Costa-Reis P, Russo PA, Zhang Z, Colonna L, Maurer K, Gallucci S, Schulz SW, Kiani AN, Petri M, Sullivan KE. The Role of MicroRNAs and Human Epidermal Growth Factor Receptor 2 in Proliferative Lupus Nephritis. Arthritis Rheumatol 2015; 67:2415-26. [PMID: 26016809 DOI: 10.1002/art.39219] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Accepted: 05/21/2015] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To understand the roles of microRNAs (miRNAs) in proliferative lupus nephritis (LN). METHODS A high-throughput analysis of the miRNA pattern of the kidneys of LN patients and controls was performed by molecular digital detection. Urinary miRNAs were measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Target gene expression in human mesangial cells was evaluated by arrays and qRT-PCR. Human epidermal growth factor receptor 2 (HER-2) was analyzed by immunohistochemistry in kidney samples from LN patients and in a murine model of lupus. Urinary levels of HER-2, monocyte chemotactic protein 1 (MCP-1), and vascular cell adhesion molecule 1 (VCAM-1) were measured by enzyme-linked immunosorbent assay. RESULTS Levels of the miRNAs miR-26a and miR-30b were decreased in the kidneys and urine of LN patients. In vitro these miRNAs controlled mesangial cell proliferation, and their expression was regulated by HER-2. HER-2 was overexpressed in lupus-prone NZM2410 mice and in the kidneys of patients with LN, but not in other mesangioproliferative glomerulonephritides. HER-2 was found to be up-regulated by interferon-α and interferon regulatory factor 1. Urinary HER-2 was increased in LN and reflected disease activity, and its levels correlated with those of 2 other recognized LN biomarkers, MCP-1 and VCAM-1. CONCLUSION The kidney miRNA pattern is broadly altered in LN, which contributes to uncontrolled cell proliferation. Levels of the miRNAs miR-26a and miR-30b are decreased in the kidneys and urine of LN patients, and they directly regulate the cell cycle in mesangial cells. The levels of these miRNAs are controlled by HER-2, which is overexpressed in NZM2410 mice and in the kidneys and urine of LN patients. HER-2, miR-26a, and miR-30b are thus potential LN biomarkers, and blocking HER-2 may be a promising new strategy to decrease cell proliferation and damage in this disease.
Collapse
Affiliation(s)
- Patrícia Costa-Reis
- The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, and University of Lisbon, Lisbon, Portugal
| | - Pierre A Russo
- The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia
| | - Zhe Zhang
- The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Lucrezia Colonna
- The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Kelly Maurer
- The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Stefania Gallucci
- The Children's Hospital of Philadelphia and Temple University, Philadelphia, Pennsylvania
| | | | - Adnan N Kiani
- Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Michelle Petri
- Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Kathleen E Sullivan
- The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia
| |
Collapse
|
|
40
|
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.
Collapse
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.
| |
Collapse
|
|
41
|
Garajová I, Giovannetti E, Caponi S, van Zweeden A, Peters GJ. MiRNAs and Their Interference with the Main Molecular Mechanisms Responsible for Drug Resistance in Pancreatic Cancer. CURRENT PHARMACOLOGY REPORTS 2015; 1:223-233. [DOI: 10.1007/s40495-014-0008-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2023]
|
|
42
|
Vivanti A, Soheili TS, Cuccuini W, Luce S, Mandelbrot L, Lechenadec J, Cordier AG, Azria E, Soulier J, Cavazzana M, Blanche S, André-Schmutz I. Comparing genotoxic signatures in cord blood cells from neonates exposed in utero to zidovudine or tenofovir. AIDS 2015; 29:1319-24. [PMID: 25513819 PMCID: PMC4502990 DOI: 10.1097/qad.0000000000000564] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2014] [Revised: 12/03/2014] [Accepted: 12/04/2014] [Indexed: 12/23/2022]
Abstract
OBJECTIVES Zidovudine and tenofovir are the two main nucleos(t)ide analogs used to prevent mother-to-child transmission of HIV. In vitro, both drugs bind to and integrate into human DNA and inhibit telomerase. The objective of the present study was to assess the genotoxic effects of either zidovudine or tenofovir-based combination therapies on cord blood cells in newborns exposed in utero. DESIGN We compared the aneuploid rate and the gene expression profiles in cord blood samples from newborns exposed either to zidovudine or tenofovir-based combination therapies during pregnancy and from unexposed controls (n = 8, 9, and 8, respectively). METHODS The aneuploidy rate was measured on the cord blood T-cell karyotype. Gene expression profiles of cord blood T cells and hematopoietic stem and progenitor cells were determined with microarrays, analyzed in a gene set enrichment analysis and confirmed by real-time quantitative PCRs. RESULTS Aneuploidy was more frequent in the zidovudine-exposed group (26.3%) than in the tenofovir-exposed group (14.2%) or in controls (13.3%; P < 0.05 for both). The transcription of genes involved in DNA repair, telomere maintenance, nucleotide metabolism, DNA/RNA synthesis, and the cell cycle was deregulated in samples from both the zidovudine and the tenofovir-exposed groups. CONCLUSION Although tenofovir has a lower clastogenic impact than zidovudine, gene expression profiling showed that both drugs alter the transcription of DNA repair and telomere maintenance genes.
Collapse
Affiliation(s)
- Alexandre Vivanti
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine
| | - Tayebeh S. Soheili
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine
| | - Wendy Cuccuini
- Laboratoire d’Hématologie Biologique, Assistance Publique-Hopitaux de Paris (AP-HP)
- Laboratoire Génome et Cancer, INSERM, U944 and UMR7212, Hôpital Saint Louis
| | - Sonia Luce
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine
| | - Laurent Mandelbrot
- Service de Gynécologie Obstétrique, Hôpital Louis Mourier, Hôpitaux Universitaire Paris Nord Val de Seine (HUPNVS), AP-HP, Colombes
- INSERM U1018, Centre de recherche en Epidémiologie et Santé des Populations
| | - Jerome Lechenadec
- INSERM U1018, Centre de recherche en Epidémiologie et Santé des Populations
- Université Paris-Sud, Le Kremlin Bicêtre
| | - Anne-Gael Cordier
- Service de Gynécologie Obstétrique, Hôpital Antoine Béclère, AP-HP, Clamart
| | - Elie Azria
- Service de Gynécologie Obstétrique, Hôpital Bichat, HUPNVS, AP-HP
| | - Jean Soulier
- Laboratoire d’Hématologie Biologique, Assistance Publique-Hopitaux de Paris (AP-HP)
- Laboratoire Génome et Cancer, INSERM, U944 and UMR7212, Hôpital Saint Louis
- Université Paris-Diderot
- Institut Universitaire d’Hématologie, Paris
| | - Marina Cavazzana
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine
- Département de Biothérapie
| | - Stéphane Blanche
- Unité d’Immunologie Hématologie Rhumatologie Pédiatrique, Hôpital Necker Enfants Malades, AP-HP
- EA 7323, Pharmacologie et évaluation des médicaments chez l’enfant et la femme enceinte, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
- Stéphane Blanche and Isabelle André-Schmutz contributed equally to the writing of this article
| | - Isabelle André-Schmutz
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine
- Stéphane Blanche and Isabelle André-Schmutz contributed equally to the writing of this article
| |
Collapse
|
|
43
|
Batchu RB, Gruzdyn OV, Qazi AM, Kaur J, Mahmud EM, Weaver DW, Gruber SA. Enhanced phosphorylation of p53 by microRNA-26a leading to growth inhibition of pancreatic cancer. Surgery 2015; 158:981-6; discussion 986-7. [PMID: 26189069 DOI: 10.1016/j.surg.2015.05.019] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Revised: 04/13/2015] [Accepted: 05/13/2015] [Indexed: 11/24/2022]
Abstract
PURPOSE MicroRNA (miR)-26a has been identified as a tumor suppressor in pancreatic cancer cells. Although wild-type p53 controls cell-cycle progression, its mutant form normally present in pancreatic cancer loses this capability. Phosphorylation is known to restore wild-type activity to mutant p53. We, therefore, examined whether miR-26a treatment can restore wild-type functions of mutant p53 via phosphorylation, resulting in inhibition of cell growth. METHODS The human pancreatic cancer cell line BxPc-3 harboring mutant p53 was used for colony formation, cell-cycle, and Western blotting assays. Gene profile analysis was conducted after transfection with pre-miR-26a. RESULTS miR-26a expression significantly decreased cell proliferation by 80% along with marked inhibition of colony formation and cell migration. Cell-cycle inhibition at the G0/G1 interface was observed along with enhanced drug retention and increased chemosensitivity to gemcitabine. Mutant p53 was phosphorylated rapidly at its Ser9 and Ser392 residues, but not at Ser15 or Ser20. Gene profile analysis of pre-miR-26a-transfected cells showed a significant increase in gene transcripts promoting apoptosis and p53 activation, with decreased levels of genes involved in cell-cycle progression. CONCLUSION Delivery of miR-26a may represent a novel strategy for inhibiting pancreatic cancer growth, at least in part by enhancing phosphorylation of mutant p53 to restore its wild-type functions.
Collapse
Affiliation(s)
- Ramesh B Batchu
- Wayne State University School of Medicine, Detroit, MI; John D. Dingell VA Medical Center, Detroit, MI; Virocan Therapeutics Pvt. Ltd, Guntur, India.
| | - Oksana V Gruzdyn
- Wayne State University School of Medicine, Detroit, MI; John D. Dingell VA Medical Center, Detroit, MI
| | - Aamer M Qazi
- Wayne State University School of Medicine, Detroit, MI; John D. Dingell VA Medical Center, Detroit, MI
| | - Jaskiran Kaur
- Wayne State University School of Medicine, Detroit, MI
| | | | | | - Scott A Gruber
- Wayne State University School of Medicine, Detroit, MI; John D. Dingell VA Medical Center, Detroit, MI
| |
Collapse
|
|
44
|
Dey N, Bera A, Das F, Ghosh-Choudhury N, Kasinath BS, Choudhury GG. High glucose enhances microRNA-26a to activate mTORC1 for mesangial cell hypertrophy and matrix protein expression. Cell Signal 2015; 27:1276-85. [PMID: 25797045 PMCID: PMC4437875 DOI: 10.1016/j.cellsig.2015.03.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Revised: 03/06/2015] [Accepted: 03/15/2015] [Indexed: 02/06/2023]
Abstract
High glucose milieu inhibits PTEN expression to activate Akt kinase and induces glomerular mesangial cell hypertrophy and matrix protein expression in diabetic nephropathy. Specific mechanism by which high glucose inhibits PTEN expression is not clear. We found that high glucose increased the expression of the microRNA-26a (miR-26a) in mesangial cells. Using a sensor plasmid with 3'UTR-driven luciferase, we showed PTEN as a target of miR-26a in response to high glucose. Overexpression of miR-26a reduced the PTEN protein levels resulting in increased Akt kinase activity similar to high glucose treatment. In contrast, anti-miR-26a reversed high glucose-induced suppression of PTEN with concomitant inhibition of Akt kinase activity. Akt-mediated phosphorylation of tuberin and PRAS40 regulates mTORC1, which is necessary for mesangial cell hypertrophy and matrix protein expression. Inhibition of high glucose-induced miR-26a blocked phosphorylation of tuberin and PRAS40, which lead to suppression of phosphorylation of S6 kinase and 4EBP-1, two substrates of mTORC1. Furthermore, we show that expression of miR-26a induced mesangial cell hypertrophy and increased fibronectin and collagen I (α2) expression similar to that observed with the cells incubated with high glucose. Anti-miR-26a inhibited these phenomena in response to high glucose. Together our results provide the first evidence for the involvement of miR-26a in high glucose-induced mesangial cell hypertrophy and matrix protein expression. These data indicate the potential therapeutic utility of anti-miR-26a for the complications of diabetic kidney disease.
Collapse
Affiliation(s)
- Nirmalya Dey
- Department of Medicine, University of Texas Health Science Center at San Antonio Texas, United States
| | - Amit Bera
- Department of Medicine, University of Texas Health Science Center at San Antonio Texas, United States
| | - Falguni Das
- Department of Medicine, University of Texas Health Science Center at San Antonio Texas, United States
| | - Nandini Ghosh-Choudhury
- VA Research, South Texas Veterans Health Care System, San Antonio, TX, United States; Department of Pathology, University of Texas Health Science Center at San Antonio, Texas, United States
| | - Balakuntalam S Kasinath
- Department of Medicine, University of Texas Health Science Center at San Antonio Texas, United States; VA Research, South Texas Veterans Health Care System, San Antonio, TX, United States
| | - Goutam Ghosh Choudhury
- Department of Medicine, University of Texas Health Science Center at San Antonio Texas, United States; VA Research, South Texas Veterans Health Care System, San Antonio, TX, United States; Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, United States.
| |
Collapse
|
|
45
|
Matsushita R, Seki N, Chiyomaru T, Inoguchi S, Ishihara T, Goto Y, Nishikawa R, Mataki H, Tatarano S, Itesako T, Nakagawa M, Enokida H. Tumour-suppressive microRNA-144-5p directly targets CCNE1/2 as potential prognostic markers in bladder cancer. Br J Cancer 2015; 113:282-9. [PMID: 26057453 PMCID: PMC4506384 DOI: 10.1038/bjc.2015.195] [Citation(s) in RCA: 110] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Revised: 03/30/2015] [Accepted: 05/06/2015] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Analysis of a microRNA (miRNA) expression signature of bladder cancer (BC) by deep-sequencing revealed that clustered miRNAs microRNA (miR)-451a, miR-144-3p, and miR-144-5p were significantly downregulated in BC tissues. We hypothesised that these miRNAs function as tumour suppressors in BC. The aim of this study was to investigate the functional roles of these miRNAs and their modulation of cancer networks in BC cells. METHODS The functional studies of BC cells were performed using transfection of mature miRNAs. Genome-wide gene expression analysis, in silico analysis, and dual-luciferase reporter assays were applied to identify miRNA targets. The association between miR-144-5p levels and expression of the target genes was determined, and overall patient survival as a function of target gene expression was estimated by the Kaplan-Meier method. RESULTS Gain-of-function studies showed that miR-144-5p significantly inhibited cell proliferation by BC cells. Four cell cycle-related genes (CCNE1, CCNE2, CDC25A, and PKMYT1) were identified as direct targets of miR-144-5p. The patients with high CCNE1 or CCNE2 expression had lower overall survival probabilities than those with low expression (P=0.025 and P=0.032). CONCLUSION miR-144-5p functions as tumour suppressor in BC cells. CCNE1 and CCNE2 were directly regulated by miR-144-5p and might be good prognostic markers for survival of BC patients.
Collapse
Affiliation(s)
- R Matsushita
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan
| | - N Seki
- Department of Functional Genomics, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - T Chiyomaru
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan
| | - S Inoguchi
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan
| | - T Ishihara
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan
| | - Y Goto
- Department of Functional Genomics, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - R Nishikawa
- Department of Functional Genomics, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - H Mataki
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan
| | - S Tatarano
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan
| | - T Itesako
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan
| | - M Nakagawa
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan
| | - H Enokida
- Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan
| |
Collapse
|
|
46
|
microRNAs with prognostic significance in pancreatic ductal adenocarcinoma: A meta-analysis. Eur J Cancer 2015; 51:1389-404. [PMID: 26002251 DOI: 10.1016/j.ejca.2015.04.006] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 04/06/2015] [Accepted: 04/10/2015] [Indexed: 01/17/2023]
Abstract
BACKGROUND Reports have described the prognostic relevance of microRNAs (miRNAs) in patients treated for pancreatic ductal adenocarcinoma (PDAC). However, many of these include small numbers of patients. To increase statistical power and improve translation, we performed a systematic review and meta-analysis to determine a pooled conclusion. We examined the impact of miRNAs on overall survival (OS) and disease-free survival (DFS) in PDAC. METHODS Eligible studies were identified and quality assessed using multiple search strategies (last search December 2014). Data were collected from studies correlating clinical outcomes with dysregulated tumoural or blood miRNAs. Studies were pooled, and combined hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate strength of the associations. RESULTS Twenty studies involving 1525 patients treated for PDAC were included. After correcting for publication bias, OS was significantly shortened in patients with high tumoural miR-21 (adjusted HR = 2.48; 1.96-3.14). This result persisted when only studies adjusting for adjuvant chemotherapy were combined (adjusted HR = 2.72; 1.91-3.89). High miR-21 also predicted reduced DFS (adjusted HR = 3.08; 1.78-5.33). Similarly, we found significant adjusted HRs for poor OS for high miR-155, high miR-203, and low miR-34a; and unadjusted HRs for high miR-222 and high miR-10b. The small number of studies, limited number of miRNAs and paucity of multivariate analyses are the limitations of our study. CONCLUSIONS This is the first rigorous pooled analysis assessing miRNAs as prognostic biomarkers in PDAC. Tumoural miR-21 overexpression emerged as an important predictor of poor prognosis after PDAC resection independent of other clinicopathologic factors, including adjuvant chemotherapy use.
Collapse
|
|
47
|
Lin R, Shen W, Zhi Y, Zhou Z. Prognostic value of miR-26a and HMGA1 in urothelial bladder cancer. Biomed Pharmacother 2014; 68:929-34. [PMID: 25455159 DOI: 10.1016/j.biopha.2014.10.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Accepted: 10/01/2014] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND MicroRNA-26a (miR-26a) functions as a tumor suppressor by regulating its direct target gene high mobility group AT-hook 1 (HMGA1). This study was aimed to investigate the associations of differential expression of miR-26a and HMGA1 with tumor progression and prognosis in urothelial bladder cancer (UBC) patients. MATERIALS AND METHODS One hundred and twenty-six UBC patients were selected and quantitative real-time PCR was performed to detect the expression of miR-26a and HMGA1 mRNA in the respective tumors. RESULTS Our data showed the decreased expression of miR-26a and the increased expression of HMGA1 mRNA in UBC tissues compared with corresponding non-cancerous tissues (both P<0.001). Then, the expression levels of miR-26a in UBC tissues were negatively correlated with those of HMGA1 mRNA significantly (r=-0.72, P<0.001). In addition, UBC patients with combined miR-26a downregulation and HMGA1 upregulation (miR-26a-low/HMGA1-high) more frequently had advanced pathological stage (P<0.001) and high tumor grade (P<0.001). Moreover, miR-26a-low/HMGA1-high expression was associated with a significantly shortest disease-free survival (P<0.001) and overall survival (P<0.001) of all miR-26a/HMGA1 combined expression groups. Furthermore, multivariate analysis indicated that miR-26a/HMGA1 expression was an independent prognostic factor for both disease-free survival and overall survival (both P=0.001) in UBC patients. CONCLUSION Interaction between miR-26a and its target gene HMGA1 may contribute to the malignant progression of human UBC. Tumors with miR-26a downregulation in combination with high expression of HMGA1 showed a worse prognosis than the other tumors. Combined detection of their expression might be particularly helpful for surveillance of disease progression and treatment stratification.
Collapse
Affiliation(s)
- Rongkai Lin
- Urological Research Institute of PLA, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Wenhao Shen
- Urological Research Institute of PLA, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Yi Zhi
- Urological Research Institute of PLA, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Zhansong Zhou
- Urological Research Institute of PLA, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
| |
Collapse
|
|
48
|
Tang SC, Chen YC. Novel therapeutic targets for pancreatic cancer. World J Gastroenterol 2014; 20:10825-10844. [PMID: 25152585 PMCID: PMC4138462 DOI: 10.3748/wjg.v20.i31.10825] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 02/13/2014] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer has become the fourth leading cause of cancer death in the last two decades. Only 3%-15% of patients diagnosed with pancreatic cancer had 5 year survival rate. Drug resistance, high metastasis, poor prognosis and tumour relapse contributed to the malignancies and difficulties in treating pancreatic cancer. The current standard chemotherapy for pancreatic cancer is gemcitabine, however its efficacy is far from satisfactory, one of the reasons is due to the complex tumour microenvironment which decreases effective drug delivery to target cancer cell. Studies of the molecular pathology of pancreatic cancer have revealed that activation of KRAS, overexpression of cyclooxygenase-2, inactivation of p16INK4A and loss of p53 activities occurred in pancreatic cancer. Co-administration of gemcitabine and targeting the molecular pathological events happened in pancreatic cancer has brought an enhanced therapeutic effectiveness of gemcitabine. Therefore, studies looking for novel targets in hindering pancreatic tumour growth are emerging rapidly. In order to give a better understanding of the current findings and to seek the direction in future pancreatic cancer research; in this review we will focus on targets suppressing tumour metastatsis and progression, KRAS activated downstream effectors, the relationship of Notch signaling and Nodal/Activin signaling with pancreatic cancer cells, the current findings of non-coding RNAs in inhibiting pancreatic cancer cell proliferation, brief discussion in transcription remodeling by epigenetic modifiers (e.g., HDAC, BMI1, EZH2) and the plausible therapeutic applications of cancer stem cell and hyaluronan in tumour environment.
Collapse
|
|
49
|
Zhang R, Zheng S, Du Y, Wang Y, Zang W, Zhao G. Levels of HOXB7 and miR-337 in pancreatic ductal adenocarcinoma patients. Diagn Pathol 2014; 9:61. [PMID: 24641834 PMCID: PMC3995144 DOI: 10.1186/1746-1596-9-61] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 03/04/2014] [Indexed: 01/24/2023] Open
Abstract
Background Many studies have revealed that homeobox-B7 (HOXB7) and miR-337 play important roles in different types of human cancers. However, the relationship of HOXB7 and miR-337 in PDAC with clinicopathological factors has not yet been examined and their biological roles remain to be explored. Methods Using quantitative real-time RT-PCR and immunohistochemical staining, the expression of HOXB7 mRNA, miR-337, and HOXB7 protein in 44 PDAC samples was detected. Survival curves were made using follow-up data. The relationship between clinical or pathological characteristics and the prognosis was analyzed. Results The expression levels of HOXB7 mRNA and HOXB7 protein were significantly elevated in PDAC samples than that in non-malignant adjacent tissues. There were obvious differences in HOXB7 mRNA and proteins between tumors of different diameters, differentiation, TNM stage, and lymph node status. The level of miR-337 was markedly lower in tumor samples than in non-malignant adjacent tissues. The expression of miR-337 was related to TNM stage and lymph node status. There were significant differences in survival curves between patients with tumors <4 cm in diameter and patients with tumors ≥4 cm, among groups of well, moderately, and poorly differentiated tumors, between groups with TNM stages I, II and III or IV, between groups with metastatic lymph nodes and non-metastatic lymph nodes, among groups of HOXB7 protein expression negative (or weak) and positive, between groups with low levels of miR-337 expression and with high levels of miR-337 expression. The levels of HOXB7 mRNA, HOXB7 protein, and miR-337 were found to be associated with longer survival. Conclusion The present study showed that HOXB7 was over-expressed and miR-337 was minimally expressed in PDAC tissues, and their levels were related to TNM stage and lymph node status. The levels of HOXB7 mRNA, HOXB7 protein, and miR-337 were associated with survival in PDAC patients. Results suggested that HOXB7 and miR-337 could be used as determinants of PDAC patient prognosis. Virtual slides The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1509730773118658.
Collapse
Affiliation(s)
- Rui Zhang
- Department of emergency, The First Affiliated Hospital of Zhengzhou University, No,1 Jianshe Road, Zhengzhou, Henan 450052, China.
| | | | | | | | | | | |
Collapse
|