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Yuan J, Yan K, Guo Y, Li Y. MicroRNAs: emerging biomarkers and therapeutic targets in pancreatic cancer. Front Mol Biosci 2024; 11:1457875. [PMID: 39290995 PMCID: PMC11406015 DOI: 10.3389/fmolb.2024.1457875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 08/23/2024] [Indexed: 09/19/2024] Open
Abstract
Pancreatic cancer (PC) is a highly malignant disease with high aggressiveness and a dismal prognosis, which is challenging to diagnose clinically early and gains low benefit from standard therapies. MicroRNAs (miRNAs) have become a hot topic in oncology research. Current evidence indicates that miRNAs are regulators involved in the entire process of PC, providing new diagnostic and therapeutic strategies for this fatal disease. Related research has been rapidly updated, making it necessary to review it to propose new directions and ideas and provide guidance for the development of precision medicine for PC. We reviewed the relevant literature through Pubmed, Embase, Web of Science and Medline, showing that abnormally expressed miRNAs in PC patients have the potential to be used as biomarkers for diagnosis and prognosis, highlighting the excellent prospect of combining miRNAs with traditional therapies, and the effective application of these factors for PC, especially miRNA mimics and inhibitors. MiRNAs participate in the entire process of PC and play important roles in diagnosis, treatment and prognosis. They are potential factors in conquering PC in the future.
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Affiliation(s)
- Jiaqian Yuan
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Kaiqi Yan
- Department of Materials Engineering and Science, Ningbo University of Technology, Ningbo, China
| | - Yong Guo
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yan Li
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
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Tiwari PK, Shanmugam P, Karn V, Gupta S, Mishra R, Rustagi S, Chouhan M, Verma D, Jha NK, Kumar S. Extracellular Vesicular miRNA in Pancreatic Cancer: From Lab to Therapy. Cancers (Basel) 2024; 16:2179. [PMID: 38927885 PMCID: PMC11201547 DOI: 10.3390/cancers16122179] [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: 05/03/2024] [Revised: 05/29/2024] [Accepted: 06/06/2024] [Indexed: 06/28/2024] Open
Abstract
Pancreatic cancer is a prevalent lethal gastrointestinal cancer that generally does not show any symptoms until it reaches advanced stages, resulting in a high mortality rate. People at high risk, such as those with a family history or chronic pancreatitis, do not have a universally accepted screening protocol. Chemotherapy and radiotherapy demonstrate limited effectiveness in the management of pancreatic cancer, emphasizing the urgent need for innovative therapeutic strategies. Recent studies indicated that the complex interaction among pancreatic cancer cells within the dynamic microenvironment, comprising the extracellular matrix, cancer-associated cells, and diverse immune cells, intricately regulates the biological characteristics of the disease. Additionally, mounting evidence suggests that EVs play a crucial role as mediators in intercellular communication by the transportation of different biomolecules, such as miRNA, proteins, DNA, mRNA, and lipids, between heterogeneous cell subpopulations. This communication mediated by EVs significantly impacts multiple aspects of pancreatic cancer pathogenesis, including proliferation, angiogenesis, metastasis, and resistance to therapy. In this review, we delve into the pivotal role of EV-associated miRNAs in the progression, metastasis, and development of drug resistance in pancreatic cancer as well as their therapeutic potential as biomarkers and drug-delivery mechanisms for the management of pancreatic cancer.
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Affiliation(s)
- Prashant Kumar Tiwari
- Biological and Bio-Computational Lab, Department of Life Science, School of Basic Sciences and Research, Sharda University, Greater Noida 201310, Uttar Pradesh, India
| | - Poojhaa Shanmugam
- Amity Institute of Biotechnology, Amity University, Mumbai 410206, Maharashtra, India
| | - Vamika Karn
- Amity Institute of Biotechnology, Amity University, Mumbai 410206, Maharashtra, India
| | - Saurabh Gupta
- Department of Biotechnology, GLA University, Mathura 281406, Uttar Pradesh, India
| | - Richa Mishra
- Department of Computer Engineering, Parul University, Ta. Waghodia, Vadodara 391760, Gujarat, India
| | - Sarvesh Rustagi
- School of Applied and Life science, Uttaranchal University, Dehradun 248007, Uttarakhand, India
| | - Mandeep Chouhan
- Biological and Bio-Computational Lab, Department of Life Science, School of Basic Sciences and Research, Sharda University, Greater Noida 201310, Uttar Pradesh, India
| | - Devvret Verma
- Department of Biotechnology, Graphic Era (Deemed to be University), Dehradun 248002, Uttarakhand, India
| | - Niraj Kumar Jha
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 602105, Tamil Nadu, India
- School of Bioengineering & Biosciences, Lovely Professional University, Phagwara 144411, Punjab, India
- Department of Biotechnology, Sharda School of Engineering and Technology, Sharda University, Greater Noida 201310, Uttar Pradesh, India
| | - Sanjay Kumar
- Biological and Bio-Computational Lab, Department of Life Science, School of Basic Sciences and Research, Sharda University, Greater Noida 201310, Uttar Pradesh, India
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Adekolujo OS, Wahab A, Akanbi MO, Oyasiji T, Hrinczenko B, Alese OB. Isolated pulmonary metastases in pancreatic ductal adenocarcinoma: a review of current evidence. Cancer Biol Ther 2023; 24:2198479. [PMID: 37526431 PMCID: PMC10395259 DOI: 10.1080/15384047.2023.2198479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 03/24/2023] [Indexed: 08/02/2023] Open
Abstract
Despite recent advances in cancer therapeutics, pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year overall survival of only 10%. Since either at or within a few months of diagnosis, most patients with PDAC will present with metastatic disease, a more individualized approach to select patients who may benefit from more aggressive therapy has been suggested. Although studies have reported improved survival in PDAC and isolated pulmonary metastasis (ISP) compared to extrapulmonary metastases, such findings remain controversial. Furthermore, the added benefit of pulmonary metastasectomy and other lung-directed therapies remains unclear. In this review, we discuss the metastatic pattern of PDAC, evaluate the available evidence in the literature for improved survival in PDAC and ISP, evaluate the evidence for the added benefit of pulmonary metastasectomy and other lung-directed therapies, identify prognostic factors for survival, discuss the biological basis for the reported improved survival and identify areas for further research.
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Affiliation(s)
- Orimisan Samuel Adekolujo
- Department of Medicine, Michigan State University, East Lansing, MI, USA
- Medical Oncology, Karmanos Cancer Institute at McLaren Greater Lansing, Lansing, MI, USA
| | - Ahsan Wahab
- Department of Medicine, Prattville Baptist Hospital, Prattville, AL, USA
| | - Maxwell Oluwole Akanbi
- Department of Medicine, Michigan State University, East Lansing, MI, USA
- Department of Medicine, McLaren Flint, Flint, MI, USA
| | - Tolutope Oyasiji
- Department of Oncology, Barbara Ann Karmanos Cancer Institute at McLaren Flint, Wayne State University, Flint, MI, USA
| | - Borys Hrinczenko
- Department of Medicine, Michigan State University, East Lansing, MI, USA
- Medical Oncology, Karmanos Cancer Institute at McLaren Greater Lansing, Lansing, MI, USA
| | - Olatunji Boladale Alese
- Department of Hematology & Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia
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4
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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.
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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.
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Seyhan AA. Circulating microRNAs as Potential Biomarkers in Pancreatic Cancer-Advances and Challenges. Int J Mol Sci 2023; 24:13340. [PMID: 37686149 PMCID: PMC10488102 DOI: 10.3390/ijms241713340] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/21/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
There is an urgent unmet need for robust and reliable biomarkers for early diagnosis, prognosis, and prediction of response to specific treatments of many aggressive and deadly cancers, such as pancreatic cancer, and liquid biopsy-based miRNA profiling has the potential for this. MiRNAs are a subset of non-coding RNAs that regulate the expression of a multitude of genes post-transcriptionally and thus are potential diagnostic, prognostic, and predictive biomarkers and have also emerged as potential therapeutics. Because miRNAs are involved in the post-transcriptional regulation of their target mRNAs via repressing gene expression, defects in miRNA biogenesis pathway and miRNA expression perturb the expression of a multitude of oncogenic or tumor-suppressive genes that are involved in the pathogenesis of various cancers. As such, numerous miRNAs have been identified to be downregulated or upregulated in many cancers, functioning as either oncomes or oncosuppressor miRs. Moreover, dysregulation of miRNA biogenesis pathways can also change miRNA expression and function in cancer. Profiling of dysregulated miRNAs in pancreatic cancer has been shown to correlate with disease diagnosis, indicate optimal treatment options and predict response to a specific therapy. Specific miRNA signatures can track the stages of pancreatic cancer and hold potential as diagnostic, prognostic, and predictive markers, as well as therapeutics such as miRNA mimics and miRNA inhibitors (antagomirs). Furthermore, identified specific miRNAs and genes they regulate in pancreatic cancer along with downstream pathways can be used as potential therapeutic targets. However, a limited understanding and validation of the specific roles of miRNAs, lack of tissue specificity, methodological, technical, or analytical reproducibility, harmonization of miRNA isolation and quantification methods, the use of standard operating procedures, and the availability of automated and standardized assays to improve reproducibility between independent studies limit bench-to-bedside translation of the miRNA biomarkers for clinical applications. Here I review recent findings on miRNAs in pancreatic cancer pathogenesis and their potential as diagnostic, prognostic, and predictive markers.
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Affiliation(s)
- Attila A. Seyhan
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA;
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI 02912, USA
- Legorreta Cancer Center, Brown University, Providence, RI 02912, USA
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Wei L, Sun J, Wang X, Huang Y, Huang L, Han L, Zheng Y, Xu Y, Zhang N, Yang M. Noncoding RNAs: an emerging modulator of drug resistance in pancreatic cancer. Front Cell Dev Biol 2023; 11:1226639. [PMID: 37560164 PMCID: PMC10407809 DOI: 10.3389/fcell.2023.1226639] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 07/17/2023] [Indexed: 08/11/2023] Open
Abstract
Pancreatic cancer is the eighth leading cause of cancer-related deaths worldwide. Chemotherapy including gemcitabine, 5-fluorouracil, adriamycin and cisplatin, immunotherapy with immune checkpoint inhibitors and targeted therapy have been demonstrated to significantly improve prognosis of pancreatic cancer patients with advanced diseases. However, most patients developed drug resistance to these therapeutic agents, which leading to shortened patient survival. The detailed molecular mechanisms contributing to pancreatic cancer drug resistance remain largely unclear. The growing evidences have shown that noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), are involved in pancreatic cancer pathogenesis and development of drug resistance. In the present review, we systematically summarized the new insight on of various miRNAs, lncRNAs and circRNAs on drug resistance of pancreatic cancer. These results demonstrated that targeting the tumor-specific ncRNA may provide novel options for pancreatic cancer treatments.
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Affiliation(s)
- Ling Wei
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Jujie Sun
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Xingwu Wang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yizhou Huang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Linying Huang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Linyu Han
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yanxiu Zheng
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yuan Xu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Nasha Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
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Anoop TM, Basu PK, Chandramohan K, Thomas A, Manoj S. Evolving utility of exosomes in pancreatic cancer management. World J Methodol 2023; 13:46-58. [PMID: 37456979 PMCID: PMC10348087 DOI: 10.5662/wjm.v13.i3.46] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/02/2023] [Accepted: 05/31/2023] [Indexed: 06/20/2023] Open
Abstract
Despite the development of newer oncological treatment, the survival of patients with pancreatic cancer (PC) remains poor. Recent studies have identified exosomes as essential mediators of intercellular communications and play a vital role in tumor initiation, metastasis and chemoresistance. Thus, the utility of liquid biopsies using exosomes in PC management can be used for early detection, diagnosis, monitoring as well as drug delivery vehicles for cancer therapy. This review summarizes the function, and clinical applications of exosomes in cancers as minimally invasive liquid biomarker in diagnostic, prognostic and therapeutic roles.
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Affiliation(s)
- Thattungal Manoharan Anoop
- Department of Medical Oncology, Regional Cancer Center, Medical College Campus, Thiruvananthapuram 695011, Kerala, India
| | - Palash Kumar Basu
- Department of Avionics, Indian Institute of Space Science & Technology (IIST), Thiruvananthapuram 695547, Kerala, India
| | - K Chandramohan
- Surgical Oncology, Regional Cancer Center, Thiruvananthapuram 695011, Kerala, India
| | - Ajai Thomas
- Department of Medical Oncology, Regional Cancer Center, Medical College Campus, Thiruvananthapuram 695011, Kerala, India
| | - S Manoj
- Department of Medical Oncology, Regional Cancer Center, Medical College Campus, Thiruvananthapuram 695011, Kerala, India
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Funamizu N, Honjo M, Tamura K, Sakamoto K, Ogawa K, Takada Y. microRNAs Associated with Gemcitabine Resistance via EMT, TME, and Drug Metabolism in Pancreatic Cancer. Cancers (Basel) 2023; 15:1230. [PMID: 36831572 PMCID: PMC9953943 DOI: 10.3390/cancers15041230] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/13/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
Despite extensive research, pancreatic cancer remains a lethal disease with an extremely poor prognosis. The difficulty in early detection and chemoresistance to therapeutic agents are major clinical concerns. To improve prognosis, novel biomarkers, and therapeutic strategies for chemoresistance are urgently needed. microRNAs (miRNAs) play important roles in the development, progression, and metastasis of several cancers. During the last few decades, the association between pancreatic cancer and miRNAs has been extensively elucidated, with several miRNAs found to be correlated with patient prognosis. Moreover, recent evidence has revealed that miRNAs are intimately involved in gemcitabine sensitivity and resistance through epithelial-to-mesenchymal transition, the tumor microenvironment, and drug metabolism. Gemcitabine is the gold standard drug for pancreatic cancer treatment, but gemcitabine resistance develops easily after chemotherapy initiation. Therefore, in this review, we summarize the gemcitabine resistance mechanisms associated with aberrantly expressed miRNAs in pancreatic cancer, especially focusing on the mechanisms associated with epithelial-to-mesenchymal transition, the tumor microenvironment, and metabolism. This novel evidence of gemcitabine resistance will drive further research to elucidate the mechanisms of chemoresistance and improve patient outcomes.
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Affiliation(s)
- Naotake Funamizu
- Department of Hepatobiliary Pancreatic and Transplantation Surgery, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
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Gökçen Demiray A, Demiray A, Yaren A, Yapar Taşköylü B, Gököz Doğu G, Değirmencioğlu S, Çakıroğlu U, Özhan N, Karan C, Çakan Demirel B, Doğan T, Özdemir M. Evaluation of Serum microRNA Let-7c and Let-7d as Predictive Biomarkers for Metastatic Pancreatic Cancer. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2022; 33:696-703. [PMID: 35943151 PMCID: PMC9524463 DOI: 10.5152/tjg.2022.21829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 12/13/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND First-line treatments for metastatic pancreatic cancer are chemotherapy regimens consisting of 5-fluorouracil or gemcitabine; however, there are no biomarkers to help determine which patients might benefit from which treatment regimens. We aimed to show that microRNAs let-7c and 7d can be used as independent predictive biomarkers for metastatic pancreatic cancer. METHODS A total of 55 patients who had first-line chemotherapy with FOLFIRINOX or gemcitabine+capecitabine were included. Patients were divided into groups based on let-7c and let-7d levels and chemotherapy treatment as let-7c-7d high FOLFIRINOX, let7c-7d high gemcitabine+capecitabine, let-7c-7d low FOLFIRINOX, and let-7c-7d low gemcitabine+capecitabine. Blood samples were taken from patients before chemotherapy for microRNA let-7c and 7d analysis. MicroRNA isolation was performed using a miRNeasy Serum/Plasma Kit and identified using spectrophotometric measurements. After isolation, microRNA was converted to cDNA using a microRNA cDNA Synthesis Kit with poly (A) polymerase tailing. The expression of microRNA was examined using quantitative real-time polymerase chain reaction. RESULTS The overall survival of patients who received FOLFIRINOX treatment with a high let-7c-7d level was statistically significantly longer than those who received gemcitabine+capecitabine with a high let-7c-7d level. In addition, patients with low let-7c expression receiving FOLFIRINOX progressed significantly 2.104 times earlier than patients with high let-7c expression receiving FOLFIRINOX. CONCLUSION The serum MicroRNA let-7c level was found to be an independent predictive biomarker in the FOLFIRINOX treatment group.
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Affiliation(s)
- Atike Gökçen Demiray
- Department of Medical Oncology, Pamukkale University Faculty of Medicine, Denizli, Turkey
| | - Aydın Demiray
- Department of Medical Genetics, Pamukkale University Faculty of Medicine, Denizli, Turkey
| | - Arzu Yaren
- Department of Medical Oncology, Pamukkale University Faculty of Medicine, Denizli, Turkey
| | - Burcu Yapar Taşköylü
- Department of Medical Oncology, Pamukkale University Faculty of Medicine, Denizli, Turkey
| | - Gamze Gököz Doğu
- Department of Medical Oncology, Pamukkale University Faculty of Medicine, Denizli, Turkey
| | - Serkan Değirmencioğlu
- Department of Medical Oncology, Pamukkale University Faculty of Medicine, Denizli, Turkey
| | - Umut Çakıroğlu
- Department of Medical Oncology, Pamukkale University Faculty of Medicine, Denizli, Turkey
| | - Nail Özhan
- Department of Medical Oncology, Pamukkale University Faculty of Medicine, Denizli, Turkey
| | - Canan Karan
- Department of Medical Oncology, Pamukkale University Faculty of Medicine, Denizli, Turkey
| | - Burçin Çakan Demirel
- Department of Medical Oncology, Pamukkale University Faculty of Medicine, Denizli, Turkey
| | - Tolga Doğan
- Department of Medical Oncology, Pamukkale University Faculty of Medicine, Denizli, Turkey
- Department of Medical Genetics, Pamukkale University Faculty of Medicine, Denizli, Turkey
| | - Melek Özdemir
- Department of Medical Oncology, Pamukkale University Faculty of Medicine, Denizli, Turkey
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Merz V, Mangiameli D, Zecchetto C, Quinzii A, Pietrobono S, Messina C, Casalino S, Gaule M, Pesoni C, Vitale P, Trentin C, Frisinghelli M, Caffo O, Melisi D. Predictive Biomarkers for a Personalized Approach in Resectable Pancreatic Cancer. Front Surg 2022; 9:866173. [PMID: 35599791 PMCID: PMC9114435 DOI: 10.3389/fsurg.2022.866173] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 03/25/2022] [Indexed: 12/15/2022] Open
Abstract
The mainstay treatment for patients with immediate resectable pancreatic cancer remains upfront surgery, which represents the only potentially curative strategy. Nevertheless, the majority of patients surgically resected for pancreatic cancer experiences disease relapse, even when a combination adjuvant therapy is offered. Therefore, aiming at improving disease free survival and overall survival of these patients, there is an increasing interest in evaluating the activity and efficacy of neoadjuvant and perioperative treatments. In this view, it is of utmost importance to find biomarkers able to select patients who may benefit from a preoperative therapy rather than upfront surgical resection. Defined genomic alterations and a dynamic inflammatory microenvironment are the major culprits for disease recurrence and resistance to chemotherapeutic treatments in pancreatic cancer patients. Signal transduction pathways or tumor immune microenvironment could predict early recurrence and response to chemotherapy. In the last decade, distinct molecular subtypes of pancreatic cancer have been described, laying the bases to a tailored therapeutic approach, started firstly in the treatment of advanced disease. Patients with homologous repair deficiency, in particular with mutant germline BRCA genes, represent the first subgroup demonstrating to benefit from specific therapies. A fraction of patients with pancreatic cancer could take advantage of genome sequencing with the aim of identifying possible targetable mutations. These genomic driven strategies could be even more relevant in a potentially curative setting. In this review, we outline putative predictive markers that could help in the next future in tailoring the best therapeutic strategy for pancreatic cancer patients with a potentially curable disease.
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Affiliation(s)
- Valeria Merz
- Medical Oncology Unit, Santa Chiara Hospital, Trento, Italy
- Digestive Molecular Clinical Oncology Research Unit, Università degli Studi di Verona, Verona, Italy
| | - Domenico Mangiameli
- Digestive Molecular Clinical Oncology Research Unit, Università degli Studi di Verona, Verona, Italy
| | - Camilla Zecchetto
- Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Alberto Quinzii
- Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Silvia Pietrobono
- Digestive Molecular Clinical Oncology Research Unit, Università degli Studi di Verona, Verona, Italy
| | | | - Simona Casalino
- Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Marina Gaule
- Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Camilla Pesoni
- Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | | | - Chiara Trentin
- Medical Oncology Unit, Santa Chiara Hospital, Trento, Italy
| | | | - Orazio Caffo
- Medical Oncology Unit, Santa Chiara Hospital, Trento, Italy
| | - Davide Melisi
- Digestive Molecular Clinical Oncology Research Unit, Università degli Studi di Verona, Verona, Italy
- Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
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11
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Distinct Response of Circulating microRNAs to the Treatment of Pancreatic Cancer Xenografts with FGFR and ALK Kinase Inhibitors. Cancers (Basel) 2022; 14:cancers14061517. [PMID: 35326668 PMCID: PMC8945909 DOI: 10.3390/cancers14061517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 03/12/2022] [Indexed: 11/16/2022] Open
Abstract
Pancreatic adenocarcinoma is typically detected at a late stage and thus shows only limited sensitivity to treatment, making it one of the deadliest malignancies. In this study, we evaluate changes in microRNA (miR) patterns in peripheral blood as a potential readout of treatment responses of pancreatic cancer to inhibitors that target tumor-stroma interactions. Mice with pancreatic cancer cell (COLO357PL) xenografts were treated with inhibitors of either fibroblast growth factor receptor kinase (FGFR; PD173074) or anaplastic lymphoma kinase receptor (ALK; TAE684). While both treatments inhibited tumor angiogenesis, signal transduction, and mitogenesis to a similar extent, they resulted in distinct changes in circulating miR signatures. Comparison of the miR pattern in the tumor versus that in circulation showed that the inhibitors can be distinguished by their differential impact on tumor-derived miRs as well as host-derived circulating miRs. Distinct signatures that include circulating miR-1 and miR-22 are associated with the efficacy of ALK and FGFR inhibition, respectively. We propose that monitoring changes in circulating miR profiles can provide an early signature of treatment response or resistance to pathway-targeted drugs, and thus provide a non-invasive measurement to rapidly assess the efficacy of candidate therapies.
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van der Sijde F, Homs MYV, van Bekkum ML, van den Bosch TPP, Bosscha K, Besselink MG, Bonsing BA, de Groot JWB, Karsten TM, Groot Koerkamp B, Haberkorn BCM, Luelmo SAC, Mekenkamp LJM, Mustafa DAM, Wilmink JW, van Eijck CHJ, Vietsch EE, on behalf of the Dutch Pancreatic Cancer Group. Serum miR-373-3p and miR-194-5p Are Associated with Early Tumor Progression during FOLFIRINOX Treatment in Pancreatic Cancer Patients: A Prospective Multicenter Study. Int J Mol Sci 2021; 22:ijms222010902. [PMID: 34681562 PMCID: PMC8535910 DOI: 10.3390/ijms222010902] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 09/28/2021] [Accepted: 10/05/2021] [Indexed: 11/16/2022] Open
Abstract
In this study, we explored the predictive value of serum microRNA (miRNA) expression for early tumor progression during FOLFIRINOX chemotherapy and its association with overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC). A total of 132 PDAC patients of all disease stages were included in this study, of whom 25% showed progressive disease during FOLFIRINOX according to the RECIST criteria. MiRNA expression was analyzed in serum collected before the start and after one cycle of chemotherapy. In the discovery cohort (n = 12), a 352-miRNA RT-qPCR panel was used. In the validation cohorts (total n = 120), miRNA expression was detected using individual RT-qPCR miRNA primers. Before the start of FOLFIRINOX, serum miR-373-3p expression was higher in patients with progressive disease compared to patients with disease control after FOLFIRINOX (Log2 fold difference (FD) 0.88, p = 0.006). MiR-194-5p expression after one cycle of FOLFIRINOX was lower in patients with progressive disease (Log2 FD -0.29, p = 0.044). Both miRNAs were predictors of early tumor progression in a multivariable model including disease stage and baseline CA19-9 level (miR-373-3p odds ratio (OR) 3.99, 95% CI 1.10-14.49; miR-194-5p OR 0.91, 95% CI 0.83-0.99). MiR-373-3p and miR-194-5p did not show an association with OS after adjustment for disease stage, baseline CA19-9, and chemotherapy response. In conclusion, high serum miR-373-3p before the start and low serum miR-194-5p after one cycle are associated with early tumor progression during FOLFIRINOX.
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Affiliation(s)
- Fleur van der Sijde
- Department of Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands; (F.v.d.S.); (B.G.K.); (E.E.V.)
| | - Marjolein Y. V. Homs
- Department of Medical Oncology, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands;
| | - Marlies L. van Bekkum
- Department of Medical Oncology, Reinier de Graaf Gasthuis, 2625 AD Delft, The Netherlands;
| | - Thierry P. P. van den Bosch
- Department of Pathology, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands;
| | - Koop Bosscha
- Department of Surgery, Jeroen Bosch Hospital, 5223 GZ ‘s Hertogenbosch, The Netherlands;
| | - Marc G. Besselink
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Bert A. Bonsing
- Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
| | | | - Thomas M. Karsten
- Department of Surgery, Onze Lieve Vrouwe Gasthuis, 1061 AE Amsterdam, The Netherlands;
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands; (F.v.d.S.); (B.G.K.); (E.E.V.)
| | | | - Saskia A. C. Luelmo
- Department of Medical Oncology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
| | - Leonie J. M. Mekenkamp
- Department of Medical Oncology, Medisch Spectrum Twente, 7512 KZ Enschede, The Netherlands;
| | - Dana A. M. Mustafa
- Tumor Immuno-Pathology Laboratory, Department of Pathology, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands;
| | - Johanna W. Wilmink
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Casper H. J. van Eijck
- Department of Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands; (F.v.d.S.); (B.G.K.); (E.E.V.)
- Correspondence: ; Tel.: +31-107-033-854
| | - Eveline E. Vietsch
- Department of Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands; (F.v.d.S.); (B.G.K.); (E.E.V.)
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Smolarz B, Durczyński A, Romanowicz H, Hogendorf P. The Role of microRNA in Pancreatic Cancer. Biomedicines 2021; 9:biomedicines9101322. [PMID: 34680441 PMCID: PMC8533140 DOI: 10.3390/biomedicines9101322] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/18/2021] [Accepted: 09/22/2021] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are small ribonucleic acid molecules that play a key role in regulating gene expression. The increasing number of studies undertaken on the functioning of microRNAs in the tumor formation clearly indicates their important potential in oncological therapy. Pancreatic cancer is one of the deadliest cancers. The expression of miRNAs released into the bloodstream appears to be a good indicator of progression and evaluation of the aggressiveness of pancreatic cancer, as indicated by studies. The work reviewed the latest literature on the importance of miRNAs for pancreatic cancer development.
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Affiliation(s)
- Beata Smolarz
- Laboratory of Cancer Genetics, Department of Pathology, Polish Mother’s Memorial Hospital Research Institute, 93-338 Lodz, Poland;
- Correspondence: ; Tel.: +48-42-271-1290
| | - Adam Durczyński
- Department of General and Transplant Surgery, N. Barlicki Memorial Clinical Hospital, Medical University of Lodz, 90-153 Lodz, Poland; (A.D.); (P.H.)
| | - Hanna Romanowicz
- Laboratory of Cancer Genetics, Department of Pathology, Polish Mother’s Memorial Hospital Research Institute, 93-338 Lodz, Poland;
| | - Piotr Hogendorf
- Department of General and Transplant Surgery, N. Barlicki Memorial Clinical Hospital, Medical University of Lodz, 90-153 Lodz, Poland; (A.D.); (P.H.)
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Mitochondrial DNA and MitomiR Variations in Pancreatic Cancer: Potential Diagnostic and Prognostic Biomarkers. Int J Mol Sci 2021; 22:ijms22189692. [PMID: 34575852 PMCID: PMC8470532 DOI: 10.3390/ijms22189692] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 08/31/2021] [Accepted: 09/04/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer is an aggressive disease with poor prognosis. Only about 15-20% of patients diagnosed with pancreatic cancer can undergo surgical resection, while the remaining 80% are diagnosed with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). In these cases, chemotherapy and radiotherapy only confer marginal survival benefit. Recent progress has been made in understanding the pathobiology of pancreatic cancer, with a particular effort in discovering new diagnostic and prognostic biomarkers, novel therapeutic targets, and biomarkers that can predict response to chemo- and/or radiotherapy. Mitochondria have become a focus in pancreatic cancer research due to their roles as powerhouses of the cell, important subcellular biosynthetic factories, and crucial determinants of cell survival and response to chemotherapy. Changes in the mitochondrial genome (mtDNA) have been implicated in chemoresistance and metastatic progression in some cancer types. There is also growing evidence that changes in microRNAs that regulate the expression of mtDNA-encoded mitochondrial proteins (mitomiRs) or nuclear-encoded mitochondrial proteins (mitochondria-related miRs) could serve as diagnostic and prognostic cancer biomarkers. This review discusses the current knowledge on the clinical significance of changes of mtDNA, mitomiRs, and mitochondria-related miRs in pancreatic cancer and their potential role as predictors of cancer risk, as diagnostic and prognostic biomarkers, and as molecular targets for personalized cancer therapy.
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15
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Mortoglou M, Tabin ZK, Arisan ED, Kocher HM, Uysal-Onganer P. Non-coding RNAs in pancreatic ductal adenocarcinoma: New approaches for better diagnosis and therapy. Transl Oncol 2021; 14:101090. [PMID: 33831655 PMCID: PMC8042452 DOI: 10.1016/j.tranon.2021.101090] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/14/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with a 5-year survival rate less than 8%, which has remained unchanged over the last 50 years. Early detection is particularly difficult due to the lack of disease-specific symptoms and a reliable biomarker. Multimodality treatment including chemotherapy, radiotherapy (used sparingly) and surgery has become the standard of care for patients with PDAC. Carbohydrate antigen 19-9 (CA 19-9) is the most common diagnostic biomarker; however, it is not specific enough especially for asymptomatic patients. Non-coding RNAs are often deregulated in human malignancies and shown to be involved in cancer-related mechanisms such as cell growth, differentiation, and cell death. Several micro, long non-coding and circular RNAs have been reported to date which are involved in PDAC. Aim of this review is to discuss the roles and functions of non-coding RNAs in diagnosis and treatments of PDAC.
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Affiliation(s)
- Maria Mortoglou
- Cancer Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK.
| | - Zoey Kathleen Tabin
- Cancer Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK.
| | - E Damla Arisan
- Institution of Biotechnology, Gebze Technical University, Gebze, Turkey.
| | - Hemant M Kocher
- Centre for Tumour Biology, Barts Cancer Institute-a CRUK Centre of Excellence, Queen Mary University London, London EC1M 6BQ, UK.
| | - Pinar Uysal-Onganer
- Cancer Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK.
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16
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CircWAC induces chemotherapeutic resistance in triple-negative breast cancer by targeting miR-142, upregulating WWP1 and activating the PI3K/AKT pathway. Mol Cancer 2021; 20:43. [PMID: 33648498 PMCID: PMC7919093 DOI: 10.1186/s12943-021-01332-8] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 02/09/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Chemotherapeutic resistance is the main cause of clinical treatment failure and poor prognosis in triple-negative breast cancer (TNBC). There is no research on chemotherapeutic resistance in TNBC from the perspective of circular RNAs (circRNAs). METHODS TNBC-related circRNAs were identified based on the GSE101124 dataset. Quantitative reverse transcription PCR was used to detect the expression level of circWAC in TNBC cells and tissues. Then, in vitro and in vivo functional experiments were performed to evaluate the effects of circWAC in TNBC. RESULTS CircWAC was highly expressed in TNBC and was associated with worse TNBC patient prognosis. Subsequently, it was verified that downregulation of circWAC can increase the sensitivity of TNBC cells to paclitaxel (PTX) in vitro and in vivo. The expression of miR-142 was negatively correlated with circWAC in TNBC. The interaction between circWAC and miR-142 in TNBC cells was confirmed by RNA immunoprecipitation assays, luciferase reporter assays, pulldown assays, and fluorescence in situ hybridization. Mechanistically, circWAC acted as a miR-142 sponge to relieve the repressive effect of miR-142 on its target WWP1. In addition, the overall survival of TNBC patients with high expression of miR-142 was significantly better than that of patients with low expression of miR-142, and these results were verified in public databases. MiR-142 regulated the expression of WWP1 and the activity of the PI3K/AKT pathway. It was confirmed that WWP1 is highly expressed in TNBC and that the prognosis of patients with high WWP1 expression is poor. CONCLUSIONS CircWAC/miR-142/WWP1 form a competing endogenous RNA (ceRNA) network to regulate PI3K/AKT signaling activity in TNBC cells and affect the chemosensitivity of cells.
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17
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Chen YL, Liu XL, Li L. Prognostic value of low microRNA-34a expression in human gastrointestinal cancer: a systematic review and meta-analysis. BMC Cancer 2021; 21:63. [PMID: 33446130 PMCID: PMC7807881 DOI: 10.1186/s12885-020-07751-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 12/18/2020] [Indexed: 11/10/2022] Open
Abstract
Background Mounting evidence shows that microRNA-34a (miR-34a) is involved in cancer prognosis. Therefore, we summarize the predictive role of miR-34a for survival in patients with gastrointestinal cancers (GICs). Methods All eligible studies were found by searching PubMed, Web of Science and EMBASE, and survival results were extracted. Then, the hazard ratio (HR) with the corresponding 95% confidence interval (CI) was calculated to evaluate the prognostic role of miR-34a in GICs. The association between miR-34a expression and clinicopathological characteristics was estimated by odds ratios (ORs) and 95% CIs. Results A total of 20 studies were included in this meta-analysis. For overall survival (OS), lower miR-34a expression could probably predict poorer outcome in GICs, with a pooled HR of 1.86 (95% CI: 1.52–2.28, P < 0.01). For disease-free survival (DFS), progression-free survival (PFS), and recurrence-free survival (RFS), lower miR-34a expression was related to worse DFS/PFS/RFS with a pooled HR of 1.86 (95% CI: 1.31–2.63, P < 0.01). A significant relation of differentiation/TNM stage/lymphatic metastasis and the expression level of miR-34a was identified. Conclusion This meta-analysis revealed that lower miR-34a expression is significantly connected with worse OS and DFS/PFS/RFS in GIC patients. In addition, the miR-34a expression level is relatively lower in patients with lymph node metastasis than in patients without lymph node metastasis, and decreased miR-34a expression levels are linked to poor tumour differentiation and late TNM stage. MiR-34a may become a new factor for the prognosis prediction and progression of GICs. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-020-07751-y.
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Affiliation(s)
- Yan-Ling Chen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 899 Ping Hai Road, Suzhou, 215006, Jiangsu, China
| | - Xiao-Lin Liu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 899 Ping Hai Road, Suzhou, 215006, Jiangsu, China.
| | - Ling Li
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 899 Ping Hai Road, Suzhou, 215006, Jiangsu, China.
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18
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Ideno N, Mori Y, Nakamura M, Ohtsuka T. Early Detection of Pancreatic Cancer: Role of Biomarkers in Pancreatic Fluid Samples. Diagnostics (Basel) 2020; 10:diagnostics10121056. [PMID: 33291257 PMCID: PMC7762187 DOI: 10.3390/diagnostics10121056] [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: 10/30/2020] [Revised: 12/03/2020] [Accepted: 12/04/2020] [Indexed: 12/28/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths worldwide. Most patients with PDAC present with symptomatic, surgically unresectable disease. Therefore, the establishment of strategies for the early detection is urgently needed. Molecular biomarkers might be useful in various phases of a strategy to identify high-risk individuals in the general population and to detect high-risk lesions during intense surveillance programs combined with imaging modalities. However, the low sensitivity and specificity of biomarkers currently available for PDAC, such as carbohydrate 19-9 (CA19-9), contribute to the late diagnosis of this deadly disease. Although almost all classes of biomarker assays have been studied, most of them are used in the context of symptomatic diseases. Compared to other body fluids, pancreatic juice and duodenal fluid are better sources of DNA, RNA, proteins, and exosomes derived from neoplastic cells and have the potential to increase the sensitivity/specificity of these biomarkers. The number of studies using duodenal fluid with or without secretin stimulation for DNA/protein marker tests have been increasing because of the less-invasiveness in comparison to pancreatic juice collection by endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). Genomic analyses have been very well-studied, and based on PDAC progression model, mutations detected in pancreatic juice/duodenal fluid seem to indicate the presence of microscopic precursors and high-grade dysplasia/invasive cancer. In addition to known proteins overexpressed both in precursors and PDACs, such as CEA and S100P, comprehensive proteomic analysis of pancreatic juice from patients with PDAC identified many proteins which were not previously described. A novel technique to isolate exosomes from pancreatic juice was recently invented and identification of exosomal microRNA’s 21 and 155 could be biomarkers for diagnosis of PDAC. Since many studies have explored biomarkers in fluid samples containing pancreatic juice and reported excellent diagnostic accuracy, we need to discuss how these biomarker assays can be validated and utilized in the strategy of early detection of PDAC.
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Affiliation(s)
- Noboru Ideno
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; (N.I.); (Y.M.); (M.N.)
| | - Yasuhisa Mori
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; (N.I.); (Y.M.); (M.N.)
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; (N.I.); (Y.M.); (M.N.)
| | - Takao Ohtsuka
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890-8520, Japan
- Correspondence: ; Tel.: +81-99-275-5361
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Lin Z, Lu S, Xie X, Yi X, Huang H. Noncoding RNAs in drug-resistant pancreatic cancer: A review. Biomed Pharmacother 2020; 131:110768. [PMID: 33152930 DOI: 10.1016/j.biopha.2020.110768] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 09/17/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is the fourth-leading cause of cancer-related deaths and is expected to be the second-leading cause of cancer-related deaths in Europe and the United States by 2030. The high fatality rate of pancreatic cancer is ascribed to untimely diagnosis, early metastasis and limited responses to both chemotherapy and radiotherapy. Although gemcitabine, 5-fluorouracil and some other drugs can profoundly improve patient prognosis, most pancreatic cancer patients eventually develop drug resistance, leading to poor clinical outcomes. The underlying mechanisms of pancreatic cancer drug resistance are complicated and inconclusive. Interestingly, accumulating evidence has demonstrated that different noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), play a crucial role in pancreatic cancer resistance to chemotherapy reagents. In this paper, we systematically summarize the molecular mechanism underlying the influence of ncRNAs on the generation and development of drug resistance in pancreatic cancer and discuss the potential role of ncRNAs as prognostic markers and new therapeutic targets for pancreatic cancer.
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Affiliation(s)
- Zhengjun Lin
- Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, China.
| | - Shiyao Lu
- Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, China.
| | - Xubin Xie
- Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, China.
| | - Xuyang Yi
- Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, China.
| | - He Huang
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, China; State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, School of Pre-Clinical Medicine/ Second Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang, 830011, China.
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20
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Non-coding RNA biomarkers in pancreatic ductal adenocarcinoma. Semin Cancer Biol 2020; 75:153-168. [PMID: 33049362 DOI: 10.1016/j.semcancer.2020.10.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/20/2020] [Accepted: 10/02/2020] [Indexed: 12/13/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, which is usually diagnosed at an advanced stage. The late disease diagnosis, the limited availability of effective therapeutic interventions and lack of robust diagnostic biomarkers, are some of the primary reasons for the dismal 5-year survival rates (∼8%) in patients with PDAC. The pancreatic cancer develops through accumulation of a series of genomic and epigenomic alterations which lead to the transformation of normal pancreatic epithelium into an invasive carcinoma - a process that can take up to 15-20 years to develop, from the occurrence of first initiating mutational event. These facts highlight a unique window of opportunity for the earlier detection of PDAC, which could allow timely disease interception and improvement in the overall survival outcomes in patients suffering from this fatal malignancy. Non-coding RNAs (ncRNAs) have been recognized to play a central role in PDAC pathogenesis and are emerging as attractive candidates for biomarker development in various cancers, including PDAC. More specifically, the ncRNAs play a pivotal role in PDAC biology as they affect tumor growth, migration, and invasion by regulating cellular processes including cell cycle, apoptosis, and epithelial-mesenchymal transition. In this review, we focus on three types of well-established ncRNAs - microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) - and discuss their potential as diagnostic, prognostic and predictive biomarkers in PDAC.
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21
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Hidalgo-Sastre A, Lubeseder-Martellato C, Engleitner T, Steiger K, Zhong S, Desztics J, Öllinger R, Rad R, Schmid RM, Hermeking H, Siveke JT, von Figura G. Mir34a constrains pancreatic carcinogenesis. Sci Rep 2020; 10:9654. [PMID: 32541781 PMCID: PMC7295749 DOI: 10.1038/s41598-020-66561-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 05/18/2020] [Indexed: 12/19/2022] Open
Abstract
Several studies have shown that over 70 different microRNAs are aberrantly expressed in pancreatic ductal adenocarcinoma (PDAC), affecting proliferation, apoptosis, metabolism, EMT and metastasis. The most important genetic alterations driving PDAC are a constitutive active mutation of the oncogene Kras and loss of function of the tumour suppressor Tp53 gene. Since the MicroRNA 34a (Mir34a) is a direct target of Tp53 it may critically contribute to the suppression of PDAC. Mir34a is epigenetically silenced in numerous cancers, including PDAC, where Mir34a down-regulation has been associated with poor patient prognosis. To determine whether Mir34a represents a suppressor of PDAC formation we generated an in vivo PDAC-mouse model harbouring pancreas-specific loss of Mir34a (KrasG12D; Mir34aΔ/Δ). Histological analysis of KrasG12D; Mir34aΔ/Δ mice revealed an accelerated formation of pre-neoplastic lesions and a faster PDAC development, compared to KrasG12D controls. Here we show that the accelerated phenotype is driven by an early up-regulation of the pro-inflammatory cytokines TNFA and IL6 in normal acinar cells and accompanied by the recruitment of immune cells. Our results imply that Mir34a restrains PDAC development by modulating the immune microenvironment of PDAC, thus defining Mir34a restauration as a potential therapeutic strategy for inhibition of PDAC development.
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Affiliation(s)
- Ana Hidalgo-Sastre
- Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany
| | | | - Thomas Engleitner
- Institute of Molecular Oncology and Functional Genomics, Department of Medicine II and TranslaTUM Cancer Center, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Katja Steiger
- Institute of Pathology, Technical University of Munich, Munich, Germany
| | - Suyang Zhong
- Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany
| | - Judit Desztics
- Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany
| | - Rupert Öllinger
- Institute of Molecular Oncology and Functional Genomics, Department of Medicine II and TranslaTUM Cancer Center, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Roland Rad
- Institute of Molecular Oncology and Functional Genomics, Department of Medicine II and TranslaTUM Cancer Center, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Roland M Schmid
- Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany
| | - Heiko Hermeking
- Experimental and Molecular Pathology, Institute of Pathology, Ludwig Maximilian University Munich, Munich, Germany.,German Cancer Consortium (DKTK), Partner site Munich, Munich, Germany
| | - Jens T Siveke
- Institute for Developmental Cancer Therapeutics, West German Cancer Center, University Hospital Essen, Essen, Germany.,Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany.,German Cancer Consortium (DKTK), Partner site Essen, Essen, Germany
| | - Guido von Figura
- Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany.
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22
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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.
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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
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23
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Bai L, Liang J, Li L, Li E. Downregulation of MiD49 contributes to tumor growth and metastasis of human pancreatic cancer. Oncol Rep 2020; 43:1208-1220. [PMID: 32323835 PMCID: PMC7057927 DOI: 10.3892/or.2020.7499] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 01/09/2020] [Indexed: 12/11/2022] Open
Abstract
Changes in mitochondrial morphology by dysregulated mitochondrial fission‑fusion proteins have been increasingly recognized as a hallmark of cancer. MiD49 (mitochondrial dynamics protein of 49 kDa) is a newly identified mitochondrial fission protein involved in the dynamic regulation of mitochondrial morphology. However, the expression pattern and biological functions of MiD49 in human cancers remain largely unexplored, especially in pancreatic cancer (PC). In the present study, the expression and clinical significance of MiD49 was firstly determined by RT‑qPCR and western blot analyses in PC cell lines and tumor tissues. In addition, the biologic functions of MiD49 in PC cell growth and metastasis were investigated using gain‑ and loss‑of‑function assays both in vitro and in vivo. Moreover, the underlying mechanisms by which MiD49 regulates PC cell growth and metastasis were further explored. Our results showed that MiD49 was markedly downregulated in both PC cell lines and human PC specimens. Forced expression of MiD49 suppressed PC cell growth and metastasis both in vitro and in vivo, while knockdown of MiD49 exhibited the opposite effect. Mechanistic exploration demonstrated that the tumor‑suppressive effect of MiD49 was mediated by decreased mitochondrial fission and subsequent reduced ROS production in PC cells. Our findings suggest a critical tumor‑suppressive role played by MiD49 in pancreatic cancer.
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Affiliation(s)
- Lu Bai
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Jing Liang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Lihong Li
- Department of Geriatric Respiration, Xi'an No. 1 Hospital, Xi'an, Shaanxi 710002, P.R. China
| | - Enxiao Li
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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24
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Capula M, Mantini G, Funel N, Giovannetti E. New avenues in pancreatic cancer: exploiting microRNAs as predictive biomarkers and new approaches to target aberrant metabolism. Expert Rev Clin Pharmacol 2019; 12:1081-1090. [PMID: 31721608 DOI: 10.1080/17512433.2019.1693256] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Accepted: 11/12/2019] [Indexed: 12/19/2022]
Abstract
Introduction: Most pancreatic cancer patients are diagnosed at advanced-stages and first-line regimens (FOLFIRINOX and gemcitabine/nab-paclitaxel) provide limited survival advantage and are associated with considerable toxicities. In this grim scenario, novel treatments and biomarkers are warranted.Areas covered: MicroRNAs (miRNAs) emerged as biomarkers for cancer prognosis and chemoresistance and blood-based miRNAs are being evaluated as indicators of therapeutic activity. Moreover, aberrant metabolism, such as aerobic glycolysis, has been correlated to tumor aggressiveness and poor prognosis. Against this background, innovative approaches to tackle metabolic aberrations are being implemented and glycolytic inhibitors targeting lactate dehydrogenase-A (LDH-A) showed promising effects in preclinical models. A PubMed search was used to compile relevant publications until February 2019.Expert opinion: Analysis of tissue/circulating miRNA might improve selection for optimal treatment regimens. For instance, miR-181a modulation seems to predict response to FOLFIRINOX. However, we need further studies to validate predictive miRNA profiles, as well as to exploit miRNAs for treatment-tailoring. Several miRNAs have also a key role in regulating metabolic aberrations. Since preliminary evidence supports the development of new agents targeting these aberrations, such as LDH-A inhibitors, the identification of biomarkers for these treatments, including the above-mentioned miRNAs, should shorten the gap between preclinical studies and personalized therapies.
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Affiliation(s)
- Mjriam Capula
- Cancer Pharmacology Lab, AIRC Start-Up Unit, Fondazione Pisa per la Scienza Pisa, Pisa, Italy
| | - Giulia Mantini
- Cancer Pharmacology Lab, AIRC Start-Up Unit, Fondazione Pisa per la Scienza Pisa, Pisa, Italy
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Niccola Funel
- Cancer Pharmacology Lab, AIRC Start-Up Unit, Fondazione Pisa per la Scienza Pisa, Pisa, Italy
| | - Elisa Giovannetti
- Cancer Pharmacology Lab, AIRC Start-Up Unit, Fondazione Pisa per la Scienza Pisa, Pisa, Italy
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands
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25
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Daoud AZ, Mulholland EJ, Cole G, McCarthy HO. MicroRNAs in Pancreatic Cancer: biomarkers, prognostic, and therapeutic modulators. BMC Cancer 2019; 19:1130. [PMID: 31752758 PMCID: PMC6868851 DOI: 10.1186/s12885-019-6284-y] [Citation(s) in RCA: 159] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 10/24/2019] [Indexed: 02/06/2023] Open
Abstract
A severe lack of early diagnosis coupled with resistance to most available therapeutic options renders pancreatic cancer as a major clinical concern. The limited efficacy of current treatments necessitates the development of novel therapeutic strategies that are based on an understanding of the molecular mechanisms involved in pancreatic cancer progression. MicroRNAs (miRNAs) are non-coding small RNAs that regulate the expression of multiple proteins in the post-translation process and thus have promise as biomarkers, prognostic agents, and as advanced pancreatic therapies. Profiling of deregulated miRNAs in pancreatic cancer can correlate to diagnosis, indicate optimal treatment and predict response to therapy. Furthermore, understanding the main effector genes in pancreatic cancer along with downstream pathways can identify possible miRNAs as therapeutic candidates. Additionally, obstacles to the translation of miRNAs into the clinic are also considered. Distinct miRNA expression profiles can correlate to stages of malignant pancreatic disease, and hold potential as biomarkers, prognostic markers and clinical targets. However, a limited understanding and validation of the specific role of such miRNAs stunts clinical application. Target prediction using algorithms provides a wide range of possible targets, but these miRNAs still require validation through pre-clinical studies to determine the knock-on genetic effects.
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Affiliation(s)
- Afra Z Daoud
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Northern Ireland, BT9 7BL, UK
| | - Eoghan J Mulholland
- Gastrointestinal Stem Cell Biology Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK
| | - Grace Cole
- Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, V5Z 1L3, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, V6T 2B5, Canada
| | - Helen O McCarthy
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Northern Ireland, BT9 7BL, UK.
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26
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Tesfaye AA, Azmi AS, Philip PA. miRNA and Gene Expression in Pancreatic Ductal Adenocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:58-70. [PMID: 30558723 DOI: 10.1016/j.ajpath.2018.10.005] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 09/20/2018] [Accepted: 10/04/2018] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease that is mostly diagnosed late in the course of the illness. Unlike other cancers in which measurable successes have been achieved with traditional chemotherapy, targeted therapy, and, recently, immunotherapy, PDAC has proved to be poorly responsive to these treatments, with only marginal to modest incremental benefits using conventional cytotoxic therapy. There is, therefore, a great unmet need to develop better therapies based on improved understanding of biology and identification of predictive and prognostic biomarkers that would guide therapy. miRNAs are small noncoding RNAs that regulate the expression of some key genes by targeting their 3'-untranslated mRNA region. Aberrant expression of miRNAs has been linked to the development of various malignancies, including PDAC. A series of miRNAs have been identified as potential tools for early diagnosis, prediction of treatment response, and prognosis of patients with PDAC. In this review, we present a summary of the miRNAs that have been studied in PDAC in the context of disease biology.
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Affiliation(s)
- Anteneh A Tesfaye
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
| | - Asfar S Azmi
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Philip A Philip
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan; Department of Pharmacology, School of Medicine, Wayne State University, Detroit, Michigan
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27
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Yao R, Xu L, Wei B, Qian Z, Wang J, Hui H, Sun Y. miR-142-5p regulates pancreatic cancer cell proliferation and apoptosis by regulation of RAP1A. Pathol Res Pract 2019; 215:152416. [PMID: 31047726 DOI: 10.1016/j.prp.2019.04.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 03/27/2019] [Accepted: 04/16/2019] [Indexed: 12/17/2022]
Abstract
Pancreatic cancer, one of the fatal and aggressive malignancies, leads the sixth cancer-associated death in China. microRNAs are believed to exert function in the diagnosis and treatment of pancreatic cancer. In the present study, we firstly found that miR-142-5p was downregulated in pancreatic cancer tumor tissues while Ras-related protein Rap-1 A (RAP1A) was upregulated compared with para-carcinoma non-tumor tissues. Then, we found that RAP1A could be a putative target gene of miR-142-5p by bioinformatics tool TargetScan. Furthermore, we conducted luciferase reporter assay, RT-qPCR, western blot and correlation analysis to demonstrate that miR-142-5p could negatively regulate RAP1A expression by binding to its 3'UTR. In addition, cell-counting kit 8 (CCK-8) and flow cytometry assays certified that miR-142-5p overexpression may inhibit pancreatic cancer cell proliferation but promote cell apoptosis; while the variation could be reversed by co-transfected with pcDNA3.1-RAP1A. Finally, miR-142-5p overexpression downregulated p-ERK1/2, phosphate p38 mitogen-activated protein kinases (p-p38); however, the variation induced by miR-142-5p mimic could be reversed by co-transfected with pcDNA3.1-RAP1A. In conclusion, our findings indicate that targeting miR-142-5p may provide a novel strategy for the treatment of pancreatic cancer.
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Affiliation(s)
- Rong Yao
- Department of Medical Oncology, The Affiliated Huaian NO.1 People's Hospital of Nanjing Medical University, Huaian, 223300, Jiangsu, China
| | - Lijuan Xu
- Department of Medical Oncology, The Affiliated Huaian NO.1 People's Hospital of Nanjing Medical University, Huaian, 223300, Jiangsu, China
| | - Bin Wei
- Department of Medical Oncology, The Affiliated Huaian NO.1 People's Hospital of Nanjing Medical University, Huaian, 223300, Jiangsu, China
| | - Zhaoye Qian
- Department of Medical Oncology, The Affiliated Huaian NO.1 People's Hospital of Nanjing Medical University, Huaian, 223300, Jiangsu, China
| | - Jiru Wang
- Department of Medical Oncology, The Affiliated Huaian NO.1 People's Hospital of Nanjing Medical University, Huaian, 223300, Jiangsu, China
| | - Hongxia Hui
- Department of Medical Oncology, The Affiliated Huaian NO.1 People's Hospital of Nanjing Medical University, Huaian, 223300, Jiangsu, China
| | - Yuan Sun
- Department of Medical Oncology, The Affiliated Huaian NO.1 People's Hospital of Nanjing Medical University, Huaian, 223300, Jiangsu, China.
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28
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Hu W, Liu Q, Pan J, Sui Z. MiR-373-3p enhances the chemosensitivity of gemcitabine through cell cycle pathway by targeting CCND2 in pancreatic carcinoma cells. Biomed Pharmacother 2018; 105:887-898. [PMID: 30021382 DOI: 10.1016/j.biopha.2018.05.091] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Revised: 05/19/2018] [Accepted: 05/20/2018] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE This study aimed to detect the expression of miR-373-3p and CCND2 in gemcitabine-resistance pancreatic carcinoma (PC) cells, investigate the relationship between miR-373-3p and CCND2, and explore their effects on PC propagation, migration, invasion and apoptosis. METHODS R software was applied for analyzing differentially expressed genes (DEGs) in cell samples. The potential biological pathway was determined by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, based on R software. The gemcitabine-resistance PC cells were screened out using MTT assay, and they were applied in the next experiments. MiR-373-3p and CCND2 expression in GEM-PANC-1 cells were measured by qRT-PCR. After transfection, the expression of CCND2 protein was examined via western blot assay. Cells viability and apoptosis were confirmed by MTT proliferation assay and Flow cytometry, whereas cells migration and invasion were analyzed by transwell assay. The targeting relationship between miR-373-3p and CCND2 was identified by dual-luciferase reporter assay. RESULTS MiR-373-3p was found to be low expressed in GEM-PANC-1 cells while CCND2 was highly expressed in GEM-PANC-1 cells. MiR-373-3p negatively regulated CCND2 expression through KEGG_Cell_Cycle_Signaling_Pathway. The targeted relationship between miR-373-3p and CCND2 could be verified using dual luciferase reporter assay. MTT proliferation assay, transwell assay and Annexin V assay demonstrated that miR-373-3p suppressed GEM-PANC-1 cells propagation and invasion and promoted cell apoptosis, while CCND2 showed totally reverse effects compared with miR-373-3p. All the results suggested that miR-373-3p could enhance the chemosensitivity of GEM-PANC-1 cells by regulating CCND2. CONCLUSION MiR-373-3p inhibited cell propagation, migration and invasion and boosted apoptosis in gemcitabine resistance pancreatic carcinoma cells by targeting CCND2.
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Affiliation(s)
- Wenjie Hu
- Department of Pharmacy, Qingdao Mental Health Center, Qingdao, 266034, Shandong, China
| | - Qilong Liu
- Department of Pharmacy, Qingdao Mental Health Center, Qingdao, 266034, Shandong, China
| | - Jie Pan
- Department of Pharmacy, Qingdao Mental Health Center, Qingdao, 266034, Shandong, China
| | - Zheng Sui
- Department of Pharmacy, Qingdao Mental Health Center, Qingdao, 266034, Shandong, China.
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29
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Zhang QA, Yang XH, Chen D, Yan X, Jing FC, Liu HQ, Zhang R. miR-34 increases in vitro PANC-1 cell sensitivity to gemcitabine via targeting Slug/PUMA. Cancer Biomark 2018; 21:755-762. [PMID: 29355113 DOI: 10.3233/cbm-170289] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
miR-34 was deregulated in tumor tissues compared with corresponding noncancerous tissue samples. Furthermore, miR-34 may contribute to cancer-stromal interaction associated with cancer progression. However, whether miR-34 could decrease chemoresistance of cancer cells to chemotherapeutic agent remains unclear. In our study, we examined whether overexpression of miR-34 could sensitize gemcitabine -mediated apoptosis in human pancreatic cancer PANC-1 cells. We found that miR-34 markedly induced gemcitabine -mediated apoptosis in PANC-1 cells. miR-34 induced down-regulation of Slug expression and upregulation of p53 up-regulated modulator of apoptosis (PUMA) expression. The over-expression of Slug or downregulation of PUMA by Slug cDNA or PUMA siRNA transfection markedly blocked miR-34-induced gemcitabine sensitization. Furthermore, miR-34 induced PUMA expression by downregulation of Slug. Taken together, our study demonstrates that miR-34 enhances sensitization against gemcitabine-mediated apoptosis through the down-regulation of Slug expression, and up-regulation of Slug-dependent PUMA expression.
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Affiliation(s)
- Qing-An Zhang
- Department of Clinical Laboratory, The Central Hospital of Linyi, Yishui, Shandong, China.,Department of Clinical Laboratory, The Central Hospital of Linyi, Yishui, Shandong, China
| | - Xu-Hai Yang
- Department of Oncology, Yantaiyuhuangding Hospital, Yantai, Shandong, China
| | - Dong Chen
- Department of General Surgery, The Affiliated Hospital of Qingdao University, Qingdao,Shandong, China
| | - Xiang Yan
- Department of Oncology, Yantaiyuhuangding Hospital, Yantai, Shandong, China
| | - Fu-Chun Jing
- Department of Gastroenterology, Taian Central Hospital, Taian, Shandong, China
| | - Hong-Qian Liu
- Department Pharmacy, The Central Hospital of Linyi, Yishui, Shandong, China
| | - Ronghua Zhang
- Department of Clinical Laboratory, The Central Hospital of Linyi, Yishui, Shandong, China
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30
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Zhang H, Li M, Xu X. MicroRNA-204 attenuates the migration and invasion of pancreatic cancer cells by targeting ZEB1/EMT axis. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:3802-3811. [PMID: 31949767 PMCID: PMC6962869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 04/13/2018] [Indexed: 06/10/2023]
Abstract
Pancreatic cancer (PC) is one of the most aggressive malignancies worldwide. MicroRNAs play an important role in the development and progression of PC, but little is known about the role of miR-204 in PC. In this study, we revealed that miR-204 was downregulated in PC tissues and cell lines, and its expression was closely correlated with aggressive clinicopathological features of PC patients. Both gain- and loss-of-function studies showed that miR-204 overexpression inhibits the proliferation, migration and invasion of PC cells, whereas miR-204 knockdown had the opposite effects. Using mouse models, we found that miR-204 overexpression suppressed PC tumor growth in vivo. Moreover, miR-204 overexpression notably suppressed epithelial-mesenchymal transition (EMT) of PC cells, and through bioinformatics analysis and dual-luciferase reporter assay, ZEB1, a critical EMT promoter, was identified to be the functional target of miR-204 in PC cells. Rescue experiments further showed that ZEB1 overexpression abrogated the effects of miR-204 in PC cells. Collectively, these findings demonstrated the tumor suppressive role of miR-204 in PC through the ZEB1/EMT axis, therefore providing a novel therapeutic target for human PC.
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Affiliation(s)
- Huihan Zhang
- Department of General Surgery II, Lanzhou University Second HospitalLanzhou 730030, Gansu Province, China
| | - Mingqiao Li
- Beijing RDFZ Chaoyang Branch SchoolBeijing 100028, China
| | - Xiaodong Xu
- Department of General Surgery II, Lanzhou University Second HospitalLanzhou 730030, Gansu Province, China
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31
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Wu Y, Wei J, Ming Y, Chen Z, Yu J, Mao R, Chen H, Zhou G, Fan Y. Orchestrating a biomarker panel with lncRNAs and mRNAs for predicting survival in pancreatic ductal adenocarcinoma. J Cell Biochem 2018; 119:7696-7706. [PMID: 29923223 DOI: 10.1002/jcb.27119] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 05/04/2018] [Indexed: 12/15/2022]
Abstract
The low survival of patients with pancreatic ductal adenocarcinoma (PDAC) makes the treatment of this disease one of the most challenging task in modern medicine. Here, by mining a large-scale cancer genome atlas data set of pancreatic cancer tissues, we identified 21 long noncoding RNAs (lncRNAs) that significantly associated with overall survival in patients with PDAC (P < .01). Further analysis revealed that 8 lncRNAs turned out to be independently correlated with patients' overall survival, and the risk score could be calculated based on their expression. To obtain a better predicting power, we integrated lncRNA data with a total of 410 differently expressed messenger RNAs (mRNAs) screened from PDAC and normal tissues in gene expression omnibus (GEO) database. The integration resulted in a much better panel including 8 lncRNAs (RP3.470B24.5, CTA.941F9.9, RP11.557H15.3, LINC00960, AP000479.1, LINC00635, LINC00636, and AC073133.1) and 8 mRNAs (DHRS9, ONECUT1, OR8D4, MT1M, TCN1, MMP9, DPYSL3, and TTN) to predict prognosis. A functional evaluation showed that these lncRNAs might play roles in pancreatic secretion, cell adhesion, and proteolysis. Using normal and pancreatic cancer cell lines, we confirmed that a majority of identified lncRNAs and mRNAs showed altered expressions in pancreatic cancer cells. Especially, LINC01589, LINC00960, TCN1, and MT1M showed a profoundly increased expression in pancreatic cancer cells, which suggests their potentially important role in pancreatic cancer. The results of our work indicate that lncRNAs have vital roles in PADC and provide new insights to integrate multiple kinds of markers in clinical practices.
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Affiliation(s)
- Yingcheng Wu
- Basic Medical Research Center, School of Medicine, Nantong University, Nantong, China
| | - Jinhuan Wei
- Basic Medical Research Center, School of Medicine, Nantong University, Nantong, China
| | - Yue Ming
- Department of Immunology, School of Medicine, Nantong University, Nantong, China
| | - Zhanghao Chen
- Department of Computer Science, New York University, New York, USA.,Department of Computer Science, New York University Shanghai, Shanghai, China
| | - Jinzhong Yu
- Department of Computer Science, New York University, New York, USA.,Department of Computer Science, New York University Shanghai, Shanghai, China
| | - Renfang Mao
- Department of Pathophysiology, School of Medicine, Nantong University, Nantong, China
| | - Hao Chen
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| | - Guoxiong Zhou
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| | - Yihui Fan
- Basic Medical Research Center, School of Medicine, Nantong University, Nantong, China.,Department of Immunology, School of Medicine, Nantong University, Nantong, China
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32
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Yadav DK, Bai X, Yadav RK, Singh A, Li G, Ma T, Chen W, Liang T. Liquid biopsy in pancreatic cancer: the beginning of a new era. Oncotarget 2018; 9:26900-26933. [PMID: 29928492 PMCID: PMC6003564 DOI: 10.18632/oncotarget.24809] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Accepted: 02/25/2018] [Indexed: 12/21/2022] Open
Abstract
With dismal survival rate pancreatic cancer remains one of the most aggressive and devastating malignancy. Predominantly, due to the absence of a dependable methodology for early identification and limited therapeutic options for advanced disease. However, it takes over 17 years to develop pancreatic cancer from initiation of mutation to metastatic cancer; therefore, if diagnosed early; it may increase overall survival dramatically, thus, providing a window of opportunity for early detection. Recently, genomic expression analysis defined 4 subtypes of pancreatic cancer based on mutated genes. Hence, we need simple and standard, minimally invasive test that can monitor those altered genes or their associated pathways in time for the success of precision medicine, and liquid biopsy seems to be one answer to all these questions. Again, liquid biopsy has an ability to pair with genomic tests. Additionally, liquid biopsy based development of circulating tumor cells derived xenografts, 3D organoids system, real-time monitoring of genetic mutations by circulating tumor DNA and exosome as the targeted drug delivery vehicle holds lots of potential for the treatment and cure of pancreatic cancer. At present, diagnosis of pancreatic cancer is frantically done on the premise of CA19-9 and radiological features only, which doesn't give a picture of genetic mutations and epigenetic alteration involved. In this manner, the current diagnostic paradigm for pancreatic cancer diagnosis experiences low diagnostic accuracy. This review article discusses the current state of liquid biopsy in pancreatic cancer as diagnostic and therapeutic tools and future perspectives of research in the light of circulating tumor cells, circulating tumor DNA and exosomes.
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Affiliation(s)
- Dipesh Kumar Yadav
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Rajesh Kumar Yadav
- Department of Pharmacology, Gandaki Medical College, Tribhuwan University, Institute of Medicine, Pokhara 33700, Nepal
| | - Alina Singh
- Department of Surgery, Bir Hospital, National Academy of Medical Science, Kanti Path, Kathmandu 44600, Nepal
| | - Guogang Li
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Tao Ma
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Wei Chen
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
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Evert J, Pathak S, Sun XF, Zhang H. A Study on Effect of Oxaliplatin in MicroRNA Expression in Human Colon Cancer. J Cancer 2018; 9:2046-2053. [PMID: 29896290 PMCID: PMC5995942 DOI: 10.7150/jca.24474] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 03/14/2018] [Indexed: 12/26/2022] Open
Abstract
Colorectal cancer is a commonly diagnosed malignancy and also the major cause of death worldwide. Chemotherapy is the primary therapy for advanced colorectal cancer. Although oxaliplatin has potential effect in colorectal cancer therapy, the molecular mechanisms involved in its cytotoxic effects are not well elucidated. This study outlines the regulatory effects of oxaliplatin on miRNAs expression in colon cancer cells and correlates it with the changing microRNA expression with p53 and p73 expression status in cells. HCT116p53+/+ and HCT116p53-/- cells were exposed to oxaliplatin, and the cellular viability was determined by XTT. p73 was knocked down using siRNA and the tumor cells were then treated with oxaliplatin. The expression profile of 384 miRNAs was determined by TaqMan® human miRNA array and calculated by the ∆∆Ct method. Cellular viability was found to decrease after the treatment with oxaliplatin in a dose-dependent manner. The wild-type p53 cells were found to be more sensitive than the null-p53 derivatives. A selective set of miRNAs were either up-regulated or down-regulated in response to the oxaliplatin treatment with a presumable role of p53 and p73 proteins. The miRNAs expression is known to influence the pharmacodynamic mechanisms of oxaliplatin and these effects have been observed to be regulated by p53 and p73. Our results may therefore provide more evidence for identifying a suitable biomarker for the diagnosis of colon cancer.
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Affiliation(s)
- Jasmine Evert
- School of Medical Sciences, Örebro University, SE 70182 Örebro, Sweden
| | - Surajit Pathak
- Department of Oncology and Department of Clinical and Experimental Medicine, SE-581 83, Linköping University, Linköping, Sweden.,Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Kelambakkam, India, 603 103
| | - Xiao-Feng Sun
- Department of Oncology and Department of Clinical and Experimental Medicine, SE-581 83, Linköping University, Linköping, Sweden
| | - Hong Zhang
- School of Medical Sciences, Örebro University, SE 70182 Örebro, Sweden
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Guo S, Fesler A, Wang H, Ju J. microRNA based prognostic biomarkers in pancreatic Cancer. Biomark Res 2018; 6:18. [PMID: 29942514 PMCID: PMC5963153 DOI: 10.1186/s40364-018-0131-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 05/07/2018] [Indexed: 02/07/2023] Open
Abstract
Despite tremendous research efforts focused on diagnosis and treatment, pancreatic ductal adenocarcinoma remains the third leading cause of cancer-related death in the United States, with a 5-year overall survival rate of less than 5%. Although resistance is rather complex, emerging evidence has demonstrated that epigenetic alterations (e.g. miRNA) have important roles in PDAC progression as well as resistance to therapy. Certain miRNAs have been identified as potential prognostic biomarkers in PDAC. In this review, we summarize the recent developments in miRNA research related to PDAC therapeutic resistance mechanisms and the potential of miRNAs as prognostic biomarkers for future clinical management of PDAC.
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Affiliation(s)
- Shixiang Guo
- 1Stony Brook University, Stony Brook, New York, 11794 USA.,2Third Military Medical University, Chongqing, 400038 People's Republic of China
| | - Andrew Fesler
- 1Stony Brook University, Stony Brook, New York, 11794 USA
| | - Huaizhi Wang
- 2Third Military Medical University, Chongqing, 400038 People's Republic of China
| | - Jingfang Ju
- 1Stony Brook University, Stony Brook, New York, 11794 USA
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35
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Ren L, Yu Y. The role of miRNAs in the diagnosis, chemoresistance, and prognosis of pancreatic ductal adenocarcinoma. Ther Clin Risk Manag 2018; 14:179-187. [PMID: 29416345 PMCID: PMC5790163 DOI: 10.2147/tcrm.s154226] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a very challenging malignancy with late presentation, metastatic potential, chemoresistance, and poor prognosis. Therefore, there is an urgent need for novel diagnostic and prognostic biomarkers. miRNAs are small noncoding RNAs that regulate the expression of multitude number of genes. Aberrant expression of miRNAs has been linked to the development of various malignancies, including PDAC. A series of miRNAs have been defined as holding promise for early diagnostics, as indicators of therapy resistance, and even as markers for prognosis in PDAC patients. In this review, we summarize the current knowledge on the role of miRNAs in diagnosis, chemoresistance, and prognosis in PDAC patients.
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Affiliation(s)
- Le Ren
- Department of Gastroenterology, Affiliated Provincial Hospital, Anhui Medical University, Hefei, China
| | - Yue Yu
- Department of Gastroenterology, Affiliated Provincial Hospital, Anhui Medical University, Hefei, China
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36
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Gibori H, Eliyahu S, Krivitsky A, Ben-Shushan D, Epshtein Y, Tiram G, Blau R, Ofek P, Lee JS, Ruppin E, Landsman L, Barshack I, Golan T, Merquiol E, Blum G, Satchi-Fainaro R. Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer. Nat Commun 2018; 9:16. [PMID: 29295989 PMCID: PMC5750234 DOI: 10.1038/s41467-017-02283-9] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 11/17/2017] [Indexed: 12/19/2022] Open
Abstract
The heterogeneity of pancreatic ductal adenocarcinoma (PDAC) suggests that successful treatment might rely on simultaneous targeting of multiple genes, which can be achieved by RNA interference-based therapeutic strategies. Here we show a potent combination of microRNA and siRNA delivered by an efficient nanocarrier to PDAC tumors. Using proteomic-microRNA profiles and survival data of PDAC patients from TCGA, we found a novel signature for prolonged survival. Accordingly, we used a microRNA-mimic to increase miR-34a together with siRNA to silence PLK1 oncogene. For in vivo dual-targeting of this combination, we developed a biodegradable amphiphilic polyglutamate amine polymeric nanocarrier (APA). APA-miRNA-siRNA polyplexes systemically administered to orthotopically inoculated PDAC-bearing mice showed no toxicity and accumulated at the tumor, resulting in an enhanced antitumor effect due to inhibition of MYC oncogene, a common target of both miR-34a and PLK1. Taken together, our findings warrant this unique combined polyplex's potential as a novel nanotherapeutic for PDAC.
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Affiliation(s)
- Hadas Gibori
- Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel
| | - Shay Eliyahu
- Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel
| | - Adva Krivitsky
- Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel
| | - Dikla Ben-Shushan
- Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel
| | - Yana Epshtein
- Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel
| | - Galia Tiram
- Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel
| | - Rachel Blau
- Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel
| | - Paula Ofek
- Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel
| | - Joo Sang Lee
- Department of Computer Science and Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, 20742, USA
| | - Eytan Ruppin
- Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel
- Department of Computer Science and Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, 20742, USA
- Blavatnik School of Computer Sciences, Tel Aviv University, Tel Aviv, 69978, Israel
| | - Limor Landsman
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel
| | - Iris Barshack
- Department of Pathology, Sheba Medical Center, Tel Hashomer, 52621, Israel
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel
| | - Talia Golan
- Department of Pathology, Sheba Medical Center, Tel Hashomer, 52621, Israel
| | - Emmanuelle Merquiol
- The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Ein Kerem Campus, The Hebrew University, Jerusalem, Israel
| | - Galia Blum
- The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Ein Kerem Campus, The Hebrew University, Jerusalem, Israel
| | - Ronit Satchi-Fainaro
- Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
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Yu G, Jia B, Cheng Y, Zhou L, Qian B, Liu Z, Wang Y. MicroRNA-429 sensitizes pancreatic cancer cells to gemcitabine through regulation of PDCD4. Am J Transl Res 2017; 9:5048-5055. [PMID: 29218103 PMCID: PMC5714789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Accepted: 09/05/2017] [Indexed: 06/07/2023]
Abstract
One of the features for pancreatic cancer is that it is often resistant to chemotherapy treatment, which is one of the major hindrances in the treatment of this malignancy. Previous studies indicated that the microRNAs (miRNAs) could mediate resistance of tumor cells to chemotherapy drug in the cancer progression. In the present study, we are aimed to examine whether microRNA-429 was involved in mediating the chemo-resistance of pancreatic cancer cells to gemcitabine. Firstly, a gemcitabine-resistant pancreatic cancer cell line (SW1990/GZ) derived from cell line (SW1990) was constructed and found to possess a decreased expression of miR-429 when it is compared to the original cell line. Ectopic expression of miR-429 in SW1990/GZ increased the cellular sensibility to the treatment of gemcitabine, which is coincided with increased expression of PDCD4. As a tumor suppressor, we found that PDCD4 knockdown in SW1990/GZ cells increased its own chemo-resistance to GZ, which indicates PDCD4 also play a regulative role on the GZ-resistance in the pancreatic cancer. To further confirm the function of miR-429 and PDCD4 in gemcitabine-resistant pancreatic cancer, a xenograft nude mouse model was utilized to examine whether miR-429 can restore treatment response of gemcitabine in gemcitabine-resistant xenografts, while protein levels of PDCD4 were up-regulated. Together with those results, these findings collectively provided that miR-429 could enhancer GZ sensitivity via regulation of PDCD4 expression in pancreatic cancer cells, which may offer a novel therapeutic target for the chemotherapy resistance in pancreatic cancer.
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Affiliation(s)
- Gang Yu
- Department of General Surgery, The Second Hospital of Anhui Medical UniversityHefei 230601, China
| | - Benli Jia
- Department of General Surgery, The Second Hospital of Anhui Medical UniversityHefei 230601, China
| | - Yunsheng Cheng
- Department of General Surgery, The Second Hospital of Anhui Medical UniversityHefei 230601, China
| | - Lianbang Zhou
- Department of General Surgery, The Second Hospital of Anhui Medical UniversityHefei 230601, China
| | - Bo Qian
- Department of General Surgery, The Second Hospital of Anhui Medical UniversityHefei 230601, China
| | - Zhining Liu
- Department of General Surgery, The Second Hospital of Anhui Medical UniversityHefei 230601, China
| | - Yong Wang
- Department of General Surgery, The Second Hospital of Anhui Medical UniversityHefei 230601, China
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Dhayat SA, Mardin WA, Senninger N. Comment on: MicroRNA Expression as a Predictive Marker for Gemcitabine Response After Surgical Resection of Pancreatic Cancer. Ann Surg Oncol 2017; 24:669. [PMID: 29094249 DOI: 10.1245/s10434-017-6207-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Indexed: 11/18/2022]
Affiliation(s)
- Sameer A Dhayat
- Department of General and Visceral Surgery, University Hospital of Muenster, Muenster, Germany.
| | - Wolf Arif Mardin
- Department of General and Visceral Surgery, University Hospital of Muenster, Muenster, Germany
| | - Norbert Senninger
- Department of General and Visceral Surgery, University Hospital of Muenster, Muenster, Germany
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39
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Ye ZH, Wen DY, Cai XY, Liang L, Wu PR, Qin H, Yang H, He Y, Chen G. The protective value of miR-204-5p for prognosis and its potential gene network in various malignancies: a comprehensive exploration based on RNA-seq high-throughput data and bioinformatics. Oncotarget 2017; 8:104960-104980. [PMID: 29285225 PMCID: PMC5739612 DOI: 10.18632/oncotarget.21950] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 09/23/2017] [Indexed: 01/26/2023] Open
Abstract
Purpose The prognostic role of miR-204-5p (previous ID: miR-204) is varied and inconclusive in diverse types of malignant neoplasm. Therefore, the purposes of the study comprehensively explore the overall prognostic role of miR-204-5p based on high-throughput microRNA sequencing data, and to investigate the potential role of miR-204-5p via bioinformatics approaches. Materials and Methods The data of microRNA sequencing and survival were downloaded from The Cancer Genome Atlas (TCGA), and the prognostic value of miR-204-5p was analyzed by using Kaplan-Meier and univariate cox regressions. Then a meta-analysis was conducted with all TCGA data and relevant studies collected from literature. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. The prospective molecular mechanism of miR-204-5p was also assessed at a functional level with Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-to-protein interactions (PPI) network. Results From TCGA data, the prognostic value of miR-204-5p obviously varied among 20 types of cancers. The pooled HR was 0.928 (95% CI: 0.774-1.113, P = 0.386, 6203 cases of malignancies). For the meta-analysis based on 15 studies from literature, the pooled HR was 0.420 (95% CI: 0.306-0.576, P < 0.001, 1783 cases of malignancies) for overall survival (OS). Furthermore, the combined HR from both TCGA and literature was 0.708 (95% CI: 0.600-0.834, P < 0.001, 7986 cases of malignancies). Subgroup analyses revealed that miR-204-5p could act as a prognostic marker in cancers of respiratory system and digestive system. Functional analysis was conducted on genes predicted as targets (n = 2057) after the overlay genes from six out of twelve software were extracted. Two significant KEGG pathways were enriched (hsa04360: Axon guidance and hsa04722: Neurotrophin signaling pathway). PPI network revealed some hub genes/proteins (CDC42, SOS1, PIK3R1, MAPK1, PLCG1, ESR1, MAPK11, and AR). Conclusions The current study demonstrates that over-expression of miR-204-5p could be a protective factor for a certain group of cancers. Clinically, the low miR-204-5p level could gain a predictive value for a poor survival in cancers of respiratory system and digestive system. The detailed molecular mechanisms of miR-204-5p remain to be verified.
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Affiliation(s)
- Zhi-Hua Ye
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Dong-Yue Wen
- Department of Ultrasonography, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xiao-Yong Cai
- Department of General Surgery, First Affiliated Hospital of Guangxi Medical University (West), Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Liang Liang
- Department of General Surgery, First Affiliated Hospital of Guangxi Medical University (West), Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Pei-Rong Wu
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Hui Qin
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Hong Yang
- Department of Ultrasonography, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Yun He
- Department of Ultrasonography, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
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40
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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.
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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
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41
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The underlying mechanisms of non-coding RNAs in the chemoresistance of pancreatic cancer. Cancer Lett 2017; 397:94-102. [PMID: 28254409 DOI: 10.1016/j.canlet.2017.02.020] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 02/08/2017] [Accepted: 02/21/2017] [Indexed: 12/21/2022]
Abstract
Pancreatic cancer, which is often asymptomatic, is currently one of the most common causes of cancer-related death. This phenomenon is most likely due to a lack of early diagnosis, a high metastasis rate and a disappointing chemotherapy outcome. Thus, improving treatment outcomes by overcoming chemotherapy resistance may be a useful strategy in pancreatic cancer. Various underlying mechanisms involved in the chemoresistance of pancreatic cancer have been investigated. Notably, non-coding RNAs (ncRNAs), especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play a pivotal role in regulating sensitivity to chemotherapy in pancreatic cancer. In this review, we highlight recent evidence regarding the role of miRNAs and lncRNAs in the chemoresistance of pancreatic cancer, including their expression levels, targets, biological functions and the regulation of chemoresistance, and discuss the potential clinical application of miRNAs and lncRNAs in the treatment of pancreatic cancer.
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42
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Li CH, Xiao Z, Tong JHM, To KF, Fang X, Cheng ASL, Chen Y. EZH2 coupled with HOTAIR to silence MicroRNA-34a by the induction of heterochromatin formation in human pancreatic ductal adenocarcinoma. Int J Cancer 2017; 140:120-129. [DOI: 10.1002/ijc.30414] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Affiliation(s)
- Chi-Han Li
- School of Biomedical Sciences, Faculty of Medicine; The Chinese University of Hong Kong; Shatin NT Hong Kong
| | - Zhangang Xiao
- School of Biomedical Sciences, Faculty of Medicine; The Chinese University of Hong Kong; Shatin NT Hong Kong
| | - Joanna Hung-Man Tong
- Department of Anatomical and Cellular Pathology; Prince of Wales Hospital, The Chinese University of Hong Kong; Shatin Hong Kong
| | - Ka-Fai To
- Department of Anatomical and Cellular Pathology; Prince of Wales Hospital, The Chinese University of Hong Kong; Shatin Hong Kong
| | - Xiangdong Fang
- CAS Key Laboratory of Genome Sciences and Information; Beijing Institute of Genomics, Chinese Academy of Sciences; Beijing China
| | - Alfred SL Cheng
- School of Biomedical Sciences, Faculty of Medicine; The Chinese University of Hong Kong; Shatin NT Hong Kong
- State Key Laboratory of Digestive Diseases; The Chinese University of Hong Kong; Shatin NT Hong Kong
| | - Yangchao Chen
- School of Biomedical Sciences, Faculty of Medicine; The Chinese University of Hong Kong; Shatin NT Hong Kong
- State Key Laboratory of Digestive Diseases; The Chinese University of Hong Kong; Shatin NT Hong Kong
- Shenzhen Research Institute, The Chinese University of Hong Kong; Shenzhen China
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43
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Namkung J, Kwon W, Choi Y, Yi SG, Han S, Kang MJ, Kim SW, Park T, Jang JY. Molecular subtypes of pancreatic cancer based on miRNA expression profiles have independent prognostic value. J Gastroenterol Hepatol 2016; 31:1160-7. [PMID: 26644397 DOI: 10.1111/jgh.13253] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Revised: 10/15/2015] [Accepted: 11/16/2015] [Indexed: 01/17/2023]
Abstract
BACKGROUND AND AIM Altered microRNAs (miRNA) expression, a typical feature of many cancers, is reportedly associated with prognosis according to several studies. Although numerous studies on miRNAs in pancreatic ductal adenocarcinoma have also attempted to identify prognostic biomarkers, more large-scale clinical studies are needed to establish the clinical significance of the results. Present study aimed to identify prognosis-related molecular subtypes of primary pancreas tumors using miRNA expression profiling. METHODS Expression profiles of 1733 miRNAs were obtained by using microarray analysis of 104 pancreatic tumors of Korean patients. To detect subgroups informative in predicting the patient's prognosis, we applied unsupervised clustering methods and then analyzed the association of the molecular subgroups with survival time. Then, we constructed a classifier to predict the subgroup using penalized regression models. RESULTS We have determined three pancreatic ductal adenocarcinoma tumor subtypes associated with prognosis based on miRNA expression profiles. These subtypes showed significantly different survival time for patients with the same clinical conditions. This demonstrates that our prognostic molecular subgroup has independent prognostic utility. The molecular subtypes can be predicted with a classifier of 19 miRNAs. Of the 19 signature miRNAs, miR-106b-star, miR-324-3p, and miR-615 were related to a p53 canonical pathway, and miR-324, miR-145-5p, miR-26b-5p, and miR-574-3p were related to a Cox-2 centered pathway. CONCLUSIONS Our prognostic molecular subtypes demonstrated that miRNA profiles could be used as prognostic markers. Additionally, we have constructed a classifier that may be used to determine the molecular subgroup of new patient sample data. Further studies are needed for validation.
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Affiliation(s)
- Junghyun Namkung
- Bioinformatics Tech. Lab, Healthcare group, Future Technology R&D Division, SK Telecom, Co., Seoul, Korea
| | - Wooil Kwon
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yonwhan Choi
- Bioinformatics Tech. Lab, Healthcare group, Future Technology R&D Division, SK Telecom, Co., Seoul, Korea
| | - Sung Gon Yi
- Bioinformatics Tech. Lab, Healthcare group, Future Technology R&D Division, SK Telecom, Co., Seoul, Korea
| | - Sangjo Han
- Bioinformatics Tech. Lab, Healthcare group, Future Technology R&D Division, SK Telecom, Co., Seoul, Korea
| | - Mee Joo Kang
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Sun-Whe Kim
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Taesung Park
- Department of Statistics, Seoul National University, Seoul, Korea
| | - Jin-Young Jang
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Amodu LI, Levy A, Kyaw C, Padmanabhan D, Osman A, Tiwari M, Nicastro J, Coppa G, Molmenti E, Rodriguez Rilo HL. Utility of Exosomes in the Diagnosis and Treatment of Pancreatic Adenocarcinoma. EUROPEAN MEDICAL JOURNAL 2016. [DOI: 10.33590/emj/10313200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/18/2023] Open
Abstract
Pancreatic cancer is the most common lethal cancer, with annual incidence and mortality rates being approximately equal. This dismal prognosis can be attributed to late diagnosis making the cancers unresectable. These cancers respond poorly to chemotherapy and radiation, and surgical resection remains the most effective treatment available. Diagnostic tests that are sensitive, specific, and capable of early detection are urgently needed and would significantly impact upon pancreatic cancer treatment and outcomes. Exosomes, small membrane-bound vesicles which are fairly uniform in size (approximately 30–100 nm in diameter), contain messenger RNA, microRNA (miRNA), and proteins. They are ubiquitous and stable in most body fluids and exosomal miRNAs are also resistant to degradation by RNAses and DNAses. Expression profiles of serum exosomal miRNAs display sensitivity and specificity in the detection of pancreatic adenocarcinoma. Markers of pancreatic cancer-initiating cells are also expressed on serum exosomes. Exosomes exhibit key functions in addition to their distinct structural properties: they are involved in immune system modulation via the transfer of antigenic proteins, and through protease activity they modulate the extracellular environment prior to metastasis. Exosomes are being studied as potent gene delivery tools and dendritic cell exosomes are already used as cancer vaccines. This review focusses on the current state of exosomal research, particularly in relation to their applicability as diagnostic and therapeutic tools for patients with pancreatic adenocarcinoma.
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Affiliation(s)
- Leo I. Amodu
- Center for Diseases of the Pancreas, Department of General Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Hempstead, New York, USA
| | - Asaph Levy
- Center for Diseases of the Pancreas, Department of General Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Hempstead, New York, USA
| | - Crystal Kyaw
- Center for Diseases of the Pancreas, Department of General Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Hempstead, New York, USA
| | - Darshan Padmanabhan
- Center for Diseases of the Pancreas, Department of General Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Hempstead, New York, USA
| | - Alexandra Osman
- Center for Diseases of the Pancreas, Department of General Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Hempstead, New York, USA
| | - Mukesh Tiwari
- Center for Diseases of the Pancreas, Department of General Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Hempstead, New York, USA
| | - Jeffrey Nicastro
- Center for Diseases of the Pancreas, Department of General Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Hempstead, New York, USA
| | - Gene Coppa
- Center for Diseases of the Pancreas, Department of General Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Hempstead, New York, USA
| | - Ernesto Molmenti
- Center for Diseases of the Pancreas, Department of General Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Hempstead, New York, USA
| | - Horacio L. Rodriguez Rilo
- Center for Diseases of the Pancreas, Department of General Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Hempstead, New York, USA
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Garajová I, Le Large TYS, Giovannetti E, Kazemier G, Biasco G, Peters GJ. The Role of MicroRNAs in Resistance to Current Pancreatic Cancer Treatment: Translational Studies and Basic Protocols for Extraction and PCR Analysis. Methods Mol Biol 2016; 1395:163-187. [PMID: 26910074 DOI: 10.1007/978-1-4939-3347-1_10] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a common cause of cancer death and has the worst prognosis of any major malignancy, with less than 5 % of patients alive 5-years after diagnosis. The therapeutic options for metastatic PDAC have changed in the past few years from single agent gemcitabine treatment to combination regimens. Nowadays, FOLFIRINOX or gemcitabine with nab-paclitaxel are new standard combinations in frontline metastatic setting in PDAC patients with good performance status. MicroRNAs (miRNA) are small, noncoding RNA molecules affecting important cellular processes such as inhibition of apoptosis, cell proliferation, epithelial-to-mesenchymal transition (EMT), metastases, and resistance to common cytotoxic and anti-signaling therapy in PDAC. A functional association between miRNAs and chemoresistance has been described for several common therapies. Therefore, in this review, we summarize the current knowledge on the role of miRNAs in the resistance to current anticancer treatment used for patients affected by metastatic PDAC.
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Affiliation(s)
- Ingrid Garajová
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, CCA 1.42, De Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Tessa Y S Le Large
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, CCA 1.42, De Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands
- Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands
| | - Elisa Giovannetti
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, CCA 1.42, De Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands
- Cancer Pharmacology Lab, AIRC Start-Up Unit, University of Pisa, Pisa, Italy
| | - Geert Kazemier
- Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands
| | - Guido Biasco
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Godefridus J Peters
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, CCA 1.42, De Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands.
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SUBRAMANI RAMADEVI, GANGWANI LAXMAN, NANDY SUSHMITABOSE, ARUMUGAM ARUNKUMAR, CHATTOPADHYAY MUNMUN, LAKSHMANASWAMY RAJKUMAR. Emerging roles of microRNAs in pancreatic cancer diagnosis, therapy and prognosis (Review). Int J Oncol 2015; 47:1203-1210. [PMID: 26314882 PMCID: PMC4583517 DOI: 10.3892/ijo.2015.3129] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 07/08/2015] [Indexed: 12/15/2022] Open
Abstract
Pancreatic cancer is one of the leading causes of cancer related death. Increasing incidence and mortality indicates a lack of detection and post diagnostic management of this disease. Recent evidences suggest that, miRNAs are very attractive target molecules that can serve as biomarkers for predicting development and progression of pancreatic cancer. Furthermore, miRNAs are also promising therapeutic targets for pancreatic cancer. The objective of the present review is to discuss the significance of miRNA in pancreatic cancer development, diagnosis, therapy and prognosis. We extracted and compiled the useful information from PubMed database, which satisfied our criteria for analysis of miRNAs in pancreatic cancer diagnosis, therapy and prognosis. A summary of the most important miRNAs known to regulate pancreatic tumorigenesis is provided. The review also provides a collection of evidence that show miRNA profiles of biofluids hold much promise for use as biomarkers to predict and detect development of pancreatic cancer in its early stages. Identification of key miRNA networks in pancreatic cancer will provide long-awaited diagnostic/therapeutic/prognostic tools for early detection, better treatment options, and extended life expectancy and quality of life in PDAC patients.
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Affiliation(s)
- RAMADEVI SUBRAMANI
- Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, 5001 El Paso Drive, El Paso, TX 79905, USA
| | - LAXMAN GANGWANI
- Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, 5001 El Paso Drive, El Paso, TX 79905, USA
| | - SUSHMITA BOSE NANDY
- Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, 5001 El Paso Drive, El Paso, TX 79905, USA
| | - ARUNKUMAR ARUMUGAM
- Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, 5001 El Paso Drive, El Paso, TX 79905, USA
| | - MUNMUN CHATTOPADHYAY
- Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, 5001 El Paso Drive, El Paso, TX 79905, USA
| | - RAJKUMAR LAKSHMANASWAMY
- Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, 5001 El Paso Drive, El Paso, TX 79905, USA
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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]
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Frampton AE, Krell J, Jamieson NB, Gall TMH, Giovannetti E, Funel N, Mato Prado M, Krell D, Habib NA, Castellano L, Jiao LR, Stebbing J. microRNAs with prognostic significance in pancreatic ductal adenocarcinoma: A meta-analysis. Eur J Cancer 2015; 51:1389-1404. [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] [MESH Headings] [Grants] [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.
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Affiliation(s)
- Adam E Frampton
- HPB Surgical Unit, Division of Surgery, Dept. of Surgery & Cancer, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0HS, UK; Division of Oncology, Dept. of Surgery & Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital campus, Du Cane Road, London W12 0NN, UK.
| | - Jonathan Krell
- Division of Oncology, Dept. of Surgery & Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital campus, Du Cane Road, London W12 0NN, UK
| | - Nigel B Jamieson
- Academic Unit of Surgery, Faculty of Medicine, Glasgow Royal Infirmary, Alexandra Parade, University of Glasgow, G31 2ER, UK
| | - Tamara M H Gall
- HPB Surgical Unit, Division of Surgery, Dept. of Surgery & Cancer, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0HS, UK
| | - Elisa Giovannetti
- Dept. of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - Niccola Funel
- Dept. of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
| | - Mireia Mato Prado
- Division of Oncology, Dept. of Surgery & Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital campus, Du Cane Road, London W12 0NN, UK
| | - Daniel Krell
- Dept. of Academic Oncology, Royal Free Hospital, Pond Street, London NW3 2QG, UK
| | - Nagy A Habib
- HPB Surgical Unit, Division of Surgery, Dept. of Surgery & Cancer, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0HS, UK
| | - Leandro Castellano
- Division of Oncology, Dept. of Surgery & Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital campus, Du Cane Road, London W12 0NN, UK
| | - Long R Jiao
- HPB Surgical Unit, Division of Surgery, Dept. of Surgery & Cancer, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0HS, UK
| | - Justin Stebbing
- Division of Oncology, Dept. of Surgery & Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College, Hammersmith Hospital campus, Du Cane Road, London W12 0NN, UK.
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MicroRNAs in Pancreatic Cancer: Involvement in Carcinogenesis and Potential Use for Diagnosis and Prognosis. Gastroenterol Res Pract 2015; 2015:892903. [PMID: 25960741 PMCID: PMC4417562 DOI: 10.1155/2015/892903] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 03/18/2015] [Indexed: 12/21/2022] Open
Abstract
Pancreatic cancer is one of the most fatal malignancies with increasing incidence and high mortality. Possibilities for early diagnosis are limited and there is currently no efficient therapy. Molecular markers that have been introduced into diagnosis and treatment of other solid tumors remain unreciprocated in this disease. Recent discoveries have shown that certain microRNAs (miRNAs) take part in fundamental molecular processes associated with pancreatic cancer initiation and progression including cell cycle, DNA repair, apoptosis, invasivity, and metastasis. The mechanism involves both positive and negative regulation of expression of protooncogenes and tumor suppressor genes. Various miRNAs are expressed at different levels among normal pancreatic tissue, chronic pancreatitis, and pancreatic cancer and may therefore serve as a tool to differentiate chronic pancreatitis from early stages of cancer. Other miRNAs can indicate the probable course of the disease or determine the survival prognosis. In addition, there is a growing interest directed at the understanding of miRNA-induced molecular mechanisms. The possibility of intervention in the molecular mechanisms of miRNAs regulation could begin a new generation of pancreatic cancer therapies. This review summarizes the recent reports describing functions of miRNAs in cellular processes underlying pancreatic cancerogenesis and their utility in diagnosis, survival prognosis, and therapy.
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Identifying microRNA-mRNA regulatory network in gemcitabine-resistant cells derived from human pancreatic cancer cells. Tumour Biol 2015; 36:4525-34. [PMID: 25722110 DOI: 10.1007/s13277-015-3097-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 01/09/2015] [Indexed: 12/19/2022] Open
Abstract
Pancreatic cancer is unresectable in over 80 % of patients owing to difficulty in early diagnosis. Chemotherapy is the most frequently adopted therapy for advanced pancreatic cancer. The development of drug resistance to gemcitabine (GEM), which is always used in standard chemotherapy, often results in therapeutic failure. However, the molecular mechanisms underlying the gemcitabine resistance remain unclear. Therefore, we sought to explore the microRNA-mRNA network that is associated with the development of gemcitabine resistance and to identify molecular targets for overcoming the gemcitabine resistance. By exposing SW1990 pancreatic cancer cells to long-term gemcitabine with increasing concentrations, we established a gemcitabine-resistant cell line (SW1990/GEM) with a high IC50 (the concentration needed for 50 % growth inhibition, 847.23 μM). The mRNA and microRNA expression profiles of SW1990 cells and SW1990/GEM cells were determined using RNA-seq analysis. By comparing the results in control SW1990 cells, 507 upregulated genes and 550 downregulated genes in SW1990/GEM cells were identified as differentially expressed genes correlated with gemcitabine sensitivity. Gene ontology (GO) analysis showed that the differentially expressed genes were related to diverse biological processes. The upregulated genes were mainly associated with drug response and apoptosis, and the downregulated genes were correlated with cell cycle progression and RNA splicing. Concurrently, the differentially expressed microRNAs, which are the important player in drug resistance development, were also examined in SW1990/GEM cells, and 56 differential microRNAs were identified. Additionally, the expression profiles of selected genes and microRNAs were confirmed by using Q-PCR assays. Furthermore, combining the differentially expressed microRNAs and mRNAs as well as the predicted targets for these microRNAs, a core microRNA-mRNA regulatory network was constructed, which included hub microRNAs, such as hsa-miR-643, hsa-miR-4644, hsa-miR-4650-5p, hsa-miR-4455, hsa-miR-1261, and hsa-miR-3676. The predicted targets of these hub microRNAs in the microRNA-mRNA network were also observed in the identified differential genes. As a result, a differential gene and microRNA expression pattern was constructed in gemcitabine-resistant pancreatic cancer cells. Therefore, these data may be useful for the detection and treatment of drug resistance in pancreatic cancer patients, and the microRNA-mRNA network-based analysis is expected to be more effective and provides deep insights into the molecular mechanism of drug resistance.
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