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Valiuska S, Elder KK, McKay SJ, Ciudad CJ, Noé V, Brooks TA. Combinatorial Anti-Cancer Effect of Polypurine Reverse Hoogsteen Hairpins against KRAS and MYC Targeting in Prostate and Pancreatic Cancer Cell Lines. Genes (Basel) 2024; 15:1332. [PMID: 39457457 PMCID: PMC11507358 DOI: 10.3390/genes15101332] [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: 07/12/2024] [Revised: 10/04/2024] [Accepted: 10/15/2024] [Indexed: 10/28/2024] Open
Abstract
Introduction: KRAS and MYC are proto-oncogenes that are strictly regulated in healthy cells that have key roles in several processes such as cell growth, proliferation, differentiation, or apoptosis. These genes are tightly interconnected, and their dysregulation can lead to cancer progression. We previously individually targeted these oncogenes using Polypurine Reverse Hoogsteen (PPRH) hairpins, mostly targeting the complementary strand of G-quadruplex-forming sequences. We validated them in vitro in different cancer cell lines with deregulated KRAS and/or MYC. In this work we focused on our understanding of the cooperative dynamics between these oncogenes, by investigating the combined impact of PPRHs targeting KRAS and MYC in pancreatic and prostate cancer cells. Results: The combinations had a modulatory impact on the expression of both oncogenes, with transcriptional and translational downregulation occurring five days post-treatment. Out of the four tested PPRHs, MYC-targeting PPRHs, especially HpMYC-G4-PR-C directed against the promoter, showed a greater cytotoxic and expression modulation effect. When both KRAS- and MYC-targeting PPRHs were applied in combination, a synergistic reduction in cell viability was observed. Conclusion: The simultaneous targeting of KRAS and MYC demonstrates efficacy in gene modulation, thus in decreasing cell proliferation and viability.
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Affiliation(s)
- Simonas Valiuska
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, University of Barcelona (UB), 08028 Barcelona, Spain; (S.V.); (C.J.C.)
- Instituto de Nanociencia y Nanotecnología (IN2UB), University of Barcelona (UB), 08028 Barcelona, Spain
| | - Kayla K. Elder
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY 13902, USA; (K.K.E.); (S.J.M.)
| | - Steven J. McKay
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY 13902, USA; (K.K.E.); (S.J.M.)
| | - Carlos J. Ciudad
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, University of Barcelona (UB), 08028 Barcelona, Spain; (S.V.); (C.J.C.)
- Instituto de Nanociencia y Nanotecnología (IN2UB), University of Barcelona (UB), 08028 Barcelona, Spain
| | - Véronique Noé
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, University of Barcelona (UB), 08028 Barcelona, Spain; (S.V.); (C.J.C.)
- Instituto de Nanociencia y Nanotecnología (IN2UB), University of Barcelona (UB), 08028 Barcelona, Spain
| | - Tracy A. Brooks
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY 13902, USA; (K.K.E.); (S.J.M.)
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Przybyszewski O, Mik M, Nowicki M, Kusiński M, Mikołajczyk-Solińska M, Śliwińska A. Using microRNAs Networks to Understand Pancreatic Cancer-A Literature Review. Biomedicines 2024; 12:1713. [PMID: 39200178 PMCID: PMC11351910 DOI: 10.3390/biomedicines12081713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 07/26/2024] [Accepted: 07/28/2024] [Indexed: 09/02/2024] Open
Abstract
Pancreatic cancer is a severe disease, challenging to diagnose and treat, and thereby characterized by a poor prognosis and a high mortality rate. Pancreatic ductal adenocarcinoma (PDAC) represents approximately 90% of pancreatic cancer cases, while other cases include neuroendocrine carcinoma. Despite the growing knowledge of the pathophysiology of this cancer, the mortality rate caused by it has not been effectively reduced. Recently, microRNAs have aroused great interest among scientists and clinicians, as they are negative regulators of gene expression, which participate in many processes, including those related to the development of pancreatic cancer. The aim of this review is to show how microRNAs (miRNAs) affect key signaling pathways and related cellular processes in pancreatic cancer development, progression, diagnosis and treatment. We included the results of in vitro studies, animal model of pancreatic cancer and those performed on blood, saliva and tumor tissue isolated from patients suffering from PDAC. Our investigation identified numerous dysregulated miRNAs involved in KRAS, JAK/STAT, PI3/AKT, Wnt/β-catenin and TGF-β signaling pathways participating in cell cycle control, proliferation, differentiation, apoptosis and metastasis. Moreover, some miRNAs (miRNA-23a, miRNA-24, miRNA-29c, miRNA-216a) seem to be engaged in a crosstalk between signaling pathways. Evidence concerning the utility of microRNAs in the diagnosis and therapy of this cancer is poor. Therefore, despite growing knowledge of the involvement of miRNAs in several processes associated with pancreatic cancer, we are beginning to recognize and understand their role and usefulness in clinical practice.
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Affiliation(s)
- Oskar Przybyszewski
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska St., 92-213 Lodz, Poland
| | - Michał Mik
- Department of General and Colorectal Surgery, Medical University of Lodz, 113 Stefana Żeromskiego St., 90-549 Lodz, Poland; (M.M.); (M.N.)
| | - Michał Nowicki
- Department of General and Colorectal Surgery, Medical University of Lodz, 113 Stefana Żeromskiego St., 90-549 Lodz, Poland; (M.M.); (M.N.)
| | - Michał Kusiński
- Department of Endocrinological, General and Oncological Surgery, Medical University of Lodz, 62 Pabianicka St., 93-513 Lodz, Poland;
| | - Melania Mikołajczyk-Solińska
- Department of Internal Medicine, Diabetology and Clinical Pharmacology, Medical University of Lodz, 251 Pomorska St., 92-213 Lodz, Poland;
| | - Agnieszka Śliwińska
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska St., 92-213 Lodz, Poland
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Guo Z, Ashrafizadeh M, Zhang W, Zou R, Sethi G, Zhang X. Molecular profile of metastasis, cell plasticity and EMT in pancreatic cancer: a pre-clinical connection to aggressiveness and drug resistance. Cancer Metastasis Rev 2024; 43:29-53. [PMID: 37453022 DOI: 10.1007/s10555-023-10125-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 07/07/2023] [Indexed: 07/18/2023]
Abstract
The metastasis is a multistep process in which a small proportion of cancer cells are detached from the colony to enter into blood cells for obtaining a new place for metastasis and proliferation. The metastasis and cell plasticity are considered major causes of cancer-related deaths since they improve the malignancy of cancer cells and provide poor prognosis for patients. Furthermore, enhancement in the aggressiveness of cancer cells has been related to the development of drug resistance. Metastasis of pancreatic cancer (PC) cells has been considered one of the major causes of death in patients and their undesirable prognosis. PC is among the most malignant tumors of the gastrointestinal tract and in addition to lifestyle, smoking, and other factors, genomic changes play a key role in its progression. The stimulation of EMT in PC cells occurs as a result of changes in molecular interaction, and in addition to increasing metastasis, EMT participates in the development of chemoresistance. The epithelial, mesenchymal, and acinar cell plasticity can occur and determines the progression of PC. The major molecular pathways including STAT3, PTEN, PI3K/Akt, and Wnt participate in regulating the metastasis of PC cells. The communication in tumor microenvironment can provide by exosomes in determining PC metastasis. The components of tumor microenvironment including macrophages, neutrophils, and cancer-associated fibroblasts can modulate PC progression and the response of cancer cells to chemotherapy.
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Affiliation(s)
- Zhenli Guo
- Department of Oncology, First Affiliated Hospital, Gannan Medical University, 128 Jinling Road, Ganzhou City, Jiangxi Province, 341000, China
| | - Milad Ashrafizadeh
- Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, Guangdong, China.
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Wei Zhang
- Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, Guangdong, China
| | - Rongjun Zou
- Department of Cardiovascular Surgery, Guangdong Provincial Hospital of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, Guangdong, China
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Gautam Sethi
- Department of Pharmacology, National University of Singapore, 16 Medical Drive, Singapore, 117600, Singapore.
| | - Xianbin Zhang
- Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, Guangdong, China.
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Izdebska WM, Daniluk J, Niklinski J. Microbiome and MicroRNA or Long Non-Coding RNA-Two Modern Approaches to Understanding Pancreatic Ductal Adenocarcinoma. J Clin Med 2023; 12:5643. [PMID: 37685710 PMCID: PMC10488817 DOI: 10.3390/jcm12175643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 08/18/2023] [Accepted: 08/19/2023] [Indexed: 09/10/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of humans' most common and fatal neoplasms. Nowadays, a number of PDAC studies are being conducted in two different fields: non-coding RNA (especially microRNA and long non-coding RNA) and microbiota. It has been recently discovered that not only does miRNA affect particular bacteria in the gut microbiome that can promote carcinogenesis in the pancreas, but the microbiome also has a visible impact on the miRNA. This suggests that it is possible to use the combined impact of the microbiome and noncoding RNA to suppress the development of PDAC. Nevertheless, insufficient research has focused on bounding both approaches to the diagnosis, treatment, and prevention of pancreatic ductal adenocarcinoma. In this article, we summarize the recent literature on the molecular basis of carcinogenesis in the pancreas, the two-sided impact of particular types of non-coding RNA and the pancreatic cancer microbiome, and possible medical implications of the discovered phenomenon.
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Affiliation(s)
- Wiktoria Maria Izdebska
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Jaroslaw Daniluk
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Jacek Niklinski
- Department of Clinical Molecular Biology, Medical University of Bialystok, 15-089 Bialystok, Poland
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Chen J, Han G, Xu A, Akutsu T, Cai H. Identifying miRNA-Gene Common and Specific Regulatory Modules for Cancer Subtyping by a High-Order Graph Matching Model. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2023; 20:421-431. [PMID: 35320104 DOI: 10.1109/tcbb.2022.3161635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Identifying regulatory modules between miRNAs and genes is crucial in cancer research. It promotes a comprehensive understanding of the molecular mechanisms of cancer. The genomic data collected from subjects usually relate to different cancer statuses, such as different TNM Classifications of Malignant Tumors (TNM) or histological subtypes. Simple integrated analyses generally identify the core of the tumorigenesis (common modules) but miss the subtype-specific regulatory mechanisms (specific modules). In contrast, separate analyses can only report the differences and ignore important common modules. Therefore, there is an urgent need to develop a novel method to jointly analyze miRNA and gene data of different cancer statuses to identify common and specific modules. To that end, we developed a High-Order Graph Matching model to identify Common and Specific modules (HOGMCS) between miRNA and gene data of different cancer statuses. We first demonstrate the superiority of HOGMCS through a comparison with four state-of-the-art techniques using a set of simulated data. Then, we apply HOGMCS on stomach adenocarcinoma data with four TNM stages and two histological types, and breast invasive carcinoma data with four PAM50 subtypes. The experimental results demonstrate that HOGMCS can accurately extract common and subtype-specific miRNA-gene regulatory modules, where many identified miRNA-gene interactions have been confirmed in several public databases.
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Indoloquinoline-Mediated Targeted Downregulation of KRAS through Selective Stabilization of the Mid-Promoter G-Quadruplex Structure. Genes (Basel) 2022; 13:genes13081440. [PMID: 36011352 PMCID: PMC9408018 DOI: 10.3390/genes13081440] [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: 06/02/2022] [Revised: 07/26/2022] [Accepted: 08/10/2022] [Indexed: 11/27/2022] Open
Abstract
KRAS is a well-validated anti-cancer therapeutic target, whose transcriptional downregulation has been demonstrated to be lethal to tumor cells with aberrant KRAS signaling. G-quadruplexes (G4s) are non-canonical nucleic acid structures that mediate central dogmatic events, such as DNA repair, telomere elongation, transcription and splicing events. G4s are attractive drug targets, as they are more globular than B-DNA, enabling more selective gene interactions. Moreover, their genomic prevalence is increased in oncogenic promoters, their formation is increased in human cancers, and they can be modulated with small molecules or targeted nucleic acids. The putative formation of multiple G4s has been described in the literature, but compounds with selectivity among these structures have not yet been able to distinguish between the biological contribution of the predominant structures. Using cell free screening techniques, synthesis of novel indoloquinoline compounds and cellular models of KRAS-dependent cancer cells, we describe compounds that choose between KRAS promoter G4near and G4mid, correlate compound cytotoxic activity with KRAS regulation, and highlight G4mid as the lead molecular non-canonical structure for further targeting efforts.
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MicroRNA-143 act as a tumor suppressor microRNA in human lung cancer cells by inhibiting cell proliferation, invasion, and migration. Mol Biol Rep 2022; 49:7637-7647. [PMID: 35717476 DOI: 10.1007/s11033-022-07580-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 04/30/2022] [Accepted: 05/06/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND/AIM MicroRNAs play crucial roles in controlling cellular biological processes. miR-143 expression is usually downregulated in different cancers. In this study, we focused on exploring the role of miR143 in NSCLC development. METHODS Bioinformatics analyses were used to detect the expression level of miR-143 in lung tumors. The cells were transfected by pCMV-miR-143 vectors. The efficacy of transfection was verified by Flow cytometry. The influence of miR-143 replacement on NSCLC cells migration, proliferation, and apoptosis was detected using wound-healing assay, MTT assay, and DAPI staining, respectively. RESULTS MTT assay revealed that overexpression of miR143 inhibited cell growth and proliferation. Scratch assay results demonstrated that restoration of miR143 suppressed cell migration. The qRT-PCR assay was further used to detect the assumed relationship between miR143 and apoptotic and metastatic-related genes. CONCLUSION The findings showed that miR-143 could reduce cell proliferation, invasion, and migration by reducing CXCR4, Vimentin, MMP-1, Snail-1, C-myc expression level, and increasing E-cadherin expression levels in lung cancer cells and might be a potential target in NSCLC's targeted therapy.
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Dai H, Abdullah R, Wu X, Li F, Ma Y, Lu A, Zhang G. Pancreatic Cancer: Nucleic Acid Drug Discovery and Targeted Therapy. Front Cell Dev Biol 2022; 10:855474. [PMID: 35652096 PMCID: PMC9149368 DOI: 10.3389/fcell.2022.855474] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 04/07/2022] [Indexed: 12/20/2022] Open
Abstract
Pancreatic cancer (PC) is one of the most lethal cancers with an almost 10% 5-year survival rate. Because PC is implicated in high heterogeneity, desmoplastic tumor-microenvironment, and inefficient drug-penetration, the chemotherapeutic strategy currently recommended for the treatment of PC has limited clinical benefit. Nucleic acid-based targeting therapies have become strong competitors in the realm of drug discovery and targeted therapy. A vast evidence has demonstrated that antibody-based or alternatively aptamer-based strategy largely contributed to the elevated drug accumulation in tumors with reduced systematic cytotoxicity. This review describes the advanced progress of antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), messenger RNA (mRNAs), and aptamer-drug conjugates (ApDCs) in the treatment of PC, revealing the bright application and development direction in PC therapy.
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Affiliation(s)
- Hong Dai
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
| | - Razack Abdullah
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute for the Advancement of Chinese medicine (IACM) .Ltd, Shatin, Hong Kong SAR, China
| | - Xiaoqiu Wu
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
| | - Fangfei Li
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen, China
| | - Yuan Ma
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen, China
| | - Aiping Lu
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen, China
| | - Ge Zhang
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China
- Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen, China
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Oncogenic Kras-Mediated Cytokine CCL15 Regulates Pancreatic Cancer Cell Migration and Invasion through ROS. Cancers (Basel) 2022; 14:cancers14092153. [PMID: 35565279 PMCID: PMC9104113 DOI: 10.3390/cancers14092153] [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: 03/25/2022] [Revised: 04/19/2022] [Accepted: 04/21/2022] [Indexed: 11/30/2022] Open
Abstract
Simple Summary Oncogenic KrasG12D and tumor inflammation are critical components of the development and dissemination of pancreatic ductal adenocarcinoma (PDAC). The aim of this study is to investigate a lesser-known cytokine, CCL15, that functions as a new downstream target of KrasG12D with the purpose of regulating PDAC cell migration and invasion. We showed increased levels of CCL15 as well as the presence of its receptors, including CCR1 and CCR3, in PDAC tissues and cell lines. The knockdown of CCL15 diminished metastatic Panc-1 cell migration, whereas the treatment of CCL15 in non-metastatic BxPC-3 cells promoted BxPC-3 cell motility. Similar results were verified using murine metastatic PDAC KP-2 cells. Furthermore, we demonstrated that CCL15-modulated PDAC cell migration through the upregulation of cellular reactive oxygen species (ROS) levels and the knockdown of KrasG12D resulted in a decrease in CCL15. Altogether, our data unveiled a new mechanism of oncogenic KrasG12D in modulating PDAC inflammation and spreading. Abstract Pancreatic ductal adenocarcinoma (PDAC) is well known for its high death rate due to prompt cancer metastasis caused by cancer cell migration and invasion within the early stages of its development. Here, we reveal a new function of cytokine CCL15, namely the upregulation of PDAC cell migration and invasion. We showed increased levels of CCL15 transcripts and protein expressions in human PDAC tissue samples, as well as in cultured cell lines. Furthermore, PDAC cells also expressed CCL15 receptors, including CCR1 and CCR3. Murine PDAC cell lines and tissues strengthened this finding. The manipulation of CCL15 in metastatic Panc-1 cells through CCL15 knockdown or CCL15 neutralization decreased Panc-1 cell motility and invasiveness. In addition, treating non-metastatic BxPC-3 cells with recombinant CCL15 accelerated the cell migration of BxPC-3. A reduction in the levels of reactive oxygen species (ROS) by either N-Acetyl-L-Cysteine treatment or p22phox knockdown led to a decrease in Panc-1 cell migration and a reversed effect on recombinant CCL15-promoted BxPC-3 cell movement. Importantly, the knockdown of oncogenic Kras in Panc-1 cells abolished CCL15 protein expression and impeded cell migration without affecting PDAC cell growth. Altogether, our work elucidates an additional molecular pathway of oncogenic Kras to promote PDAC metastasis through the upregulation of cell migration and invasion by the Kras downstream CCL15, a lesser-known cytokine within the cancer research field.
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Pekarek L, Fraile-Martinez O, Garcia-Montero C, Saez MA, Barquero-Pozanco I, Del Hierro-Marlasca L, de Castro Martinez P, Romero-Bazán A, Alvarez-Mon MA, Monserrat J, García-Honduvilla N, Buján J, Alvarez-Mon M, Guijarro LG, Ortega MA. Clinical Applications of Classical and Novel Biological Markers of Pancreatic Cancer. Cancers (Basel) 2022; 14:1866. [PMID: 35454771 PMCID: PMC9029823 DOI: 10.3390/cancers14081866] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/02/2022] [Accepted: 04/06/2022] [Indexed: 01/27/2023] Open
Abstract
The incidence and prevalence of pancreatic adenocarcinoma have increased in recent years. Pancreatic cancer is the seventh leading cause of cancer death, but it is projected to become the second leading cause of cancer-related mortality by 2040. Most patients are diagnosed in an advanced stage of the disease, with very limited 5-year survival. The discovery of different tissue markers has elucidated the underlying pathophysiology of pancreatic adenocarcinoma and allowed stratification of patient risk at different stages and assessment of tumour recurrence. Due to the invasive capacity of this tumour and the absence of screening markers, new immunohistochemical and serological markers may be used as prognostic markers for recurrence and in the study of possible new therapeutic targets because the survival of these patients is low in most cases. The present article reviews the currently used main histopathological and serological markers and discusses the main characteristics of markers under development.
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Affiliation(s)
- Leonel Pekarek
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Oncology Service, Guadalajara University Hospital, 19002 Guadalajara, Spain
| | - Oscar Fraile-Martinez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Cielo Garcia-Montero
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Miguel A Saez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Pathological Anatomy Service, Central University Hospital of Defence-UAH Madrid, 28801 Alcala de Henares, Spain
| | - Ines Barquero-Pozanco
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
| | - Laura Del Hierro-Marlasca
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
| | - Patricia de Castro Martinez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
| | - Adoración Romero-Bazán
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
| | - Miguel A Alvarez-Mon
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Jorge Monserrat
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Natalio García-Honduvilla
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Julia Buján
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Melchor Alvarez-Mon
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Immune System Diseases-Rheumatology, Oncology Service an Internal Medicine (CIBEREHD), University Hospital Príncipe de Asturias, 28806 Alcala de Henares, Spain
| | - Luis G Guijarro
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Unit of Biochemistry and Molecular Biology, Department of System Biology (CIBEREHD), University of Alcalá, 28801 Alcala de Henares, Spain
| | - Miguel A Ortega
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Cancer Registry and Pathology Department, Principe de Asturias University Hospital, 28806 Alcala de Henares, Spain
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Psaras AM, Valiuska S, Noé V, Ciudad CJ, Brooks TA. Targeting KRAS Regulation with PolyPurine Reverse Hoogsteen Oligonucleotides. Int J Mol Sci 2022; 23:2097. [PMID: 35216221 PMCID: PMC8876201 DOI: 10.3390/ijms23042097] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/02/2022] [Accepted: 02/09/2022] [Indexed: 02/04/2023] Open
Abstract
KRAS is a GTPase involved in the proliferation signaling of several growth factors. The KRAS gene is GC-rich, containing regions with known and putative G-quadruplex (G4) forming regions. Within the middle of the G-rich proximal promoter, stabilization of the physiologically active G4mid structure downregulates transcription of KRAS; the function and formation of other G4s within the gene are unknown. Herein we identify three putative G4-forming sequences (G4FS) within the KRAS gene, explore their G4 formation, and develop oligonucleotides targeting these three regions and the G4mid forming sequence. We tested Polypurine Reverse Hoogsteen hairpins (PPRHs) for their effects on KRAS regulation via enhancing G4 formation or displacing G-rich DNA strands, downregulating KRAS transcription and mediating an anti-proliferative effect. Five PPRH were designed, two against the KRAS promoter G4mid and three others against putative G4FS in the distal promoter, intron 1 and exon 5. PPRH binding was confirmed by gel electrophoresis. The effect on KRAS transcription was examined by luciferase, FRET Melt2, qRT-PCR. Cytotoxicity was evaluated in pancreatic and ovarian cancer cells. PPRHs decreased activity of a luciferase construct driven by the KRAS promoter. PPRH selectively suppressed proliferation in KRAS dependent cancer cells. PPRH demonstrated synergistic activity with a KRAS promoter selective G4-stabilizing compound, NSC 317605, in KRAS-dependent pancreatic cells. PPRHs selectively stabilize G4 formation within the KRAS mid promoter region and represent an innovative approach to both G4-stabilization and to KRAS modulation with potential for development into novel therapeutics.
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Affiliation(s)
- Alexandra Maria Psaras
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY 13902, USA;
| | - Simonas Valiuska
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, & IN2UB, University of Barcelona, 08028 Barcelona, Spain; (S.V.); (V.N.); (C.J.C.)
| | - Véronique Noé
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, & IN2UB, University of Barcelona, 08028 Barcelona, Spain; (S.V.); (V.N.); (C.J.C.)
| | - Carlos J. Ciudad
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, & IN2UB, University of Barcelona, 08028 Barcelona, Spain; (S.V.); (V.N.); (C.J.C.)
| | - Tracy A. Brooks
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY 13902, USA;
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12
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Asghariazar V, Kadkhodayi M, Mansoori B, Mohammadi A, Baradaran B. Restoration of miR-143 reduces migration and proliferation of bladder cancer cells by regulating signaling pathways involved in EMT. Mol Cell Probes 2022; 61:101794. [DOI: 10.1016/j.mcp.2022.101794] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 01/29/2022] [Accepted: 01/31/2022] [Indexed: 11/25/2022]
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13
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Xia T, Chen XY, Zhang YN. MicroRNAs as biomarkers and perspectives in the therapy of pancreatic cancer. Mol Cell Biochem 2021; 476:4191-4203. [PMID: 34324119 DOI: 10.1007/s11010-021-04233-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 07/20/2021] [Indexed: 12/12/2022]
Abstract
Pancreatic cancer is considered as one of the most aggressive tumor types, representing over 45,750 mortality cases annually in the USA solely. The aggressive nature and late identification of pancreatic cancer, combined with the restrictions of existing chemotherapeutics, present the mandatory need for the advancement of novel treatment systems. Ongoing reports have shown an important role of microRNAs (miRNAs) in the initiation, migration, and metastasis of malignancies. Besides, abnormal transcriptional levels of miRNAs have regularly been related with etiopathogenesis of pancreatic malignancy, underlining the conceivable utilization of miRNAs in the management of pancreatic disease patients. In this review article, we give a concise outline of molecular pathways involved in etiopathogenesis of pancreatic cancer patients as well as miRNA implications in pancreatic cancer patients. Ensuing sections describe the involvement of miRNAs in the diagnosis, prognosis, and therapy of pancreatic cancer patients. The involvement of miRNAs in the chemoresistance of pancreatic cancers was also discussed. End area portrays the substance of survey with future headings.
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Affiliation(s)
- Tao Xia
- Department of Gastrointestinal-Pancreatic Surgery, General Surgery, Zhejiang Provincial People's Hospital, Affiliated Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang Province, People's Republic of China
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang Province, People's Republic of China
| | - Xiao-Yi Chen
- Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated Hospital of Hangzhou Medical College, No. 158 Shangtang Road, Hangzhou, 310014, Zhejiang Province, People's Republic of China.
| | - You-Ni Zhang
- Department of Laboratory Medicine, Tiantai People's Hospital of Zhejiang Province (Tiantai Branch of Zhejiang People's Hospital), Kangning Middle Road, Shifeng Street, Tiantai County, Taizhou, 317200, Zhejiang Province, People's Republic of China.
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14
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Shafabakhsh R, Arianfar F, Vosough M, Mirzaei HR, Mahjoubin-Tehran M, Khanbabaei H, Kowsari H, Shojaie L, Azar MEF, Hamblin MR, Mirzaei H. Autophagy and gastrointestinal cancers: the behind the scenes role of long non-coding RNAs in initiation, progression, and treatment resistance. Cancer Gene Ther 2021; 28:1229-1255. [PMID: 33432087 DOI: 10.1038/s41417-020-00272-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 10/06/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023]
Abstract
Gastrointestinal (GI) cancers comprise a heterogeneous group of complex disorders that affect different organs, including esophagus, stomach, gallbladder, liver, biliary tract, pancreas, small intestine, colon, rectum, and anus. Recently, an explosion in nucleic acid-based technologies has led to the discovery of long non-coding RNAs (lncRNAs) that have been found to possess unique regulatory functions. This class of RNAs is >200 nucleotides in length, and is characterized by their lack of protein coding. LncRNAs exert regulatory effects in GI cancer development by affecting different functions such as the proliferation and metastasis of cancer cells, apoptosis, glycolysis and angiogenesis. Over the past few decades, considerable evidence has revealed the important role of autophagy in both GI cancer progression and suppression. In addition, recent studies have confirmed a significant correlation between lncRNAs and the regulation of autophagy. In this review, we summarize how lncRNAs play a behind the scenes role in the pathogenesis of GI cancers through regulation of autophagy.
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Affiliation(s)
- Rana Shafabakhsh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Farzaneh Arianfar
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Massoud Vosough
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, 1665659911, Iran
| | - Hamid Reza Mirzaei
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Mahjoubin-Tehran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hashem Khanbabaei
- Medical Physics Department, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hamed Kowsari
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Layla Shojaie
- Research Center for Liver Diseases, Keck School of Medicine, Department of Medicine, University of Southern California, Los Angeles, CA, USA
| | | | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028, South Africa.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Abstract
ABSTRACT Pancreatic cancer is one of the most aggressive malignancies. The poor prognosis of pancreatic cancer patients is mainly attributed to low diagnostic rate at the early stage, highly aggressive nature coupled with the inadequate efficacy of current chemotherapeutic regimens. Novel therapeutic strategies are urgently needed for pancreatic cancer. MicroRNAs (miRNAs) play an important regulatory role in key processes of cancer development. The aberrant expression of miRNAs is often involved in the initiation, progression, and metastasis of pancreatic cancer. The discovery of tumor suppressor miRNAs provides prospects for the development of a novel treatment strategy for pancreatic cancer. We reviewed recent progress on the understanding of the role of miRNAs in pancreatic cancer, highlighted the efficient application of miRNAs-based therapies for pancreatic cancer in animal models and clinical trials, and proposed future prospects. This review focuses on the promise of integrating miRNAs into the treatment of pancreatic cancer and provides guidance for the development of precision medicine for pancreatic cancer.
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16
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Role of non-coding RNAs in tumor progression and metastasis in pancreatic cancer. Cancer Metastasis Rev 2021; 40:761-776. [PMID: 34591242 PMCID: PMC8556175 DOI: 10.1007/s10555-021-09995-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 09/13/2021] [Indexed: 12/13/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer with an overall 5-year survival rate of less than 10%. The 1-year survival rate of patients with locally advanced or metastatic disease is abysmal. The aggressive nature of cancer cells, hypovascularization, extensive desmoplastic stroma, and immunosuppressive tumor microenvironment (TME) endows PDAC tumors with multiple mechanisms of drug resistance. With no obvious genetic mutation(s) driving tumor progression or metastatic transition, the challenges for understanding the biological mechanism(s) of these processes are paramount. A better understanding of the molecular and cellular mechanisms of these processes could lead to new diagnostic tools for patient management and new targets for therapeutic intervention. microRNAs (miRNAs) are an evolutionarily conserved gene class of short non-coding regulatory RNAs. miRNAs are an extensive regulatory layer that controls gene expression at the posttranscriptional level. This review focuses on preclinical models that functionally dissect miRNA activity in tumor progression or metastatic processes in PDAC. Collectively, these studies suggest an influence of miRNAs and RNA-RNA networks in the processes of epithelial to mesenchymal cell transition and cancer cell stemness. At a cell-type level, some miRNAs mainly influence cancer cell–intrinsic processes and pathways, whereas other miRNAs predominantly act in distinct cellular compartments of the TME to regulate fibroblast and immune cell functions and/or influence other cell types’ function via cell-to-cell communications by transfer of extracellular vesicles. At a molecular level, the influence of miRNA-mediated regulation often converges in core signaling pathways, including TGF-β, JAK/STAT, PI3K/AKT, and NF-κB.
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17
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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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18
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Abdel-Hamid NM, Abass SA. Matrix metalloproteinase contribution in management of cancer proliferation, metastasis and drug targeting. Mol Biol Rep 2021; 48:6525-6538. [PMID: 34379286 DOI: 10.1007/s11033-021-06635-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 08/06/2021] [Indexed: 12/16/2022]
Abstract
Matrix metalloproteinases (MMPs) or matrixins, are members of a zinc-dependent endopeptidase family. They cause remodeling of the extracellular matrix (ECM) leading to numerous diseases. MMPs subfamilies possess: collagenases, gelatinases, stromelysins and membrane-type MMPs (MT-MMP). They consist of several domains; pro-peptide, catalytic, linker peptide and the hemopexin (Hpx) domains. MMPs are involved in initiation, proliferation and metastasis of cancer through the breakdown of ECM physical barriers. Overexpression of MMPs is associated with poor prognosis of cancer. This review will discuss both types of MMPs and current inhibitors, which target them in different aspects, including, biosynthesis, activation, secretion and catalytic activity. Several synthetic and natural inhibitors of MMPs (MMPIs) that can bind the catalytic domain of MMPs have been designed including; peptidomimetic, non-peptidomimetic, tetracycline derivatives, off-target MMPI, natural products, microRNAs and monoclonal antibodies.
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Affiliation(s)
- Nabil M Abdel-Hamid
- Biochemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt.
| | - Shimaa A Abass
- Biochemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt
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19
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Barman S, Fatima I, Singh AB, Dhawan P. Pancreatic Cancer and Therapy: Role and Regulation of Cancer Stem Cells. Int J Mol Sci 2021; 22:ijms22094765. [PMID: 33946266 PMCID: PMC8124621 DOI: 10.3390/ijms22094765] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/20/2021] [Accepted: 04/20/2021] [Indexed: 12/21/2022] Open
Abstract
Despite significant improvements in clinical management, pancreatic cancer (PC) remains one of the deadliest cancer types, as it is prone to late detection with extreme metastatic properties. The recent findings that pancreatic cancer stem cells (PaCSCs) contribute to the tumorigenesis, progression, and chemoresistance have offered significant insight into the cancer malignancy and development of precise therapies. However, the heterogeneity of cancer and signaling pathways that regulate PC have posed limitations in the effective targeting of the PaCSCs. In this regard, the role for K-RAS, TP53, Transforming Growth Factor-β, hedgehog, Wnt and Notch and other signaling pathways in PC progression is well documented. In this review, we discuss the role of PaCSCs, the underlying molecular and signaling pathways that help promote pancreatic cancer development and metastasis with a specific focus on the regulation of PaCSCs. We also discuss the therapeutic approaches that target different PaCSCs, intricate mechanisms, and therapeutic opportunities to eliminate heterogeneous PaCSCs populations in pancreatic cancer.
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Affiliation(s)
- Susmita Barman
- Department of Biochemistry and Molecular Biology, Omaha, NE 68198, USA; (S.B.); (I.F.); (A.B.S.)
| | - Iram Fatima
- Department of Biochemistry and Molecular Biology, Omaha, NE 68198, USA; (S.B.); (I.F.); (A.B.S.)
| | - Amar B. Singh
- Department of Biochemistry and Molecular Biology, Omaha, NE 68198, USA; (S.B.); (I.F.); (A.B.S.)
- VA Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, Omaha, NE 68198, USA; (S.B.); (I.F.); (A.B.S.)
- VA Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA
- Correspondence:
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20
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Bi F, Chen C, Fu J, Yu L, Geng J. Inhibiting proliferation and metastasis of osteosarcoma cells by downregulation of long non-coding RNA colon cancer-associated transcript 2 targeting microRNA-143. Oncol Lett 2021; 21:265. [PMID: 33664828 PMCID: PMC7882883 DOI: 10.3892/ol.2021.12526] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 12/18/2020] [Indexed: 02/07/2023] Open
Abstract
Osteosarcoma is a malignant bone tumor, which has a high incidence in children and adolescents. However, the pathogenesis of osteosarcoma remains unclear. Long noncoding RNA (lncRNA) is a new potential therapeutic target and diagnostic biomarker for osteosarcoma. Hence, the present study aimed to explore the effect of lncRNA colon cancer-associated transcript (CCAT2) on osteosarcoma and its potential underlying mechanisms. For this purpose, the proliferation of osteosarcoma cells was measured using the CCK-8 assay. The scratch-wound and cell invasion assays were used to determine the migration and invasion of osteosarcoma cells, respectively. LncRNA CCAT2 and microRNA (miR)-143 binding sites were identified by the dual-luciferase reporter assay. RNA and protein expression levels were detected by reverse-transcription quantitative PCR and western blotting, respectively. Downregulation of lncRNA CCAT2 inhibited the proliferation, migration, and invasion of osteosarcoma cells. The findings also revealed that miR-143 bound directly to lncRNA CCAT2. The expression of miR-143 was upregulated by the knockdown of lncRNA CCAT2. Downregulation of the FOS-like antigen 2 was also observed after knockdown of lncRNA CCAT2. The function of lncRNA CCAT2 in osteosarcoma cells was attenuated by co-transfection with anti-miR-143 oligodeoxyribonucleotide. In conclusion, downregulation of lncRNA CCAT2 inhibited the proliferation and metastasis of osteosarcoma cells by targeting miR-143. lncRNA CCAT2 was identified as a potential target for osteosarcoma treatment.
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Affiliation(s)
- Fengjiang Bi
- Department of Orthopedics, The First Hospital of Qiqihaer, Qiqihaer, Heilongjiang 161005, P.R. China
| | - Can Chen
- Department of Orthopedics, The First Hospital of Qiqihaer, Qiqihaer, Heilongjiang 161005, P.R. China
| | - Jing Fu
- Department of Orthopedics, The First Hospital of Qiqihaer, Qiqihaer, Heilongjiang 161005, P.R. China
| | - Lei Yu
- Department of Orthopedics, The First Hospital of Qiqihaer, Qiqihaer, Heilongjiang 161005, P.R. China
| | - Jia Geng
- Department of Orthopedics, The First Hospital of Qiqihaer, Qiqihaer, Heilongjiang 161005, P.R. China,Correspondence to: Dr Jia Geng, Department of Orthopedics, The First Hospital of Qiqihaer, 30 Park Road, Qiqihaer, Heilongjiang 161005, P.R. China, E-mail:
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21
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Liu YF, Luo D, Li X, Li ZQ, Yu X, Zhu HW. PVT1 Knockdown Inhibits Autophagy and Improves Gemcitabine Sensitivity by Regulating the MiR-143/HIF-1α/VMP1 Axis in Pancreatic Cancer. Pancreas 2021; 50:227-234. [PMID: 33565800 DOI: 10.1097/mpa.0000000000001747] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVES Elucidation of the regulatory mechanisms of gemcitabine sensitivity is needed to improve the therapeutic effects of this drug in pancreatic cancer. METHODS PANC-1 cells were transfected with small hairpin RNA against PVT1 or microRNA (miR)-143 mimics or inhibitor. The gemcitabine sensitivity of pancreatic cancer was evaluated. Autophagosomes were analyzed with an immunofluorescence assay. Cell viability and proliferation were examined with MTT assays. Quantitative reverse transcription-polymerase chain reaction and Western blotting were used to analyze the expression of PVT1, miR-143, HIF-1α, VMP1, LC3I/II, p62, and Beclin-1. The interactions of PVT1/miR-143 and miR-143/HIF-1α were assessed by dual-luciferase reporter assays. RESULTS PVT1 was upregulated while miR-143 was downregulated in pancreatic cancer. Both PVT1 knockdown and miR-143 overexpression suppressed autophagy and improved gemcitabine sensitivity in pancreatic cancer. PVT1 directly sponged miR-143 to regulate HIF-1α expression. MiR-143 inhibitor reversed the effect of PVT1 knockdown on autophagy and gemcitabine sensitivity. CONCLUSIONS PVT1 knockdown inhibited autophagy and improved gemcitabine sensitivity via the miR-143/HIF-1α/VMP1 axis in pancreatic cancer. Our investigation elucidated a novel regulatory mechanism of gemcitabine sensitivity and may contribute to improve the therapeutic effects of chemotherapy drugs on pancreatic cancer.
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Affiliation(s)
- Yun-Fei Liu
- From the Departments of Hepatobiliary and Pancreatic Surgery II
| | - Dong Luo
- From the Departments of Hepatobiliary and Pancreatic Surgery II
| | - Xia Li
- Endocrinology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Zhi-Qiang Li
- From the Departments of Hepatobiliary and Pancreatic Surgery II
| | - Xiao Yu
- From the Departments of Hepatobiliary and Pancreatic Surgery II
| | - Hong-Wei Zhu
- From the Departments of Hepatobiliary and Pancreatic Surgery II
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22
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Sharma PC, Gupta A. MicroRNAs: potential biomarkers for diagnosis and prognosis of different cancers. Transl Cancer Res 2020; 9:5798-5818. [PMID: 35117940 PMCID: PMC8798648 DOI: 10.21037/tcr-20-1294] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 06/12/2020] [Indexed: 12/14/2022]
Abstract
A thorough understanding of the tumor environment and underlying genetic factors helps in the better formulation of cancer management strategies. Availability of efficient diagnostic and prognostic biomarkers facilitates early detection and progression of the disease. MicroRNAs affect different biological processes participating in tumorigenesis through regulation of their target genes. An expanding list of unique RNAs and understanding of their regulatory role has opened up a new field in cancer research. Based on a comprehensive literature search, we identified 728 miRNAs dysregulated in sixteen cancer types namely bladder cancer (BC), breast cancer (BrC), cervical cancer (CC), colorectal cancer (CRC), esophageal cancer (EC), endometrial cancer (EnC), gastric cancer (GC), hepatocellular cancer (HCC), head and neck squamous cell cancer (HNSCC), lung cancer (LC), ovarian cancer (OC), pancreatic cancer (PC), prostate cancer (PrC), renal cell cancer (RCC), skin cancer (SC), and thyroid cancer (TC). Expression of 43 miRNAs was either upregulated or downregulated in six or more of these cancers. Finally, seven miRNAs namely mir-18a, mir-21, mir-143/145, mir-210, mir-218, mir-221, showing maximum dysregulation, either up- or down-regulation in the majority of cancers, were selected for a detailed presentation of their expression and evaluation of their potential as biomarkers in the diagnosis and prognosis of different cancers.
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Affiliation(s)
- Prakash Chand Sharma
- University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India
| | - Alisha Gupta
- University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India
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23
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Nabipoorashrafi SA, Shomali N, Sadat-Hatamnezhad L, Mahami-Oskouei M, Mahmoudi J, Sandoghchian Shotorbani B, Akbari M, Xu H, Sandoghchian Shotorbani S. miR-143 acts as an inhibitor of migration and proliferation as well as an inducer of apoptosis in melanoma cancer cells in vitro. IUBMB Life 2020; 72:2034-2044. [PMID: 32687246 DOI: 10.1002/iub.2345] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 06/11/2020] [Accepted: 06/12/2020] [Indexed: 12/20/2022]
Abstract
Melanoma is a serious form of skin cancers begins in the melanocyte. Micro-RNAs are small noncoding RNA with 19 to 25 nucleotides in length involves in the regulation of a wide range of biological processes. MicroRNAs are affected by an aberrant epigenetic alteration in the tumors that may lead to their dysregulation and formation of cancer. Recently, dysregulation of numerous microRNAs has been reported in different types of cancer. The present study focused on the role of miR-143 in carcinogenesis of melanoma cancer. Here, we evaluated the expression level of miR-143 in three melanoma cell lines in comparison with the normal human epidermal melanocyte cell line. Then, miR-143 gene plasmid transfected into the WM115 cell line, for having the lowest expression of miR-143. In addition, the effect of miR-143 transfection on mRNA and protein levels of metastasis-related genes was performed along with MTT assay, wound healing assay, and flow cytometry. The results showed that mRNA and protein expression levels of metastasis-related genes including MMP-9, E-cadherin, Vimentin, and CXCR4 have been reduced following transfection of miR-143. Moreover, the results of the scratch test showed that miR-143 re-expression inhibited cell migration. Also, the role of miR-143 in the induction of apoptosis and inhibition of proliferation by flow cytometry and MTT was confirmed. As a result, the present study showed that miR-143 was involved in metastatic and apoptotic pathways, suggesting that miR-143 acts as a tumor-suppressor microRNA in melanoma cancer.
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Affiliation(s)
| | - Navid Shomali
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Javad Mahmoudi
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Huaxi Xu
- Department of Immunology, Jiangsu University of Medical Sciences, Zhenjiang, China
| | - Siamak Sandoghchian Shotorbani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Jiangsu University of Medical Sciences, Zhenjiang, China
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24
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Humphries BA, Wang Z, Yang C. MicroRNA Regulation of the Small Rho GTPase Regulators-Complexities and Opportunities in Targeting Cancer Metastasis. Cancers (Basel) 2020; 12:E1092. [PMID: 32353968 PMCID: PMC7281527 DOI: 10.3390/cancers12051092] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 04/24/2020] [Accepted: 04/25/2020] [Indexed: 02/07/2023] Open
Abstract
The small Rho GTPases regulate important cellular processes that affect cancer metastasis, such as cell survival and proliferation, actin dynamics, adhesion, migration, invasion and transcriptional activation. The Rho GTPases function as molecular switches cycling between an active GTP-bound and inactive guanosine diphosphate (GDP)-bound conformation. It is known that Rho GTPase activities are mainly regulated by guanine nucleotide exchange factors (RhoGEFs), GTPase-activating proteins (RhoGAPs), GDP dissociation inhibitors (RhoGDIs) and guanine nucleotide exchange modifiers (GEMs). These Rho GTPase regulators are often dysregulated in cancer; however, the underlying mechanisms are not well understood. MicroRNAs (miRNAs), a large family of small non-coding RNAs that negatively regulate protein-coding gene expression, have been shown to play important roles in cancer metastasis. Recent studies showed that miRNAs are capable of directly targeting RhoGAPs, RhoGEFs, and RhoGDIs, and regulate the activities of Rho GTPases. This not only provides new evidence for the critical role of miRNA dysregulation in cancer metastasis, it also reveals novel mechanisms for Rho GTPase regulation. This review summarizes recent exciting findings showing that miRNAs play important roles in regulating Rho GTPase regulators (RhoGEFs, RhoGAPs, RhoGDIs), thus affecting Rho GTPase activities and cancer metastasis. The potential opportunities and challenges for targeting miRNAs and Rho GTPase regulators in treating cancer metastasis are also discussed. A comprehensive list of the currently validated miRNA-targeting of small Rho GTPase regulators is presented as a reference resource.
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Affiliation(s)
- Brock A. Humphries
- Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA
| | - Zhishan Wang
- Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, 1095 V A Drive, Lexington, KY 40536, USA;
| | - Chengfeng Yang
- Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, 1095 V A Drive, Lexington, KY 40536, USA;
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Tokumaru Y, Takabe K, Yoshida K, Akao Y. Effects of MIR143 on rat sarcoma signaling networks in solid tumors: A brief overview. Cancer Sci 2020; 111:1076-1083. [PMID: 32077199 PMCID: PMC7156858 DOI: 10.1111/cas.14357] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 02/01/2020] [Accepted: 02/14/2020] [Indexed: 12/18/2022] Open
Abstract
Rat sarcoma (RAS) is a well-known oncogene that plays important roles in cancer proliferation, cell survival and cell invasion. RAS exists as three major isoforms, Kirsten rat sarcoma (KRAS), Harvey rat sarcoma (HRAS) and neuroblastoma rat sarcoma (NRAS). Mutations of these genes account for approximately 30% of all cancers. Among them, KRAS mutations are the most common, responsible for 85%, followed by NRAS (12%) and HRAS (3%). Although the development of RAS inhibitors has been explored for over the past decade, so far, no effective inhibitor has been found. MicroRNA (miRNA) are a class of small non-coding RNA that control the gene expression of pleural target genes at the post-transcriptional level. MiRNA play critical roles in the physiological and pathological processes at work in cancers, such as cell proliferation, cell death, cell invasion and metastasis. MicroRNA-143 (MIR143) is known to function as a tumor suppressor in a variety of cancers. One of its known mechanisms is suppression of RAS expression and its effector signaling pathways, such as PI3K/AKT and MAPK/ERK. Within the last five years, we developed a potent chemically modified MIR143-3p that enabled us to elucidate the details of the KRAS signaling networks at play in colon and other cancer cells. In this review, we will discuss the role of MIR143-3p in those RAS signaling networks that are related to various biological processes of cancer cells. In addition, we will discuss the possibility of the use of MIR143 as a therapeutic drug for targeting RAS signaling networks.
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Affiliation(s)
- Yoshihisa Tokumaru
- Breast SurgeryDepartment of Surgical OncologyRoswell Park Comprehensive Cancer CenterBuffaloNew York
- Department of Surgical OncologyGraduate School of MedicineGifu UniversityGifuJapan
| | - Kazuaki Takabe
- Breast SurgeryDepartment of Surgical OncologyRoswell Park Comprehensive Cancer CenterBuffaloNew York
- Department of SurgeryUniversity at Buffalo Jacobs School of Medicine and Biomedical SciencesThe State University of New YorkBuffaloNew York
| | - Kazuhiro Yoshida
- Department of Surgical OncologyGraduate School of MedicineGifu UniversityGifuJapan
| | - Yukihiro Akao
- United Graduate School of Drug and Medical Information SciencesGifu UniversityGifuJapan
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Gong R, Jiang Y. Non-coding RNAs in Pancreatic Ductal Adenocarcinoma. Front Oncol 2020; 10:309. [PMID: 32257946 PMCID: PMC7089935 DOI: 10.3389/fonc.2020.00309] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 02/20/2020] [Indexed: 12/15/2022] Open
Abstract
Non-coding RNAs (ncRNAs) are reported to be expressed in human cancers, including pancreatic ductal adenocarcinoma (PDAC). These ncRNAs affect the growth, migration and invasion of tumor cells by regulating cell cycle and apoptosis, as well as playing important roles in epigenetic processes, transcription and post-transcriptional regulation. It is still unclear whether alterations in ncRNAs influence PDAC development and progression. Because of this, analysis based on existing data on ncRNAs, which are crucial for modulating pancreatic tumorigenesis, will be important for future research on PDAC. Here, we summarize ncRNAs with tumor-promoting functions: HOTAIR, HOTTIP, MALAT1, lncRNA H19, lncRNA PVT1, circ-RNA ciRS-7, circ-0030235, circ-RNA_100782, circ-LDLRAD3, circ-0007534, circRHOT1, circZMYM2, circ-IARS, circ-RNA PDE8A, miR-21, miR-155, miR-221/222, miR-196b, miR-10a. While others including GAS5, MEG3, and lncRNA ENST00000480739, has_circ_0001649, miR-34a, miR-100, miR-217, miR-143 inhibit the proliferation and invasion of PDAC. Hence, we summarize the functions of ncRNAs in the occurrence, development and metastasis of PDAC, with the goal to provide guidance in the clinical diagnosis and treatment of PDAC.
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Affiliation(s)
- Ruining Gong
- Department of Gastroenterology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yueping Jiang
- Department of Gastroenterology, Affiliated Hospital of Qingdao University, Qingdao, China
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27
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Weidle UH, Birzele F, Nopora A. Pancreatic Ductal Adenocarcinoma: MicroRNAs Affecting Tumor Growth and Metastasis in Preclinical In Vivo Models. Cancer Genomics Proteomics 2020; 16:451-464. [PMID: 31659100 DOI: 10.21873/cgp.20149] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 07/30/2019] [Accepted: 08/01/2019] [Indexed: 02/08/2023] Open
Abstract
Patients with pancreatic ductal adenocarcinoma have a dismall prognosis because at the time of diagnosis, in the vast majority of patients the tumor has already disseminated to distant organs and the therapeutic benefit of approved agents such as gemcitabine is limited. Therefore, the identification and preclinical and clinical validation of therapeutic agents covering new targets is of paramount importance. In this review we have summarized microRNAs and corresponding targets which affect growth and metastasis of pancreatic tumors in preclinical mouse in vivo models. We identified four up-regulated and 16 down-regulated miRs in PDAC in comparison to corresponding normal tissues. Three sub-categories of miRs have emerged: miRs affecting tumor growth and miRs with an impact on both, tumor growth and metastasis or metastasis only. Finally, we discuss technical and therapeutic aspects of miR-related therapeutic agents for the treatment of pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Ulrich H Weidle
- Roche Innovation Center Munich, Roche Diagnostics GmbH, Penzberg, Germany
| | - Fabian Birzele
- Roche Innovation Center Basel, F. Hofman La Roche, Basel, Switzerland
| | - Adam Nopora
- Roche Innovation Center Munich, Roche Diagnostics GmbH, Penzberg, Germany
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Venkat S, Tisdale AA, Schwarz JR, Alahmari AA, Maurer HC, Olive KP, Eng KH, Feigin ME. Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma. Genome Res 2020; 30:347-360. [PMID: 32029502 PMCID: PMC7111527 DOI: 10.1101/gr.257550.119] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 02/04/2020] [Indexed: 01/08/2023]
Abstract
Alternative polyadenylation (APA) is a gene regulatory process that dictates mRNA 3'-UTR length, resulting in changes in mRNA stability and localization. APA is frequently disrupted in cancer and promotes tumorigenesis through altered expression of oncogenes and tumor suppressors. Pan-cancer analyses have revealed common APA events across the tumor landscape; however, little is known about tumor type-specific alterations that may uncover novel events and vulnerabilities. Here, we integrate RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project and The Cancer Genome Atlas (TCGA) to comprehensively analyze APA events in 148 pancreatic ductal adenocarcinomas (PDACs). We report widespread, recurrent, and functionally relevant 3'-UTR alterations associated with gene expression changes of known and newly identified PDAC growth-promoting genes and experimentally validate the effects of these APA events on protein expression. We find enrichment for APA events in genes associated with known PDAC pathways, loss of tumor-suppressive miRNA binding sites, and increased heterogeneity in 3'-UTR forms of metabolic genes. Survival analyses reveal a subset of 3'-UTR alterations that independently characterize a poor prognostic cohort among PDAC patients. Finally, we identify and validate the casein kinase CSNK1A1 (also known as CK1alpha or CK1a) as an APA-regulated therapeutic target in PDAC. Knockdown or pharmacological inhibition of CSNK1A1 attenuates PDAC cell proliferation and clonogenic growth. Our single-cancer analysis reveals APA as an underappreciated driver of protumorigenic gene expression in PDAC via the loss of miRNA regulation.
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Affiliation(s)
- Swati Venkat
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, USA
| | - Arwen A Tisdale
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, USA
| | - Johann R Schwarz
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, USA
| | - Abdulrahman A Alahmari
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, USA
| | - H Carlo Maurer
- Klinikum rechts der Isar, II. Medizinische Klinik, Technische Universität München, 81675 Munich, Germany
| | - Kenneth P Olive
- Herbert Irving Comprehensive Cancer Center, Department of Medicine, Division of Digestive and Liver Diseases, Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York 10032, USA
| | - Kevin H Eng
- Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, USA
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, USA
| | - Michael E Feigin
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, USA
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Yu B, Yu M, Zhang H, Xie D, Nie W, Shi K. Suppression of miR-143-3p contributes to the anti-fibrosis effect of atorvastatin on myocardial tissues via the modulation of Smad2 activity. Exp Mol Pathol 2020; 112:104346. [PMID: 31758917 DOI: 10.1016/j.yexmp.2019.104346] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 08/20/2019] [Accepted: 11/19/2019] [Indexed: 01/17/2023]
Abstract
Atorvastatin is a commonly prescribed statin drug for the control of lipid synthesis and recent studies have shown the cardiac protection potential of atorvastatin. Cardiac fibrosis is a critical process that impairs heart function. In the current study, the anti-fibrosis potential of atorvastatin was assessed and the mechanism associated with the treatment was explored. Fibrotic symptoms were induced using transverse aortic constriction (TAC) method in vivo and using TGF-β1 in vitro. The effect of atorvastatin on the development of cardiac fibrosis was firstly measured. Moreover, the influence of miR-143-3p induction on the anti-fibrosis function of atorvastatin was determined. TAC administration induced cardiac fibrosis and heart weight increase, which was associated with the induced expressions of TGF-β1, miR-143-3p, p-Smad2, and collagens. Atorvastatin restored the levels of TGF-β1, miR-143-3p, p-Smad2, and collagens. The administration of TGF-β1 induced the expressions of miR-143-3p, p-Smad2, and collagens in cardiac fibroblasts (CFs) and the effect was inhibited by atorvastatin. However, the function of atorvastatin was blocked by miR-143-3p mimics. The current study demonstrated that the suppression of miR-143-3p contributed to the anti-fibrosis effect of atorvastatin on myocardial tissues, which subsequently inhibited Smad2-mediated production of collagens.
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Affiliation(s)
- Bo Yu
- Department of Cardiology, Jilin Provincial Key Laboratory for Genetic Diagnosis of Cardiovascular Disease, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China
| | - Ming Yu
- Department of Cardiology, Jilin Provincial Key Laboratory for Genetic Diagnosis of Cardiovascular Disease, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China
| | - Hongli Zhang
- Department of Cardiology, Jilin Provincial Key Laboratory for Genetic Diagnosis of Cardiovascular Disease, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China
| | - Di Xie
- Department of Cardiology, Jilin Provincial Key Laboratory for Genetic Diagnosis of Cardiovascular Disease, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China
| | - Wei Nie
- Department of Cardiology, Jilin Provincial Key Laboratory for Genetic Diagnosis of Cardiovascular Disease, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China
| | - Kaiyao Shi
- Department of Cardiology, Jilin Provincial Key Laboratory for Genetic Diagnosis of Cardiovascular Disease, China-Japan Union Hospital of Jilin University, Changchun 130033, People's Republic of China.
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30
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Wang ZL, Wang C, Liu W, Ai ZL. Upregulation of microRNA-143-3p induces apoptosis and suppresses proliferation, invasion, and migration of papillary thyroid carcinoma cells by targeting MSI2. Exp Mol Pathol 2019; 112:104342. [PMID: 31738908 DOI: 10.1016/j.yexmp.2019.104342] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 10/14/2019] [Accepted: 11/15/2019] [Indexed: 12/24/2022]
Abstract
As a tumor-associated biological molecule, microRNA-143-3p (miR-143-3p) is implicated in the progression of papillary thyroid carcinoma (PTC). We conducted this study to elucidate the effects of miR-143-3p mediated by Musashi RNA binding protein 2 (MSI2) on the biological activities of PTC cells. The K1 cells with the lowest miR-143-3p expression were selected for the experiments. The targeting relationship between miR-143-3p and MSI2 was verified. The biological functions of miR-143-3p and MSI2 with respect to K1 cell proliferation, cycle distribution, apoptosis, invasion, migration, and tumorigenesis were studied using gain- and loss-of-function assays both in vitro and in vivo. MSI2 was verified to be a target gene of miR-143-3p. Cells treated with upregulation of miR-143-3p or silencing of MSI2 exhibited significantly decreased the expression of Bcl-2, PCNA, MCM2, Ki67, MSI2, MMP-2, and MMP-9. This was accompanied by inhibited cell proliferation, cell invasion, and migration, as well as a significant increase in Bax expression, cell cycle arrest, and cell apoptosis. More importantly, the tumor inhibitory effects of upregulated miR-143-3p were also confirmed in the tumor xenografts in nude mice. Our results indicate that upregulation of miR-143-3p suppresses the progression of PTC by impeding cell growth, invasion, and migration via downregulation of MSI2, highlighting the potential of miR-143-3p as a target for future PTC treatment.
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Affiliation(s)
- Zheng-Lin Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Cong Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Wei Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Zhi-Long Ai
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China.
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31
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Mesgarzadeh AH, Aali M, Farhadi F, Noorolyai S, Baghbani E, Mohammadnejad F, Baradaran B. Transfection of microRNA-143 mimic could inhibit migration of HN-5 cells through down-regulating of metastatic genes. Gene 2019; 716:144033. [DOI: 10.1016/j.gene.2019.144033] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 07/30/2019] [Accepted: 07/31/2019] [Indexed: 11/17/2022]
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Rawat M, Kadian K, Gupta Y, Kumar A, Chain PSG, Kovbasnjuk O, Kumar S, Parasher G. MicroRNA in Pancreatic Cancer: From Biology to Therapeutic Potential. Genes (Basel) 2019; 10:752. [PMID: 31557962 PMCID: PMC6827136 DOI: 10.3390/genes10100752] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 09/19/2019] [Accepted: 09/20/2019] [Indexed: 12/20/2022] Open
Abstract
Pancreatic cancer is one of the most aggressive malignancies, accounting for more than 45,750 deaths annually in the U.S. alone. The aggressive nature and late diagnosis of pancreatic cancer, coupled with the limitations of existing chemotherapy, present the pressing need for the development of novel therapeutic strategies. Recent reports have demonstrated a critical role of microRNAs (miRNAs) in the initiation, progression, and metastasis of cancer. Furthermore, aberrant expressions of miRNAs have often been associated with the cause and consequence of pancreatic cancer, emphasizing the possible use of miRNAs in the effective management of pancreatic cancer patients. In this review, we provide a brief overview of miRNA biogenesis and its role in fundamental cellular process and miRNA studies in pancreatic cancer patients and animal models. Subsequent sections narrate the role of miRNA in, (i) cell cycle and proliferation; (ii) apoptosis; (iii) invasions and metastasis; and (iv) various cellular signaling pathways. We also describe the role of miRNA's in pancreatic cancer; (i) diagnosis; (ii) prognosis and (iii) therapeutic intervention. Conclusion section describes the gist of review with future directions.
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Affiliation(s)
- Manmeet Rawat
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
| | - Kavita Kadian
- Department of Biotechnology, Kumaun University, Nainital, Uttarakhand 263001, India.
| | - Yash Gupta
- Department of Internal Medicine, Loyola University Medical Center, Chicago, IL 60153, USA.
| | - Anand Kumar
- Biosecurity and Public Health Group, Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
| | - Patrick S G Chain
- Biosecurity and Public Health Group, Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
| | - Olga Kovbasnjuk
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
| | - Suneel Kumar
- Department of Biomedical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
| | - Gulshan Parasher
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
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Liu C, Wang JO, Zhou WY, Chang XY, Zhang MM, Zhang Y, Yang XH. Long non-coding RNA LINC01207 silencing suppresses AGR2 expression to facilitate autophagy and apoptosis of pancreatic cancer cells by sponging miR-143-5p. Mol Cell Endocrinol 2019; 493:110424. [PMID: 30991076 DOI: 10.1016/j.mce.2019.04.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 04/03/2019] [Accepted: 04/03/2019] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is a serious malignancy accompanied by a well-documented poor prognosis. Accumulating studies have indicated the crucial roles played by long non-coding RNAs (lncRNAs) in proliferation, apoptosis and invasion of cancer cells. The aim of the current study was to investigate the role of lncRNA LINC01207 in autophagy and apoptosis of pancreatic cancer cells and its regulatory mechanism interacting with miR-143-5p. Initially, expression profiles of lncRNAs and genes associated with pancreatic cancer were identified. The expression patterns of LINC01207, miR-143-5p and AGR2 in both pancreatic cancer and adjacent tissues were then determined. The binding relationship of LINC01207 to miR-143-5p and targeting relationship of miR-143-5p to AGR2 were subsequently verified. Silencing of LINC01207, or up-regulation or down-regulation of miR-143-5p was introduced into the pancreatic cancer cells, so as to analyze their effects on the cell growth, apoptosis and autophagy. Besides, these regulatory effects were further explored with the determination of the autophagy- and apoptosis-related gene or proteins. LINC01207 and AGR2 were highly expressed while miR-143-5p was poorly expressed in pancreatic cancer. Functionally, LINC01207 can bind to miR-143-5p, and AGR2 was a target gene of miR-143-5p. Importantly, silencing of LINC01207 down-regulated the expression of AGR2 by up-regulating miR-143-5p. Moreover, silencing of LINC01207 and up-regulation of miR-143-5p promoted cell apoptosis and autophagy, corresponding to increased expression of autophagy- and apoptosis-related proteins, in addition to inhibited cell growth. Taken together, silencing of LINC01207 prevents the progression of pancreatic cancer by impairing miR-143-5p-targeted AGR2 expression, providing a potential target for pancreatic cancer treatment.
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Affiliation(s)
- Chang Liu
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, 110004, PR China
| | - Jin-Ou Wang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, 110004, PR China
| | - Wen-Yang Zhou
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, 110004, PR China
| | - Xiao-Ying Chang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, 110004, PR China
| | - Ming-Ming Zhang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, 110004, PR China
| | - Ying Zhang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, 110004, PR China
| | - Xiang-Hong Yang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, 110004, PR China.
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Nisha KJ, Janam P, Harshakumar K. Identification of a novel salivary biomarker miR-143-3p for periodontal diagnosis: A proof of concept study. J Periodontol 2019; 90:1149-1159. [PMID: 31021403 DOI: 10.1002/jper.18-0729] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 03/22/2019] [Accepted: 03/22/2019] [Indexed: 01/06/2023]
Abstract
BACKGROUND Though the use of salivary miRNAs as potential biomarkers has been reported in few diseases/conditions such as rheumatoid arthritis and oral cancer, there are no reported studies on their utility in periodontal diagnostics. Thus, the aim of the present study was to profile salivary miRNAs and identify the most suitable salivary miRNA biomarker in chronic periodontitis. METHODS In this study, we have explored the potential application of next generation sequencing (NGS) technology for profiling miRNAs in two unstimulated saliva samples collected by passive drool method from a patient diagnosed with generalized chronic periodontitis and a healthy control. Subsequently, the validation of most highly expressed known miRNA in periodontitis was performed in saliva samples collected from an independent set of 16 chronic periodontitis patients and 16 periodontally healthy controls using quantitative real-time PCR (qRT-PCR). Target gene prediction and pathway mapping were performed using bioinformatic tools. RESULTS NGS analysis identified 40 upregulated and 40 downregulated known miRNAs in chronic periodontitis compared to healthy controls, of which miR-143-3p was the most highly expressed miRNA in periodontitis (Read count - 227630; fold change - 5.82). Validation using qRT-PCR showed significant upregulation of miR-143-3p expression in the test group compared with controls (P < 0.05). K-RAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene) gene was predicted as the target gene for miR-143-3p in humans. KEGG (Kyoto Encyclopedia of genes and genomes) pathway mapping revealed the involvement of K-RAS in mitogen-activated protein kinases (MAPK) pathway. CONCLUSIONS The application of NGS for miRNA expression profiling can be considered a valuable tool in detection of novel biomarkers in periodontal diagnostics. Also, the results of the study points to the potential utility of miR143-3p as a novel salivary biomarker for chronic periodontitis.
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Affiliation(s)
- K J Nisha
- Department of Periodontics, Vydehi Institute of Dental Sciences and Research Centre, Bangalore, Karnataka, India
| | - Presanthila Janam
- Department of Periodontics, PMS College of Dental Science and Research, Thiruvananthapuram, Kerala, India
| | - K Harshakumar
- Department of Prosthodontics, Government Dental College, Thiruvananthapuram, Kerala, India
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Karimi L, Zeinali T, Hosseinahli N, Mansoori B, Mohammadi A, Yousefi M, Asadi M, Sadreddini S, Baradaran B, Shanehbandi D. miRNA-143 replacement therapy harnesses the proliferation and migration of colorectal cancer cells in vitro. J Cell Physiol 2019; 234:21359-21368. [PMID: 31032951 DOI: 10.1002/jcp.28745] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 04/02/2019] [Accepted: 04/05/2019] [Indexed: 12/18/2022]
Abstract
miR-143 is a tumor suppressor miRNA which its downregulation is frequently reported in colorectal cancer (CRC). This miRNA is a negative regulator of K-RAS, c-MYC, BCL-2, and MMP-9 genes which are engaged in tumor growth and metastasis. In the present study, miR-143 restoration was performed by transfection of the pCMV-miR-143 vector into the SW-480 CRC cells. Subsequently, alterations in proliferative and migratory potential of the cells were investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and wound-healing assays, respectively. Moreover, to detect apoptosis incidence in the transfected cells, 4',6-diamidino-2-phenylindole (DAPI) staining was used. Furthermore, mRNA levels of c-MYC, K-RAS, MMP-9, and BCL-2, as potential targets of miR-143, were assessed by quantitative Real-Time PCR (qRT-PCR). Also the expression levels of c-MYC, K-RAS, and MMP-9 proteins were investigated by the western blot analysis. Finally, the ratio of BAX to BCL-2 expression, as a potential marker of the response to apoptosis stimuli, was compared between the control and test groups. Furthermore, the trypan blue test was performed to determine the cell viability in cell suspension. According to the results, a decreased viability and migratory potential was observed for the miR-143 receiving cells. The DAPI staining also confirmed the occurrence of apoptosis. Moreover, BCL-2, K-RAS, MMP-9, and c-MYC mRNAs were significantly downregulated in the miR-143 grafted cells. The BAX/BCL-2 ratio also indicated a notable increase in the cells with miR-143 overexpression. In brief, miR-143 replacement could be considered as an effective strategy for the management of CRC and attenuating its invasive features.
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Affiliation(s)
- Leila Karimi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tahereh Zeinali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nayer Hosseinahli
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Mohammadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Milad Asadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sanam Sadreddini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Chen J, Yu Y, Li H, Hu Q, Chen X, He Y, Xue C, Ren F, Ren Z, Li J, Liu L, Duan Z, Cui G, Sun R. Long non-coding RNA PVT1 promotes tumor progression by regulating the miR-143/HK2 axis in gallbladder cancer. Mol Cancer 2019; 18:33. [PMID: 30825877 PMCID: PMC6397746 DOI: 10.1186/s12943-019-0947-9] [Citation(s) in RCA: 284] [Impact Index Per Article: 47.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 01/23/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The long non-coding RNA PVT1 (lncRNA PVT1) has been reported to act as an oncogenic regulator of several cancers. However, its expression and function in gallbladder cancer (GBC) remain largely unknown. METHODS In situ hybridization (ISH) and quantitative real-time PCR (qPCR) were performed to detect the expression of PVT1 and miR-143 in GBC tissues and cell lines. Immunohistochemistry (IHC) assays were performed to assess the expression of the hexokinase 2 (HK2) protein. The relationships among PVT1, miR-143 and HK2 were evaluated using dual-luciferase reporter, RNA immunoprecipitation (RIP) and biotin pull-down assays. The biological functions of PVT1, miR-143 and HK2 in GBC cells were explored with cell counting kit 8 (CCK-8), 5-ethynyl-20-deoxyuridine (EdU), colony formation, transwell, wound healing and glucose metabolism assays in vitro. For in vivo experiments, a xenograft model was used to investigate the effects of PVT1 and HK2 on GBC. RESULTS PVT1 was upregulated in GBC tissues and cells and was positively associated with malignancies and worse overall survival. PVT1 knockdown inhibited cell proliferation, migration, and invasion in vitro and restrained tumor growth in vivo. Further studies demonstrated that PVT1 positively regulated HK2 expression via its competing endogenous RNA (ceRNA) activity on miR-143. Additionally, HK2 expression and function were positively correlated with PVT1. Furthermore, we observed that the PVT1/miR-143/HK2 axis promoted cell proliferation and metastasis by regulating aerobic glucose metabolism in GBC cells. CONCLUSIONS The results of our study reveal a potential ceRNA regulatory pathway in which PVT1 modulates HK2 expression by competitively binding to endogenous miR-143 in GBC cells, which may provide new insights into novel molecular therapeutic targets for GBC.
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Affiliation(s)
- Jianan Chen
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Yan Yu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Hua Li
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Qiuyue Hu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Xiaolong Chen
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Yuting He
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Chen Xue
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Fang Ren
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Zhigang Ren
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Juan Li
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Liwen Liu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Zhenfeng Duan
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095 USA
| | - Guangying Cui
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
| | - Ranran Sun
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China
- National Engineering Laboratory for Internet Medical System and Application, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
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Khatri I, Ganguly K, Sharma S, Carmicheal J, Kaur S, Batra SK, Bhasin MK. Systems Biology Approach to Identify Novel Genomic Determinants for Pancreatic Cancer Pathogenesis. Sci Rep 2019; 9:123. [PMID: 30644396 PMCID: PMC6333820 DOI: 10.1038/s41598-018-36328-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 11/05/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a 5-year survival rate of <8%. Its dismal prognosis stems from inefficient therapeutic modalities owing to the lack of understanding about pancreatic cancer pathogenesis. Considering the molecular complexity and heterogeneity of PDAC, identification of novel molecular contributors involved in PDAC onset and progression using global "omics" analysis will pave the way to improved strategies for disease prevention and therapeutic targeting. Meta-analysis of multiple miRNA microarray datasets containing healthy controls (HC), chronic pancreatitis (CP) and PDAC cases, identified 13 miRNAs involved in the progression of PDAC. These miRNAs showed dysregulation in both tissue as well as blood samples, along with progressive decrease in expression from HC to CP to PDAC. Gene-miRNA interaction analysis further elucidated 5 miRNAs (29a/b, 27a, 130b and 148a) that are significantly downregulated in conjunction with concomitant upregulation of their target genes throughout PDAC progression. Among these, miRNA-29a/b targeted genes were found to be most significantly altered in comparative profiling of HC, CP and PDAC, indicating its involvement in malignant evolution. Further, pathway analysis suggested direct involvement of miRNA-29a/b in downregulating the key pathways associated with PDAC development and metastasis including focal adhesion signaling and extracellular matrix organization. Our systems biology data analysis, in combination with real-time PCR validation indicates direct functional involvement of miRNA-29a in PDAC progression and is a potential prognostic marker and therapeutic candidate for patients with progressive disease.
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Affiliation(s)
- Indu Khatri
- BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Koelina Ganguly
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Sunandini Sharma
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Joseph Carmicheal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Sukhwinder Kaur
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
| | - Manoj K Bhasin
- BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, MA, USA.
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38
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Yang X, Wang W, Zhang X, Zou Q, Cai L, Yu B. Downregulation of miR-183 inhibits the growth of PANC-1 pancreatic cancer cells in vitro and in vivo, and increases chemosensitivity to 5-fluorouracil and gemcitabine. Exp Ther Med 2018; 17:1697-1705. [PMID: 30783438 PMCID: PMC6364144 DOI: 10.3892/etm.2018.7112] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 07/26/2018] [Indexed: 12/15/2022] Open
Abstract
Pancreatic cancer (PC) is a common malignancy with a poorly understood pathogenesis. Currently, the efficacy of anti-PC therapies is insufficient, partially due to the chemoresistance of cancer cells. The present study aimed to elucidate the role of miR-183 in the proliferation, apoptosis, and chemosensitivity to 5-fluorouracil and gemcitabine of human PC cells and the associated mechanisms. PANC-1 cells were transfected with microRNA (miR)-183 inhibitors, and the effect of miR-183 on cell proliferation was evaluated via MTT assay. Apoptosis and cell cycle distribution were determined by flow cytometry. In vivo tumor xenograft models of PANC-1 cells were generated in BALB/c nude mice to examine the effect of miR-183 downregulation on tumor growth. Furthermore, components of the phosphatase and tensin homolog deleted on chromosome ten (PTEN)/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway were examined via reverse transcription-quantitative polymerase chain reaction and western blotting in the collected cells. Finally, PANC-1 cells were treated with 5-fluorouracil or gemcitabine and transfected with miR-183 inhibitors, and the viability of cells was determined by MTT assay. The results demonstrated that knockdown of miR-183 could significantly decrease proliferation and promote apoptosis of PANC-1 cells. The cells transfected with miR-183 inhibitors were significantly arrested at the G1 phase (P<0.01). Furthermore, miR-183 downregulation led to significant decreases in the mRNA levels of PI3K, Akt and B cell lymphoma-2 (Bcl-2) expression (P<0.001), and significant increases in PTEN and Bcl-2 associated X protein expression in PANC-1 cells (P<0.001). Knockdown of miR-183 was able to significantly increase the chemosensitivity of PANC-1 cells to 5-fluorouracil and gemcitabine. These results indicate that downregulation of miR-183 can inhibit the growth of PC cells in vitro and in vivo, and increase cell sensitivity to 5-fluorouracil and gemcitabine through regulating the PTEN/PI3K/Akt signaling pathway.
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Affiliation(s)
- Xiaoping Yang
- Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China
| | - Wei Wang
- Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China
| | - Xiong Zhang
- Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China
| | - Qi Zou
- Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China
| | - Lei Cai
- Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China
| | - Bo Yu
- Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China
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Zhang L, Yu S, Wang C, Jia C, Lu Z, Chen J. Establishment of a non‑coding RNAomics screening platform for the regulation of KRAS in pancreatic cancer by RNA sequencing. Int J Oncol 2018; 53:2659-2670. [PMID: 30221677 DOI: 10.3892/ijo.2018.4560] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 08/09/2018] [Indexed: 11/05/2022] Open
Affiliation(s)
- Li Zhang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Shuangni Yu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Cuiping Wang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Congwei Jia
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Zhaohui Lu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Jie Chen
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
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40
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Noruzi S, Azizian M, Mohammadi R, Hosseini SA, Rashidi B, Mohamadi Y, Nesaei A, Seiri P, Sahebkar A, Salarinia R, Aghdam AM, Mirzaei H. Micro-RNAs as critical regulators of matrix metalloproteinases in cancer. J Cell Biochem 2018; 119:8694-8712. [PMID: 30132957 DOI: 10.1002/jcb.27182] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Accepted: 05/24/2018] [Indexed: 12/25/2022]
Abstract
Metastasis is known to be one of the important factors associated with cancer-related deaths worldwide. Several cellular and molecular targets are involved in the metastasis process. Among these targets, matrix metalloproteinases (MMPs) play central roles in promoting cancer metastasis. MMPs could contribute toward tumor growth, angiogenesis, migration, and invasion via degradation of the extracellular matrix and activation of pre-pro-growth factors. Therefore, identification of various cellular and molecular pathways that affect MMPs could contribute toward a better understanding of the metastatic pathways involved in various tumors. Micro-RNAs are important targets that could affect MMPs. Multiple lines of evidence have indicated that deregulation of various micro-RNAs, including miR-9, Let-7, miR-10b, and miR-15b, affects metastasis of tumor cells via targeting MMPs.
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Affiliation(s)
- Somaye Noruzi
- Department of Medical Biotechnology and Molecular Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnourd, Iran
| | - Mitra Azizian
- Department of Clinical Biochemistry, Ftabaculty of Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Rezvan Mohammadi
- Department of Medical Biotechnology and Molecular Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnourd, Iran
| | - Seyede Atefe Hosseini
- Department of Medical Biotechnology and Molecular Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnourd, Iran
| | - Bahman Rashidi
- Department of Anatomical Sciences, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yousef Mohamadi
- Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Department of Anatomy, Faculty of medicine, Qom University of Medical Sciences, Qom, Iran
| | - Abolfazl Nesaei
- Department of Basic Sciences, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Parvaneh Seiri
- Department of Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Salarinia
- Department of Medical Biotechnology and Molecular Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnourd, Iran
| | - Arad Mobasher Aghdam
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Department of Biomaterials, Tissue Engineering and Nanotechnology, School of Advanced Technologies in Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Feng X, Peng F, Zhang B, Wang L, Guo E, Li Y, Jiang C, Wu Z, Liu A. Lower miR-143/145 and higher matrix metalloproteinase-9 levels in circulation may be associated with intracranial aneurysm formation and rupture: A pilot study. Clin Neurol Neurosurg 2018; 173:124-129. [PMID: 30121455 DOI: 10.1016/j.clineuro.2018.08.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 08/02/2018] [Accepted: 08/05/2018] [Indexed: 12/17/2022]
Abstract
OBJECTIVES We analyzed the relationship between plasma miR-143/145 and serum MMP-9 in patients with unruptured or ruptured intracranial aneurysms (IAs) to identify new biomarkers for predicting rupture in IAs. PATIENTS AND METHODS We prospectively enrolled 24 consecutive patients, including seven patients without IAs as a control group, nine patients with unruptured IAs, and eight patients with ruptured IAs (enrolled within 3 days after rupture). Plasma miR-143/145 and MMP-9 were measured in blood samples collected from the femoral artery. Spearman ρ values were used for correlation analyses. RESULTS The level of plasma miR-143/145 in patients with ruptured IAs was significantly lower than that of the control group. Moreover, patients with ruptured IAs had a significantly higher level of serum MMP-9 compared with that in patients with unruptured IAs and in control patients. A lower level of plasma miR-143 was significantly correlated with a lower level of plasma miR-145 (Spearman ρ = 0.771; P < 0.0001). CONCLUSION These findings showed that a lower of plasma miR-143/145 is potentially associated with IA formation, while higher serum MMP-9 levels may be associated with IA rupture and could serve as a useful biomarker for the evaluation of IA rupture.
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Affiliation(s)
- Xin Feng
- Department of Neurosurgery, Beijing Hospital, National Center of Gerontology; Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, China
| | - Fei Peng
- Beijing Neurosurgical Institute, Capital Medical University, 100050, China; Department of Interventional Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, 100050, China
| | - Baorui Zhang
- Beijing Neurosurgical Institute, Capital Medical University, 100050, China; Department of Interventional Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, 100050, China
| | - Luyao Wang
- Beijing Neurosurgical Institute, Capital Medical University, 100050, China; Department of Interventional Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, 100050, China
| | - Erkang Guo
- Beijing Neurosurgical Institute, Capital Medical University, 100050, China; Department of Interventional Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, 100050, China
| | - Youxiang Li
- Beijing Neurosurgical Institute, Capital Medical University, 100050, China; Department of Interventional Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, 100050, China
| | - Chuhan Jiang
- Beijing Neurosurgical Institute, Capital Medical University, 100050, China; Department of Interventional Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, 100050, China
| | - Zhongxue Wu
- Beijing Neurosurgical Institute, Capital Medical University, 100050, China; Department of Interventional Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, 100050, China
| | - Aihua Liu
- Beijing Neurosurgical Institute, Capital Medical University, 100050, China; Department of Interventional Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, 100050, China.
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Piperigkou Z, Manou D, Karamanou K, Theocharis AD. Strategies to Target Matrix Metalloproteinases as Therapeutic Approach in Cancer. Methods Mol Biol 2018; 1731:325-348. [PMID: 29318564 DOI: 10.1007/978-1-4939-7595-2_27] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are capable of degrading numerous extracellular matrix (ECM) components thus participating in physiological and pathological processes. Apart from the remodeling of ECM, they affect cell-cell and cell-matrix interactions and are implicated in the development and progression of various diseases such as cancer. Numerous studies have demonstrated that MMPs evoke epithelial to mesenchymal transition (EMT) of cancer cells and affect their signaling, adhesion, migration and invasion to promote cancer cell aggressiveness. Various studies have suggested MMPs as suitable targets for treatment of malignancies, and several MMP inhibitors (MMPIs) have been developed. Although initial trials have failed to establish MMPIs as anticancer agents due to lack of specificity and side effects, new MMPIs have been developed with improved action that are currently being investigated. Furthermore, novel strategies that target MMPs for improving drug delivery and regulating their activity in tumors are presented. This review summarizes the implication of MMPs in cancer progression and discusses the advancements in their targeting.
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Affiliation(s)
- Zoi Piperigkou
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
| | - Dimitra Manou
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
| | - Konstantina Karamanou
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
| | - Achilleas D Theocharis
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece.
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43
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Karmakar S, Kaushik G, Nimmakayala R, Rachagani S, Ponnusamy MP, Batra SK. MicroRNA regulation of K-Ras in pancreatic cancer and opportunities for therapeutic intervention. Semin Cancer Biol 2017; 54:63-71. [PMID: 29199014 DOI: 10.1016/j.semcancer.2017.11.020] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Revised: 11/28/2017] [Accepted: 11/28/2017] [Indexed: 01/17/2023]
Abstract
The Ras family of GTPases is involved in cell proliferation, cell survival, and angiogenesis. It is upregulated in several cancers, including pancreatic cancer (PC) and leads to uncontrolled growth and aggressiveness. PC is well known to be a lethal disease with poor prognosis, plagued by limited therapeutic modalities. MicroRNAs (miRNAs), which are short non-coding RNA molecules, have recently emerged as regulators of signaling networks and have shown potential to target pathway components for therapeutic use in several malignancies. K-Ras mutations are widespread in PC cases (90%), with mutations detectable as early as pancreatic intraepithelial neoplasias and in later metastatic stages alike; therefore, these mutations in K-Ras are obvious drivers and potential targets for PC therapy. Several K-Ras targeting miRNAs have lately been discovered, and many of them have shown promise in combating pancreatic tumor growth in vitro and in mouse models. However, the field of miRNA therapy is still in its infancy, and miRNA mimics or anti-miRNA oligonucleotides that target Ras pathway have thus far not been evaluated in PC patients. In this review, we summarize the role of several miRNAs that regulate oncogenic K-Ras signaling in PC, with their prospective roles as therapeutic agents for targeting K-Ras pathway.
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Affiliation(s)
- Saswati Karmakar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Garima Kaushik
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Ramakrishna Nimmakayala
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Eppley Institute for Research in Cancer and Allied Diseases and Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Eppley Institute for Research in Cancer and Allied Diseases and Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
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44
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Taguchi YH. Tensor decomposition-based unsupervised feature extraction applied to matrix products for multi-view data processing. PLoS One 2017; 12:e0183933. [PMID: 28841719 PMCID: PMC5571984 DOI: 10.1371/journal.pone.0183933] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 08/04/2017] [Indexed: 01/17/2023] Open
Abstract
In the current era of big data, the amount of data available is continuously increasing. Both the number and types of samples, or features, are on the rise. The mixing of distinct features often makes interpretation more difficult. However, separate analysis of individual types requires subsequent integration. A tensor is a useful framework to deal with distinct types of features in an integrated manner without mixing them. On the other hand, tensor data is not easy to obtain since it requires the measurements of huge numbers of combinations of distinct features; if there are m kinds of features, each of which has N dimensions, the number of measurements needed are as many as Nm, which is often too large to measure. In this paper, I propose a new method where a tensor is generated from individual features without combinatorial measurements, and the generated tensor was decomposed back to matrices, by which unsupervised feature extraction was performed. In order to demonstrate the usefulness of the proposed strategy, it was applied to synthetic data, as well as three omics datasets. It outperformed other matrix-based methodologies.
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Affiliation(s)
- Y-h. Taguchi
- Department of Physics, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan
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45
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Li H, Wu Y, Li P. MicroRNA-452 suppresses pancreatic cancer migration and invasion by directly targeting B-cell-specific Moloney murine leukemia virus insertion site 1. Oncol Lett 2017; 14:3235-3242. [PMID: 28927071 DOI: 10.3892/ol.2017.6566] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 04/28/2017] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer, one of the most common cancers globally, is the fourth most common cause of cancer-associated mortality in the USA. The 5-year relative survival rate for patients with pancreatic cancer is ~5% and the median survival time is only 6 months. The poor prognosis is mainly due to early and aggressive local invasion and metastasis, as well as dissemination of the pancreatic cancer cells. The present study demonstrated that microRNA-452 (miR-452) was markedly downregulated in pancreatic cancer tissues, particularly in metastatic tumors and pancreatic cancer cell lines. Overexpression of miR-452 significantly inhibited migration and invasion in pancreatic cancer cells. In addition, the molecular mechanism underlying the inhibitory functions of miR-452 in pancreatic cancer was also investigated. The results indicated that B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI1) was a direct target gene of miR-452 in pancreatic cancer. Overexpression of miR-452 inhibited the migration and invasion of pancreatic cancer, at least partially by knockdown of BMI1 expression. The results provided novel insight with potential therapeutic applications for the treatment of metastatic pancreatic cancer.
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Affiliation(s)
- Hongyan Li
- Department of Endocrinology, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
| | - Yan Wu
- Department of Endocrinology, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
| | - Peixiu Li
- Department of Endocrinology, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
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Karimi L, Mansoori B, shanebandi D, Mohammadi A, Aghapour M, Baradaran B. Function of microRNA-143 in different signal pathways in cancer: New insights into cancer therapy. Biomed Pharmacother 2017; 91:121-131. [DOI: 10.1016/j.biopha.2017.04.060] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 04/05/2017] [Accepted: 04/13/2017] [Indexed: 01/05/2023] Open
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LncRNA-SARCC suppresses renal cell carcinoma (RCC) progression via altering the androgen receptor(AR)/miRNA-143-3p signals. Cell Death Differ 2017. [PMID: 28644440 DOI: 10.1038/cdd.2017.74] [Citation(s) in RCA: 123] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
While the androgen receptor (AR) might promote renal cell carcinoma (RCC) initiation and progression, the molecular mechanisms involved remain largely unclear. Here, we discovered the novel LncRNA-SARCC, which was suppressed and associated with better prognosis in RCC. Preclinical studies using multiple RCC cells and in vivo mouse model indicated that LncRNA-SARCC could attenuate RCC cell invasion, migration and proliferation in vitro and in vivo. Mechanistically, LncRNA-SARCC bound and destabilized AR protein with an inhibition of AR function, which led to transcriptionally de-repress miR-143-3p expression, thus inhibition of its downstream signals including AKT, MMP-13, K-RAS and P-ERK. In addition, bisulfite sequencing analysis substantiated that LncRNA-SARCC promoter was highly methylated in renal cancer tissues compared with paired non-cancerous renal tissues. Notably, treating with Sunitinib, the multi-targeted receptor tyrosine kinase inhibitor, increased the expression of LncRNA-SARCC, which decreased RCC cells resistance to Sunitinib. Thus, our study presented a road map for targeting this newly identified LncRNA-SARCC and its pathway, which expands potential therapeutic strategies for RCC treatment.
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MicroRNA-143 suppresses oral squamous cell carcinoma cell growth, invasion and glucose metabolism through targeting hexokinase 2. Biosci Rep 2017; 37:BSR20160404. [PMID: 28174335 PMCID: PMC5463264 DOI: 10.1042/bsr20160404] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Revised: 11/16/2016] [Accepted: 02/07/2017] [Indexed: 11/17/2022] Open
Abstract
miRNAs are non-coding RNAs that have functions to regulate gene expression and play essential roles in a variety of biological processes of cancers. In the present study, we report miR-143 acts as a tumor suppressor in human oral squamous cell carcinoma (OSCC). The expressions of miR-143 are down-regulated in both OSCC cell lines and patient samples compared with normal adjacent tissues. We found overexpression of miR-143 in oral cancer cell lines suppresses cell migration, cellular glucose metabolism and proliferation. Moreover, overexpression of miR-143 promoted apoptosis and significantly caused cell cycle arrest at G1 stage. The colony formation of oral cancer cells was also suppressed by miR-143 We identified hexokinase 2 (HK2) as a direct target of miR-143 in oral cancer cells. Our data show that miR-143 complementary pairs to the 3'-UTR of HK2 in oral cancer cells, leading to the inhibition of glycolysis in vitro and in vivo Moreover, knockdown of HK2 by siRNA in oral cancer cells inhibited glucose metabolism, proliferation and migration. Recovery of glucose metabolism by overexpression of HK2 in miR-143 overexpressing cells restores the cell migration and proliferation, suggesting that the miR-143-mediated cancer suppression is through the direct inhibition of HK2. In summary, the present studies highlight miR-143 as a tumor suppressor in OSCC by the suppression of cell migration, glucose metabolism and proliferation through directly targeting HK2, rendering miR-143 a therapeutic strategy for the treatment of clinical OSCC patients.
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Huang FT, Peng JF, Cheng WJ, Zhuang YY, Wang LY, Li CQ, Tang J, Chen WY, Li YH, Zhang SN. MiR-143 Targeting TAK1 Attenuates Pancreatic Ductal Adenocarcinoma Progression via MAPK and NF-κB Pathway In Vitro. Dig Dis Sci 2017; 62:944-957. [PMID: 28194669 DOI: 10.1007/s10620-017-4472-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Accepted: 01/20/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Transforming growth factor (TGF)-β-activated kinase 1 (TAK1) is one of the major regulators of inflammation-induced cancer cell growth and progression. MiR-143 dysregulation is a common event in a variety of human diseases including pancreatic ductal adenocarcinoma (PDA). AIMS To identify the interaction between TAK1 and miR-143 in PDA. METHODS Data mining of TAK1 expression in PDA patient gene profiling was conducted. QRT-PCR and western blot were performed to detect the expression of TAK1 in PDA tissues and cell lines. Ectopic miR-143 and TAK1 were introduced to PDA cells. Cell growth, apoptosis and migration were examined. Xenograft models were used to examine the function of TAK1 in vivo. Western blot and luciferase assay were carried out to investigate the direct target of miR-143. RESULTS PDA patient gene profiling data (GSE15471 and GSE16515) showed that TAK1 mRNA was aberrantly up-regulated in PDA tissues. TAK1 protein levels were overexpressed in PDA tissues and cell lines. Overexpression of TAK1 was strongly associated with positive lymph node metastasis. Inhibition of TAK1 suppressed cell growth, migration, and induced cell apoptosis in vitro and in vivo. Further studies demonstrated that TAK1 was a direct target gene of miR-143. MiR-143 also inhibited PDA cells proliferation and migration, induced apoptosis and G1/S arrest. Moreover, TAK1 depletion inactivated MAPK and NF-κB pathway, mimicking the function of miR-143. CONCLUSIONS The study highlights that miR-143 acts as a tumor suppressor in PDA through directly targeting TAK1, and their functional regulation may provide potential therapeutic strategies in clinics.
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Affiliation(s)
- Feng-Ting Huang
- Department of Gastroenterology and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 Yanjiang West Road, Guangzhou, 510120, Guangdong Province, People's Republic of China
| | - Juan-Fei Peng
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 Yanjiang West Road, Guangzhou, 510120, Guangdong Province, People's Republic of China
| | - Wen-Jie Cheng
- Department of Ultrasound, the Sixth Affiliated Hospital, Sun Yat-sen University, No. 26 Yuancun Erheng Road, Guangzhou, 510655, Guangdong Province, People's Republic of China
| | - Yan-Yan Zhuang
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 Yanjiang West Road, Guangzhou, 510120, Guangdong Province, People's Republic of China
| | - Ling-Yun Wang
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 Yanjiang West Road, Guangzhou, 510120, Guangdong Province, People's Republic of China
| | - Chu-Qiang Li
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 Yanjiang West Road, Guangzhou, 510120, Guangdong Province, People's Republic of China
| | - Jian Tang
- Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, No. 26 Yuancun Erheng Road, Guangzhou, 510655, Guangdong Province, People's Republic of China
| | - Wen-Ying Chen
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 Yanjiang West Road, Guangzhou, 510120, Guangdong Province, People's Republic of China
| | - Yuan-Hua Li
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 Yanjiang West Road, Guangzhou, 510120, Guangdong Province, People's Republic of China
| | - Shi-Neng Zhang
- Department of Gastroenterology and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 Yanjiang West Road, Guangzhou, 510120, Guangdong Province, People's Republic of China.
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Miller HC, Frampton AE, Malczewska A, Ottaviani S, Stronach EA, Flora R, Kaemmerer D, Schwach G, Pfragner R, Faiz O, Kos-Kudła B, Hanna GB, Stebbing J, Castellano L, Frilling A. MicroRNAs associated with small bowel neuroendocrine tumours and their metastases. Endocr Relat Cancer 2016; 23:711-26. [PMID: 27353039 DOI: 10.1530/erc-16-0044] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Accepted: 06/27/2016] [Indexed: 12/17/2022]
Abstract
Novel molecular analytes are needed in small bowel neuroendocrine tumours (SBNETs) to better determine disease aggressiveness and predict treatment response. In this study, we aimed to profile the global miRNome of SBNETs, and identify microRNAs (miRNAs) involved in tumour progression for use as potential biomarkers. Two independent miRNA profiling experiments were performed (n=90), including primary SBNETs (n=28), adjacent normal small bowel (NSB; n=14), matched lymph node (LN) metastases (n=24), normal LNs (n=7), normal liver (n=2) and liver metastases (n=15). We then evaluated potentially targeted genes by performing integrated computational analyses. We discovered 39 miRNAs significantly deregulated in SBNETs compared with adjacent NSB. The most upregulated (miR-204-5p, miR-7-5p and miR-375) were confirmed by qRT-PCR. Two miRNAs (miR-1 and miR-143-3p) were significantly downregulated in LN and liver metastases compared with primary tumours. Furthermore, we identified upregulated gene targets for miR-1 and miR-143-3p in an existing SBNET dataset, which could contribute to disease progression, and show that these miRNAs directly regulate FOSB and NUAK2 oncogenes. Our study represents the largest global miRNA profiling of SBNETs using matched primary tumour and metastatic samples. We revealed novel miRNAs deregulated during SBNET disease progression, and important miRNA-mRNA interactions. These miRNAs have the potential to act as biomarkers for patient stratification and may also be able to guide treatment decisions. Further experiments to define molecular mechanisms and validate these miRNAs in larger tissue cohorts and in biofluids are now warranted.
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Affiliation(s)
- Helen C Miller
- Department of Surgery and CancerImperial College, Hammersmith Hospital Campus, London, UK
| | - Adam E Frampton
- Department of Surgery and CancerImperial College, Hammersmith Hospital Campus, London, UK
| | - Anna Malczewska
- Department of Surgery and CancerImperial College, Hammersmith Hospital Campus, London, UK Department of Pathophysiology and EndocrinologySchool of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Silvia Ottaviani
- Department of Surgery and CancerImperial College, Hammersmith Hospital Campus, London, UK
| | - Euan A Stronach
- Department of Surgery and CancerImperial College, Hammersmith Hospital Campus, London, UK
| | - Rashpal Flora
- Department of HistopathologyImperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK
| | - Daniel Kaemmerer
- Zentralklinik Bad Berka GmbHRobert-Koch-Allee, Bad Berka, Germany
| | - Gert Schwach
- Institute of PathophysiologyCenter for Molecular Medicine, Medical University of Graz, Graz, Austria
| | - Roswitha Pfragner
- Institute of PathophysiologyCenter for Molecular Medicine, Medical University of Graz, Graz, Austria
| | | | - Beata Kos-Kudła
- Department of Pathophysiology and EndocrinologySchool of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
| | - George B Hanna
- Academic Surgical UnitDepartment of Surgery and Cancer, Imperial College, St Mary's Campus, London, UK
| | - Justin Stebbing
- Department of Pathophysiology and EndocrinologySchool of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Leandro Castellano
- Department of Pathophysiology and EndocrinologySchool of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Andrea Frilling
- Department of Surgery and CancerImperial College, Hammersmith Hospital Campus, London, UK
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