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Ajadee A, Mahmud S, Sarkar A, Noor T, Ahmmed R, Haque Mollah MN. Screening of common genomic biomarkers to explore common drugs for the treatment of pancreatic and kidney cancers with type-2 diabetes through bioinformatics analysis. Sci Rep 2025; 15:7363. [PMID: 40025145 PMCID: PMC11873208 DOI: 10.1038/s41598-025-91875-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 02/24/2025] [Indexed: 03/04/2025] Open
Abstract
Type 2 diabetes (T2D) is a crucial risk factor for both pancreatic cancer (PC) and kidney cancer (KC). However, effective common drugs for treating PC and/or KC patients who are also suffering from T2D are currently lacking, despite the probability of their co-occurrence. Taking disease-specific multiple drugs during the co-existence of multiple diseases may lead to adverse side effects or toxicity to the patients due to drug-drug interactions. This study aimed to identify T2D-, PC and KC-causing common genomic biomarkers (cGBs) highlighting their pathogenetic mechanisms to explore effective drugs as their common treatment. We analyzed transcriptomic profile datasets, applying weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network analysis approaches to identify T2D-, PC-, and KC-causing cGBs. We then disclosed common pathogenetic mechanisms through gene ontology (GO) terms, KEGG pathways, regulatory networks, and DNA methylation of these cGBs. Initially, we identified 78 common differentially expressed genes (cDEGs) that could distinguish T2D, PC, and KC samples from controls based on their transcriptomic profiles. From these, six top-ranked cDEGs (TOP2A, BIRC5, RRM2, ALB, MUC1, and E2F7) were selected as cGBs and considered targets for exploring common drug molecules for each of three diseases. Functional enrichment analyses, including GO terms, KEGG pathways, and regulatory network analyses involving transcription factors (TFs) and microRNAs, along with DNA methylation and immune infiltration studies, revealed critical common molecular mechanisms linked to PC, KC, and T2D. Finally, we identified six top-ranked drug molecules (NVP.BHG712, Irinotecan, Olaparib, Imatinib, RG-4733, and Linsitinib) as potential common treatments for PC, KC and T2D during their co-existence, supported by the literature reviews. Thus, this bioinformatics study provides valuable insights and resources for developing a genome-guided common treatment strategy for PC and/or KC patients who are also suffering from T2D.
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Affiliation(s)
- Alvira Ajadee
- Bioinformatics Lab, Department of Statistics, University of Rajshahi, Rajshahi, 6205, Bangladesh
| | - Sabkat Mahmud
- Bioinformatics Lab, Department of Statistics, University of Rajshahi, Rajshahi, 6205, Bangladesh
| | - Arnob Sarkar
- Bioinformatics Lab, Department of Statistics, University of Rajshahi, Rajshahi, 6205, Bangladesh
- Department of Biochemistry & Molecular Biology, University of Rajshahi, Rajshahi, 6205, Bangladesh
| | - Tasfia Noor
- Department of Computer Science and Engineering, Rajshahi University of Engineering & Technology (RUET), Rajshahi, 6204, Bangladesh
| | - Reaz Ahmmed
- Bioinformatics Lab, Department of Statistics, University of Rajshahi, Rajshahi, 6205, Bangladesh
- Department of Biochemistry & Molecular Biology, University of Rajshahi, Rajshahi, 6205, Bangladesh
| | - Md Nurul Haque Mollah
- Bioinformatics Lab, Department of Statistics, University of Rajshahi, Rajshahi, 6205, Bangladesh.
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Popov A, Hrudka J, Szabó A, Oliverius M, Šubrt Z, Vránová J, Ciprová V, Moravcová J, Mandys V. Expression of Selected miRNAs in Undifferentiated Carcinoma with Osteoclast-like Giant Cells (UCOGC) of the Pancreas: Comparison with Poorly Differentiated Pancreatic Ductal Adenocarcinoma. Biomedicines 2024; 12:962. [PMID: 38790924 PMCID: PMC11117927 DOI: 10.3390/biomedicines12050962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 04/18/2024] [Accepted: 04/23/2024] [Indexed: 05/26/2024] Open
Abstract
Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) of the pancreas represents a rare subtype of pancreatic ductal adenocarcinoma (PDAC). Despite a distinct morphology and specific clinical behavior, UCOGCs exhibit unexpected similarities in regard to DNA mutational profiles with conventional PDAC. Treating pancreatic ductal adenocarcinoma is particularly challenging, with limited prospects for cure. As with many other malignant neoplasms, the exploration of microRNAs (miRNAs, miRs) in regulating the biological characteristics of pancreatic cancer is undergoing extensive investigation to enhance tumor diagnostics and unveil the therapeutic possibilities. Herein, we evaluated the expression of miR-21, -96, -148a, -155, -196a, -210, and -217 in UCOGCs and poorly differentiated (grade 3, G3) PDACs. The expression of miR-21, miR-155, and miR-210 in both UCOGCs and G3 PDACs was significantly upregulated compared to the levels in normal tissue, while the levels of miR-148a and miR-217 were downregulated. We did not find any significant differences between cancerous and normal tissues for the expression of miR-96 and miR-196a in G3 PDACs, whereas miR-196a was slightly, but significantly, downregulated in UCOGCs. On the other hand, we have not observed significant differences in the expression of the majority of miRNAs between UCOGC and G3 PDAC, with the exception of miR-155. UCOGC samples demonstrated lower mean levels of miR-155 in comparison with those in G3 PDACs.
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Affiliation(s)
- Alexey Popov
- Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (A.P.); (A.S.)
| | - Jan Hrudka
- Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (A.P.); (A.S.)
| | - Arpád Szabó
- Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (A.P.); (A.S.)
| | - Martin Oliverius
- Department of Surgery, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (M.O.); (Z.Š.)
| | - Zdeněk Šubrt
- Department of Surgery, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (M.O.); (Z.Š.)
| | - Jana Vránová
- Department of Medical Biophysics and Medical Informatics, 3rd Faculty of Medicine, Charles University, 100 00 Prague, Czech Republic;
| | - Vanda Ciprová
- Institute of Pathology, 1st Faculty of Medicine, Charles University, General University Hospital, 100 00 Prague, Czech Republic
| | - Jana Moravcová
- Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (A.P.); (A.S.)
- Clinical and Transplant Pathology Centre, Institute for Clinical and Experimental Medicine, 140 00 Prague, Czech Republic
| | - Václav Mandys
- Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (A.P.); (A.S.)
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Kzar Al-Shukri HH, Abdul-Jabbar Ali S, Al-Akkam KA, Hjazi A, Rasulova I, Mustafa YF, Al-Saidi DN, Alasheqi MQ, Alawadi A, Alsaalamy A. The role of exo-miRNA in diagnosis and treatment of cancers, focusing on effective miRNAs in colorectal cancer. Cell Biol Int 2024; 48:280-289. [PMID: 38225535 DOI: 10.1002/cbin.12122] [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: 09/24/2023] [Revised: 11/26/2023] [Accepted: 12/27/2023] [Indexed: 01/17/2024]
Abstract
Small extracellular (EV) particles known as exosomes are released by a variety of cell types, including immune system cells, stem cells, and tumor cells. They are regarded as a subgroup of EVs and have a diameter that ranges from 30 to 150 nm. Proteins, lipids, nucleic acids (including RNA and DNA), and different bioactive compounds are among the wide range of biomolecules that make up the cargo of exosomes. Exosomes are crucial for intercellular communication because they let cells share information and signaling chemicals. They are involved in various physiological and pathological processes, including immune responses, tissue regeneration, cancer progression, and neurodegenerative diseases. In conclusion, it is essential to continue research into exosome-based cancer medicines to advance understanding, improve treatment plans, create personalized tactics, ensure safety, and speed up clinical translation.
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Affiliation(s)
- Hamzah H Kzar Al-Shukri
- Department of Biochemistry, College of Veterinary Medicine, Al-Qasim Green University, Babylon, Iraq
| | | | | | - Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Irodakhon Rasulova
- School of Humanities, Natural & Social Sciences, New Uzbekistan University, Uzbekistan
- Department of Public Health, Samarkand State Medical University, Samarkand, Uzbekistan
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq
| | - Dahlia N Al-Saidi
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
| | | | - Ahmed Alawadi
- College of Technical Engineering, The Islamic University, Najaf, Iraq
- College of Technical Engineering, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Technical Engineering, The Islamic University of Babylon, Babylon, Iraq
| | - Ali Alsaalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Kirkuk, Iraq
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Wei L, Sun J, Wang X, Huang Y, Huang L, Han L, Zheng Y, Xu Y, Zhang N, Yang M. Noncoding RNAs: an emerging modulator of drug resistance in pancreatic cancer. Front Cell Dev Biol 2023; 11:1226639. [PMID: 37560164 PMCID: PMC10407809 DOI: 10.3389/fcell.2023.1226639] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 07/17/2023] [Indexed: 08/11/2023] Open
Abstract
Pancreatic cancer is the eighth leading cause of cancer-related deaths worldwide. Chemotherapy including gemcitabine, 5-fluorouracil, adriamycin and cisplatin, immunotherapy with immune checkpoint inhibitors and targeted therapy have been demonstrated to significantly improve prognosis of pancreatic cancer patients with advanced diseases. However, most patients developed drug resistance to these therapeutic agents, which leading to shortened patient survival. The detailed molecular mechanisms contributing to pancreatic cancer drug resistance remain largely unclear. The growing evidences have shown that noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), are involved in pancreatic cancer pathogenesis and development of drug resistance. In the present review, we systematically summarized the new insight on of various miRNAs, lncRNAs and circRNAs on drug resistance of pancreatic cancer. These results demonstrated that targeting the tumor-specific ncRNA may provide novel options for pancreatic cancer treatments.
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Affiliation(s)
- Ling Wei
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Jujie Sun
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Xingwu Wang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yizhou Huang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Linying Huang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Linyu Han
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yanxiu Zheng
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yuan Xu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Nasha Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
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Di Giorgio C, Bellini R, Lupia A, Massa C, Bordoni M, Marchianò S, Rosselli R, Sepe V, Rapacciuolo P, Moraca F, Morretta E, Ricci P, Urbani G, Monti MC, Biagioli M, Distrutti E, Catalanotti B, Zampella A, Fiorucci S. Discovery of BAR502, as potent steroidal antagonist of leukemia inhibitory factor receptor for the treatment of pancreatic adenocarcinoma. Front Oncol 2023; 13:1140730. [PMID: 36998446 PMCID: PMC10043345 DOI: 10.3389/fonc.2023.1140730] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 02/20/2023] [Indexed: 03/15/2023] Open
Abstract
IntroductionThe leukemia inhibitory factor (LIF), is a cytokine belonging to IL-6 family, whose overexpression correlate with poor prognosis in cancer patients, including pancreatic ductal adenocarcinoma (PDAC). LIF signaling is mediate by its binding to the heterodimeric LIF receptor (LIFR) complex formed by the LIFR receptor and Gp130, leading to JAK1/STAT3 activation. Bile acids are steroid that modulates the expression/activity of membrane and nuclear receptors, including the Farnesoid-X-Receptor (FXR) and G Protein Bile Acid Activated Receptor (GPBAR1).MethodsHerein we have investigated whether ligands to FXR and GPBAR1 modulate LIF/LIFR pathway in PDAC cells and whether these receptors are expressed in human neoplastic tissues. ResultsThe transcriptome analysis of a cohort of PDCA patients revealed that expression of LIF and LIFR is increased in the neoplastic tissue in comparison to paired non-neoplastic tissues. By in vitro assay we found that both primary and secondary bile acids exert a weak antagonistic effect on LIF/LIFR signaling. In contrast, BAR502 a non-bile acid steroidal dual FXR and GPBAR1 ligand, potently inhibits binding of LIF to LIFR with an IC50 of 3.8 µM.DiscussionBAR502 reverses the pattern LIF-induced in a FXR and GPBAR1 independent manner, suggesting a potential role for BAR502 in the treatment of LIFR overexpressing-PDAC.
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Affiliation(s)
| | - Rachele Bellini
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Antonio Lupia
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
- Net4Science srl, University “Magna Græcia”, Catanzaro, Italy
| | - Carmen Massa
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Martina Bordoni
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Silvia Marchianò
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Valentina Sepe
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | | | - Federica Moraca
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
- Net4Science srl, University “Magna Græcia”, Catanzaro, Italy
| | - Elva Morretta
- Department of Pharmacy, University of Salerno, Salerno, Italy
| | - Patrizia Ricci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Ginevra Urbani
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Michele Biagioli
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Eleonora Distrutti
- Department of Gastroenterology, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Bruno Catalanotti
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
- *Correspondence: Stefano Fiorucci,
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Funamizu N, Honjo M, Tamura K, Sakamoto K, Ogawa K, Takada Y. microRNAs Associated with Gemcitabine Resistance via EMT, TME, and Drug Metabolism in Pancreatic Cancer. Cancers (Basel) 2023; 15:1230. [PMID: 36831572 PMCID: PMC9953943 DOI: 10.3390/cancers15041230] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/13/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
Despite extensive research, pancreatic cancer remains a lethal disease with an extremely poor prognosis. The difficulty in early detection and chemoresistance to therapeutic agents are major clinical concerns. To improve prognosis, novel biomarkers, and therapeutic strategies for chemoresistance are urgently needed. microRNAs (miRNAs) play important roles in the development, progression, and metastasis of several cancers. During the last few decades, the association between pancreatic cancer and miRNAs has been extensively elucidated, with several miRNAs found to be correlated with patient prognosis. Moreover, recent evidence has revealed that miRNAs are intimately involved in gemcitabine sensitivity and resistance through epithelial-to-mesenchymal transition, the tumor microenvironment, and drug metabolism. Gemcitabine is the gold standard drug for pancreatic cancer treatment, but gemcitabine resistance develops easily after chemotherapy initiation. Therefore, in this review, we summarize the gemcitabine resistance mechanisms associated with aberrantly expressed miRNAs in pancreatic cancer, especially focusing on the mechanisms associated with epithelial-to-mesenchymal transition, the tumor microenvironment, and metabolism. This novel evidence of gemcitabine resistance will drive further research to elucidate the mechanisms of chemoresistance and improve patient outcomes.
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Affiliation(s)
- Naotake Funamizu
- Department of Hepatobiliary Pancreatic and Transplantation Surgery, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
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7
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Di Giorgio C, Lupia A, Marchianò S, Bordoni M, Bellini R, Massa C, Urbani G, Roselli R, Moraca F, Sepe V, Catalanotti B, Morretta E, Monti MC, Biagioli M, Distrutti E, Zampella A, Fiorucci S. Repositioning Mifepristone as a Leukaemia Inhibitory Factor Receptor Antagonist for the Treatment of Pancreatic Adenocarcinoma. Cells 2022; 11:3482. [PMID: 36359879 PMCID: PMC9657739 DOI: 10.3390/cells11213482] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/27/2022] [Accepted: 11/01/2022] [Indexed: 11/12/2023] Open
Abstract
Pancreatic cancer is a leading cause of cancer mortality and is projected to become the second-most common cause of cancer mortality in the next decade. While gene-wide association studies and next generation sequencing analyses have identified molecular patterns and transcriptome profiles with prognostic relevance, therapeutic opportunities remain limited. Among the genes that are upregulated in pancreatic ductal adenocarcinomas (PDAC), the leukaemia inhibitory factor (LIF), a cytokine belonging to IL-6 family, has emerged as potential therapeutic candidate. LIF is aberrantly secreted by tumour cells and promotes tumour progression in pancreatic and other solid tumours through aberrant activation of the LIF receptor (LIFR) and downstream signalling that involves the JAK1/STAT3 pathway. Since there are no LIFR antagonists available for clinical use, we developed an in silico strategy to identify potential LIFR antagonists and drug repositioning with regard to LIFR antagonists. The results of these studies allowed the identification of mifepristone, a progesterone/glucocorticoid antagonist, clinically used in medical abortion, as a potent LIFR antagonist. Computational studies revealed that mifepristone binding partially overlapped the LIFR binding site. LIF and LIFR are expressed by human PDAC tissues and PDAC cell lines, including MIA-PaCa-2 and PANC-1 cells. Exposure of these cell lines to mifepristone reverses cell proliferation, migration and epithelial mesenchymal transition induced by LIF in a concentration-dependent manner. Mifepristone inhibits LIFR signalling and reverses STAT3 phosphorylation induced by LIF. Together, these data support the repositioning of mifepristone as a potential therapeutic agent in the treatment of PDAC.
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Affiliation(s)
- Cristina Di Giorgio
- Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy
| | - Antonio Lupia
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy
- Campus Salvatore Venuta, Net4Science Srl, University “Magna Græcia”, Viale Europa, 88100 Catanzaro, Italy
| | - Silvia Marchianò
- Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy
| | - Martina Bordoni
- Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy
| | - Rachele Bellini
- Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy
| | - Carmen Massa
- Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy
| | - Ginevra Urbani
- Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy
| | - Rosalinda Roselli
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy
| | - Federica Moraca
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy
- Campus Salvatore Venuta, Net4Science Srl, University “Magna Græcia”, Viale Europa, 88100 Catanzaro, Italy
| | - Valentina Sepe
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy
| | - Bruno Catalanotti
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy
| | - Elva Morretta
- Department of Pharmacy, University of Salerno, 84084 Salerno, Italy
| | | | - Michele Biagioli
- Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy
| | | | - Angela Zampella
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy
| | - Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy
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Wu L, Yin L, Ma L, Yang J, Yang F, Sun B, Nianzeng X. Comprehensive bioinformatics analysis of ribonucleoside diphosphate reductase subunit M2(RRM2) gene correlates with prognosis and tumor immunotherapy in pan-cancer. Aging (Albany NY) 2022; 14:7890-7905. [PMID: 36202136 PMCID: PMC9596216 DOI: 10.18632/aging.204315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 08/31/2022] [Indexed: 06/16/2023]
Abstract
Ribonucleotide reductase (RNR) small subunit M2 (RRM2) levels are known to regulate the activity of RNR, a rate-limiting enzyme in the synthesis of deoxyribonucleotide triphosphates (dNTPs) and essential for both DNA replication and repair. The high expression of RRM2 enhances the proliferation of cancer cells, thereby implicating its role as an anti-cancer agent. However, little research has been performed on its role in the prognosis of different types of cancers. This pan-cancer study aimed to evaluate the effect of high expression of RRM2 the tumor prognosis based on clinical information collected from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) databases. We found RRM2 gene was highly expressed in 30 types of cancers. And we performed a pan-cancer analysis of the genetic alteration status and methylation of RRM2. Results indicated that RRM2 existed hypermethylation, associated with m6A, m1A, and m5C related genes. Subsequently, we explored the microRNAs (miRNA), long non-coding RNAs (lncRNA), and the transcription factors responsible for the high expression of RRM2 in cancer cells. Results indicated that has-miR-125b-5p and has-miR-30a-5p regulated the expression of RRM2 along with transcription factors, such as CBFB, E2F1, and FOXM. Besides, we established the competing endogenous RNA (ceRNA) diagram of lncRNAs-miRNAs-circular RNAs (circRNA) involved in the regulation of RRM2 expression. Meanwhile, our study demonstrated that high-RRM2 levels correlated with patients' worse prognosis survival and immunotherapy effects through the consensus clustering and risk scores analysis. Finally, we found RRM2 regulated the resistance of immune checkpoint inhibitors through the PI3K-AKT single pathways. Collectively, our findings elucidated that high expression of RRM2 correlates with prognosis and tumor immunotherapy in pan-cancer. Moreover, these findings may provide insights for further investigation of the RRM2 gene as a biomarker in predicting immunotherapy's response and therapeutic target.
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Affiliation(s)
- Liyuan Wu
- Department of Urology, National Cancer Center/National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Le Yin
- Research and Development Department, Allife Medicine Inc., Beijing 100176, China
| | - Linxiang Ma
- Department of Urology, Weifang Hospital of Traditional Chinese Medicine, Weifang 261000, Shandong, China
| | - Jiarui Yang
- Tianjin Key Laboratory of Animal and Plant Resistance, College of Life Sciences, Tianjin Normal University, Xiqing, Tianjin 300382, China
| | - Feiya Yang
- Department of Urology, National Cancer Center/National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Baofa Sun
- Department of Zoology, College of Life Science, Nankai University, Nankai, Tianjin 300071, China
| | - Xing Nianzeng
- Department of Urology, National Cancer Center/National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Department of Urology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Shanxi, Taiyuan 030013, China
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Han D, Wang L, Long L, Su P, Luo D, Zhang H, Li Z, Chen B, Zhao W, Zhang N, Wang X, Liang Y, Li Y, Hu G, Yang Q. The E3 Ligase TRIM4 Facilitates SET Ubiquitin-Mediated Degradation to Enhance ER-α Action in Breast Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2201701. [PMID: 35843886 PMCID: PMC9443474 DOI: 10.1002/advs.202201701] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 06/10/2022] [Indexed: 06/15/2023]
Abstract
Estrogen receptor alpha (ER-α) action is critical for hormone-dependent breast cancer, and ER-α dysregulation can lead to the emergence of resistance to endocrine therapy. Here, it is found that TRIM4 is downregulated in tamoxifen (TAM)-resistant breast cancer cells, while the loss of TRIM4 is associated with an unfavorable prognosis. In vitro and in vivo experiments confirm that TRIM4 increased ER-α expression and the sensitivity of breast cancer cells to TAM. Mechanistically, TRIM4 is found to target SET, and TRIM4-SET interactions are mediated by the RING and B-box domains of TRIM4 and the carboxyl terminus of SET. Moreover, it is determined that TRIM4 catalyzed the K48-linked polyubiquitination of SET (K150 and K172), promoting its proteasomal degradation and disassociation from p53 and PP2A. Once released, p53 and PP2A are able to further promote ESR1 gene transcription and enhance mRNA stability. Moreover, univariate and multivariate Cox proportional hazards regression analyses confirm that TRIM4 expression is an independent predictor of overall survival and recurrence-free survival outcomes in patients with ER-α positive breast cancer. Taken together, the data highlights a previously undiscovered mechanism and suggest that TRIM4 is a valuable biomarker that can be analyzed to predict response to endocrine therapy in breast cancer patients.
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Affiliation(s)
- Dianwen Han
- Department of Breast Surgery, General SurgeryQilu Hospital of Shandong UniversityJinanShandong250012China
| | - Lijuan Wang
- Pathology Tissue BankQilu Hospital of Shandong UniversityJinanShandong250012China
| | - Li Long
- Department of Breast Surgery, General SurgeryQilu Hospital of Shandong UniversityJinanShandong250012China
- Mianyang Central HospitalSchool of MedicineUniversity of Electronic Science and Technology of ChinaMianyangSichuan621000China
| | - Peng Su
- Department of PathologyQilu Hospital of Shandong UniversityJinanShandong250012China
| | - Dan Luo
- Department of Breast Surgery, General SurgeryQilu Hospital of Shandong UniversityJinanShandong250012China
| | - Hanwen Zhang
- Department of Breast Surgery, General SurgeryQilu Hospital of Shandong UniversityJinanShandong250012China
| | - Zheng Li
- Department of Breast Surgery, General SurgeryQilu Hospital of Shandong UniversityJinanShandong250012China
| | - Bing Chen
- Pathology Tissue BankQilu Hospital of Shandong UniversityJinanShandong250012China
| | - Wenjing Zhao
- Pathology Tissue BankQilu Hospital of Shandong UniversityJinanShandong250012China
| | - Ning Zhang
- Department of Breast Surgery, General SurgeryQilu Hospital of Shandong UniversityJinanShandong250012China
| | - Xiaolong Wang
- Department of Breast Surgery, General SurgeryQilu Hospital of Shandong UniversityJinanShandong250012China
| | - Yiran Liang
- Department of Breast Surgery, General SurgeryQilu Hospital of Shandong UniversityJinanShandong250012China
| | - Yaming Li
- Department of Breast Surgery, General SurgeryQilu Hospital of Shandong UniversityJinanShandong250012China
| | - Guohong Hu
- The Key Laboratory of Stem Cell BiologyInstitute of Health SciencesShanghai Institutes for Biological SciencesChinese Academy of Sciences & Shanghai Jiao Tong University School of MedicineUniversity of Chinese Academy of SciencesShanghai200233China
| | - Qifeng Yang
- Department of Breast Surgery, General SurgeryQilu Hospital of Shandong UniversityJinanShandong250012China
- Pathology Tissue BankQilu Hospital of Shandong UniversityJinanShandong250012China
- Research Institute of Breast CancerShandong UniversityJinanShandong250012China
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10
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Rahnama N, Jahangir M, Alesaeid S, Kahrizi MS, Adili A, Mohammed RN, Aslaminabad R, Akbari M, Özgönül AM. Association between microRNAs and chemoresistance in pancreatic cancer: Current knowledge, new insights, and forthcoming perspectives. Pathol Res Pract 2022; 236:153982. [PMID: 35779293 DOI: 10.1016/j.prp.2022.153982] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/27/2022] [Accepted: 06/11/2022] [Indexed: 11/25/2022]
Abstract
Pancreatic duct adenocarcinoma, commonly known as pancreatic cancer (PC), is a cancer-related cause of death due to delayed diagnosis, metastasis, and drug resistance. Patients with PC suffer from incorrect responses to chemotherapy due to inherent and acquired chemical resistance. Numerous studies have shown the mechanism of the effect of chemoresistance on PC, such as genetic and epigenetic changes or the elucidation of signaling pathways. In this regard, microRNAs (miRNAs) have been identified as essential modulators of gene expression in various cellular functions, including chemoresistance. Thus, identifying the underlying link between microRNAs and PC chemoresistance helps determine the exact pathogenesis of PC. This study aims to classify miRNAs and signaling pathways related to PC chemoresistance, suggesting new therapeutic approaches to overcome PC chemoresistance.
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Affiliation(s)
- Negin Rahnama
- Department of Internal Medicine and Health Services, Semnan University of Medical Sciences, Semnan, Iran
| | | | - Samira Alesaeid
- Department of Internal Medicine and Rheumatology, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Ali Adili
- Senior Adult Oncology Department, Moffitt Cancer Center, University of South Florida, FL, USA; Department of Oncology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rebar N Mohammed
- Medical Laboratory Analysis Department, College of Health Sciences, Cihan University of Sulaimaniya, Kurdistan Region, Iraq; College of Veterinary Medicine, University of Sulaimani, Sulaimaniyah, Iraq
| | - Ramin Aslaminabad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Ali Mert Özgönül
- Department of Biochemistry, Faculty of Medicine, Ege University, Bornova, Izmir, Turkey.
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11
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Nunes C, Depestel L, Mus L, Keller KM, Delhaye L, Louwagie A, Rishfi M, Whale A, Kara N, Andrews SR, Dela Cruz F, You D, Siddiquee A, Cologna CT, De Craemer S, Dolman E, Bartenhagen C, De Vloed F, Sanders E, Eggermont A, Bekaert SL, Van Loocke W, Bek JW, Dewyn G, Loontiens S, Van Isterdael G, Decaesteker B, Tilleman L, Van Nieuwerburgh F, Vermeirssen V, Van Neste C, Ghesquiere B, Goossens S, Eyckerman S, De Preter K, Fischer M, Houseley J, Molenaar J, De Wilde B, Roberts SS, Durinck K, Speleman F. RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition. SCIENCE ADVANCES 2022; 8:eabn1382. [PMID: 35857500 PMCID: PMC9278860 DOI: 10.1126/sciadv.abn1382] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 05/26/2022] [Indexed: 05/06/2023]
Abstract
High-risk neuroblastoma, a pediatric tumor originating from the sympathetic nervous system, has a low mutation load but highly recurrent somatic DNA copy number variants. Previously, segmental gains and/or amplifications allowed identification of drivers for neuroblastoma development. Using this approach, combined with gene dosage impact on expression and survival, we identified ribonucleotide reductase subunit M2 (RRM2) as a candidate dependency factor further supported by growth inhibition upon in vitro knockdown and accelerated tumor formation in a neuroblastoma zebrafish model coexpressing human RRM2 with MYCN. Forced RRM2 induction alleviates excessive replicative stress induced by CHK1 inhibition, while high RRM2 expression in human neuroblastomas correlates with high CHK1 activity. MYCN-driven zebrafish tumors with RRM2 co-overexpression exhibit differentially expressed DNA repair genes in keeping with enhanced ATR-CHK1 signaling activity. In vitro, RRM2 inhibition enhances intrinsic replication stress checkpoint addiction. Last, combinatorial RRM2-CHK1 inhibition acts synergistic in high-risk neuroblastoma cell lines and patient-derived xenograft models, illustrating the therapeutic potential.
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Affiliation(s)
- Carolina Nunes
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Lisa Depestel
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Liselot Mus
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | | | - Louis Delhaye
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- VIB-UGent Center for Medical Biotechnology, Ghent University, Ghent, Belgium
| | - Amber Louwagie
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Muhammad Rishfi
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Alex Whale
- Epigenetics Programme, Babraham Institute, Cambridge, UK
| | - Neesha Kara
- Epigenetics Programme, Babraham Institute, Cambridge, UK
| | | | - Filemon Dela Cruz
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Daoqi You
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Armaan Siddiquee
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Camila Takeno Cologna
- Metabolomics Expertise Center, Center for Cancer Biology (CCB), VIB, Leuven, Belgium
- Metabolomics Expertise Center, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Sam De Craemer
- Metabolomics Expertise Center, Center for Cancer Biology (CCB), VIB, Leuven, Belgium
- Metabolomics Expertise Center, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Emmy Dolman
- Princess Maxima Center, Utrecht, Netherlands
| | - Christoph Bartenhagen
- Center for Molecular Medicine Cologne, Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany
- Department of Experimental Pediatric Oncology, University Children’s Hospital of Cologne, Cologne, Germany
| | - Fanny De Vloed
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Ellen Sanders
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Aline Eggermont
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Sarah-Lee Bekaert
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Wouter Van Loocke
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Jan Willem Bek
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Givani Dewyn
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Siebe Loontiens
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | | | - Bieke Decaesteker
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Laurentijn Tilleman
- NXTGNT, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium
| | | | - Vanessa Vermeirssen
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Christophe Van Neste
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Bart Ghesquiere
- Metabolomics Expertise Center, Center for Cancer Biology (CCB), VIB, Leuven, Belgium
- Metabolomics Expertise Center, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Steven Goossens
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Sven Eyckerman
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- VIB-UGent Center for Medical Biotechnology, Ghent University, Ghent, Belgium
| | - Katleen De Preter
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Matthias Fischer
- Center for Molecular Medicine Cologne, Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany
- Department of Experimental Pediatric Oncology, University Children’s Hospital of Cologne, Cologne, Germany
| | - Jon Houseley
- Epigenetics Programme, Babraham Institute, Cambridge, UK
| | | | - Bram De Wilde
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Stephen S. Roberts
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kaat Durinck
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Frank Speleman
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
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12
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Liu Q, Song C, Li J, Liu M, Fu L, Jiang J, Zeng Z, Zhu H. E2F2 enhances the chemoresistance of pancreatic cancer to gemcitabine by regulating the cell cycle and upregulating the expression of RRM2. Med Oncol 2022; 39:124. [PMID: 35716217 DOI: 10.1007/s12032-022-01715-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 03/25/2022] [Indexed: 11/27/2022]
Abstract
Both pro-oncogenic and anti-oncogenic effects of E2F2 have been revealed in different malignancies. However, the precise role of E2F2 in pancreatic cancer, in particular in relation to therapeutic intervention with gemcitabine, remains unclear. In this study, the effect of E2F2 on the proliferation and cell cycle modulation of pancreatic cancer cells, and whether E2F2 plays a role in the treatment of pancreatic cancer cells by gemcitabine, were investigated. The expression of E2F2 in pancreatic cancer was assessed by various methods including bioinformatics prediction, Western blotting, and real-time PCR. The effect of E2F2 on the proliferation and cell cycling of pancreatic cancer cells was analyzed by tissue culture and flow cytometry. In addition, the effect of E2F2 on the intervention of pancreatic cancer by gemcitabine was investigated using both in vitro and in vivo approaches. The expression of E2F2 was found to be significantly increased in pancreatic cancer tissues and cell lines. The pathogenic capacity of E2F2 lied in the fact that this transcription factor promoted the transformation of pancreatic cancer cell cycle from G1-phase to S-phase, thus enhancing the proliferation of pancreatic cancer cells. Furthermore, the expression of E2F2 was increased in pancreatic cancer cells in the presence of gemcitabine, and the augmented expression of E2F2 upregulated the gemcitabine resistance-related gene RRM2 and its downstream signaling molecule deoxycytidine kinase (DCK). The resistance of pancreatic cancer cells to gemcitabine was confirmed using both in vitro and in vivo models. In this study, E2F2 has been demonstrated for the first time to play a pro-oncogenic role in pancreatic cancer by promoting the transition of the cell cycle from G1-phase to S-phase and, therefore, enhancing the proliferation of pancreatic cancer cells. E2F2 has also been demonstrated to enhance the chemotherapy resistance of pancreatic cancer cells to gemcitabine by upregulating the expression of RRM2 and DCK that is downstream of RRM2.
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Affiliation(s)
- Qianfan Liu
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, Guizhou, People's Republic of China.,Department of General Surgery, Northern Jiangsu People's Hospital, Yangzhou, 225000, Jiangsu Province, People's Republic of China
| | - Chunzhuo Song
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, Guizhou, People's Republic of China.,Department of Hepatobiliary Surgery, The Second Affiliated Hospital, Army Medical University, Chongqing, 400037, People's Republic of China
| | - Junjun Li
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, Guizhou, People's Republic of China
| | - Meng Liu
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, Guizhou, People's Republic of China
| | - Liyue Fu
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, Guizhou, People's Republic of China
| | - Jiuliang Jiang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, Guizhou, People's Republic of China
| | - Zhirui Zeng
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research On Common Chronic Diseases, Guiyang, 550001, Guizhou, People's Republic of China
| | - Haitao Zhu
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, Guizhou, People's Republic of China.
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13
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Popov A, Mandys V. Senescence-Associated miRNAs and Their Role in Pancreatic Cancer. Pathol Oncol Res 2022; 28:1610156. [PMID: 35570840 PMCID: PMC9098800 DOI: 10.3389/pore.2022.1610156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 04/12/2022] [Indexed: 01/17/2023]
Abstract
Replicative senescence is irreversible cell proliferation arrest for somatic cells which can be circumvented in cancers. Cellular senescence is a process, which may play two opposite roles. On the one hand, this is a natural protection of somatic cells against unlimited proliferation and malignant transformation. On the other hand, cellular secretion caused by senescence can stimulate inflammation and proliferation of adjacent cells that may promote malignancy. The main genes controlling the senescence pathways are also well known as tumor suppressors. Almost 140 genes regulate both cellular senescence and cancer pathways. About two thirds of these genes (64%) are regulated by microRNAs. Senescence-associated miRNAs can stimulate cancer progression or act as tumor suppressors. Here we review the role playing by senescence-associated miRNAs in development, diagnostics and treatment of pancreatic cancer.
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Affiliation(s)
- Alexey Popov
- Department of Pathology, Third Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady, Prague, Czechia
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14
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Szczepanek J, Skorupa M, Tretyn A. MicroRNA as a Potential Therapeutic Molecule in Cancer. Cells 2022; 11:1008. [PMID: 35326459 PMCID: PMC8947269 DOI: 10.3390/cells11061008] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/11/2022] [Accepted: 03/16/2022] [Indexed: 12/11/2022] Open
Abstract
Small noncoding RNAs, as post-translational regulators of many target genes, are not only markers of neoplastic disease initiation and progression, but also markers of response to anticancer therapy. Hundreds of miRNAs have been identified as biomarkers of drug resistance, and many have demonstrated the potential to sensitize cancer cells to therapy. Their properties of modulating the response of cells to therapy have made them a promising target for overcoming drug resistance. Several methods have been developed for the delivery of miRNAs to cancer cells, including introducing synthetic miRNA mimics, DNA plasmids containing miRNAs, and small molecules that epigenetically alter endogenous miRNA expression. The results of studies in animal models and preclinical studies for solid cancers and hematological malignancies have confirmed the effectiveness of treatment protocols using microRNA. Nevertheless, the use of miRNAs in anticancer therapy is not without limitations, including the development of a stable nanoconstruct, delivery method choices, and biodistribution. The aim of this review was to summarize the role of miRNAs in cancer treatment and to present new therapeutic concepts for these molecules. Supporting anticancer therapy with microRNA molecules has been verified in numerous clinical trials, which shows great potential in the treatment of cancer.
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Affiliation(s)
- Joanna Szczepanek
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Ul. Wilenska 4, 87-100 Torun, Poland;
| | - Monika Skorupa
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Ul. Wilenska 4, 87-100 Torun, Poland;
- Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Ul. Lwowska 1, 87-100 Torun, Poland;
| | - Andrzej Tretyn
- Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Ul. Lwowska 1, 87-100 Torun, Poland;
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15
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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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16
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Misiak D, Bauer M, Lange J, Haase J, Braun J, Lorenz K, Wickenhauser C, Hüttelmaier S. MiRNA Deregulation Distinguishes Anaplastic Thyroid Carcinoma (ATC) and Supports Upregulation of Oncogene Expression. Cancers (Basel) 2021; 13:5913. [PMID: 34885022 PMCID: PMC8657272 DOI: 10.3390/cancers13235913] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 11/19/2021] [Accepted: 11/23/2021] [Indexed: 12/13/2022] Open
Abstract
Anaplastic thyroid carcinoma (ATC) is the most fatal and rapidly evolving endocrine malignancy invading the head and neck region and accounts for up to 50% of thyroid cancer-associated deaths. Deregulation of the microRNA (miRNA) expression promotes thyroid carcinoma progression by modulating the reorganization of the ATC transcriptome. Here, we applied comparative miRNA-mRNA sequencing on a cohort of 28 thyroid carcinomas to unravel the association of deregulated miRNA and mRNA expression. This identified 85 miRNAs significantly deregulated in ATC. By establishing a new analysis pipeline, we unraveled 85 prime miRNA-mRNA interactions supporting the downregulation of candidate tumor suppressors and the upregulation of bona fide oncogenes such as survivin (BIRC5) in ATC. This miRNA-dependent reprogramming of the ATC transcriptome provided an mRNA signature comprising 65 genes sharply distinguishing ATC from other thyroid carcinomas. The validation of the deregulated protein expression in an independent thyroid carcinoma cohort demonstrates that miRNA-dependent oncogenes comprised in this signature, the transferrin receptor TFRC (CD71) and the E3-ubiquitin ligase DTL, are sharply upregulated in ATC. This upregulation is sufficient to distinguish ATC even from poorly differentiated thyroid carcinomas (PDTC). In sum, these findings provide new diagnostic tools and a robust resource to explore the key miRNA-mRNA regulation underlying the progression of thyroid carcinoma.
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Affiliation(s)
- Danny Misiak
- Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany; (D.M.); (J.L.); (J.H.); (J.B.)
| | - Marcus Bauer
- Institute of Pathology, Martin Luther University Halle-Wittenberg, 06112 Halle, Germany; (M.B.); (C.W.)
| | - Jana Lange
- Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany; (D.M.); (J.L.); (J.H.); (J.B.)
| | - Jacob Haase
- Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany; (D.M.); (J.L.); (J.H.); (J.B.)
- Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Juliane Braun
- Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany; (D.M.); (J.L.); (J.H.); (J.B.)
- Merck KGaA, 64293 Darmstadt, Germany
| | - Kerstin Lorenz
- Department of Visceral, Vascular, and Endocrine Surgery, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany;
| | - Claudia Wickenhauser
- Institute of Pathology, Martin Luther University Halle-Wittenberg, 06112 Halle, Germany; (M.B.); (C.W.)
| | - Stefan Hüttelmaier
- Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany; (D.M.); (J.L.); (J.H.); (J.B.)
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17
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Lee YQ, Rajadurai P, Abas F, Othman I, Naidu R. Proteomic Analysis on Anti-Proliferative and Apoptosis Effects of Curcumin Analog, 1,5-bis(4-Hydroxy-3-Methyoxyphenyl)-1,4-Pentadiene-3-One-Treated Human Glioblastoma and Neuroblastoma Cells. Front Mol Biosci 2021; 8:645856. [PMID: 33996900 PMCID: PMC8119891 DOI: 10.3389/fmolb.2021.645856] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 03/04/2021] [Indexed: 12/31/2022] Open
Abstract
Curcumin analogs with excellent biological properties have been synthesized to address and overcome the poor pharmacokinetic profiles of curcumin. This study aims to investigate the cytotoxicity, anti-proliferative, and apoptosis-inducing ability of curcumin analog, MS13 on human glioblastoma U-87 MG, and neuroblastoma SH-SY5Y cells, and to examine the global proteome changes in these cells following treatment. Our current findings showed that MS13 induced potent cytotoxicity and anti-proliferative effects on both cells. Increased caspase-3 activity and decreased bcl-2 concentration upon treatment indicate that MS13 induces apoptosis in these cells in a dose- and time-dependent manner. The label-free shotgun proteomic analysis has defined the protein profiles in both glioblastoma and neuroblastoma cells, whereby a total of nine common DEPs, inclusive of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), alpha-enolase (ENO1), heat shock protein HSP 90-alpha (HSP90AA1), Heat shock protein HSP 90-beta (HSP90AB1), Eukaryotic translation initiation factor 5A-1 (EFI5A), heterogenous nuclear ribonucleoprotein K (HNRNPK), tubulin beta chain (TUBB), histone H2AX (H2AFX), and Protein SET were identified. Pathway analysis further elucidated that MS13 may induce its anti-tumor effects in both cells via the common enriched pathways, “Glycolysis” and “Post-translational protein modification.” Conclusively, MS13 demonstrates an anti-cancer effect that may indicate its potential use in the management of brain malignancies.
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Affiliation(s)
- Yee Qian Lee
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Subang Jaya, Malaysia
| | - Pathmanathan Rajadurai
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Subang Jaya, Malaysia
| | - Faridah Abas
- Laboratory of Natural Products, Faculty of Science, University Putra Malaysia, Seri Kembangan, Malaysia.,Department of Food Science, Faculty of Food Science and Technology, University Putra Malaysia, Seri Kembangan, Malaysia
| | - Iekhsan Othman
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Subang Jaya, Malaysia
| | - Rakesh Naidu
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Subang Jaya, Malaysia
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18
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Inhibiting RRM2 to enhance the anticancer activity of chemotherapy. Biomed Pharmacother 2020; 133:110996. [PMID: 33227712 DOI: 10.1016/j.biopha.2020.110996] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 10/28/2020] [Accepted: 11/01/2020] [Indexed: 12/13/2022] Open
Abstract
RRM2, the small subunit of ribonucleotide reductase, is identified as a tumor promotor and therapeutic target. It is common to see the overexpression of RRM2 in chemo-resistant cancer cells and patients. RRM2 mediates the resistance of many chemotherapeutic drugs and could become the predictor for chemosensitivity and prognosis. Therefore, inhibition of RRM2 may be an effective means to enhance the anticancer activity of chemotherapy. This review tries to discuss the mechanisms of RRM2 overexpression and the role of RRM2 in resistance to chemotherapy. Additionally, we compile the studies on small interfering RNA targets RRM2, RRM2 inhibitors, kinase inhibitors, and other ways that could overcome the resistance of chemotherapy or exert synergistic anticancer activity with chemotherapy through the expression inhibition or the enzyme inactivation of RRM2.
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19
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Lin Z, Lu S, Xie X, Yi X, Huang H. Noncoding RNAs in drug-resistant pancreatic cancer: A review. Biomed Pharmacother 2020; 131:110768. [PMID: 33152930 DOI: 10.1016/j.biopha.2020.110768] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 09/17/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is the fourth-leading cause of cancer-related deaths and is expected to be the second-leading cause of cancer-related deaths in Europe and the United States by 2030. The high fatality rate of pancreatic cancer is ascribed to untimely diagnosis, early metastasis and limited responses to both chemotherapy and radiotherapy. Although gemcitabine, 5-fluorouracil and some other drugs can profoundly improve patient prognosis, most pancreatic cancer patients eventually develop drug resistance, leading to poor clinical outcomes. The underlying mechanisms of pancreatic cancer drug resistance are complicated and inconclusive. Interestingly, accumulating evidence has demonstrated that different noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), play a crucial role in pancreatic cancer resistance to chemotherapy reagents. In this paper, we systematically summarize the molecular mechanism underlying the influence of ncRNAs on the generation and development of drug resistance in pancreatic cancer and discuss the potential role of ncRNAs as prognostic markers and new therapeutic targets for pancreatic cancer.
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Affiliation(s)
- Zhengjun Lin
- Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, China.
| | - Shiyao Lu
- Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, China.
| | - Xubin Xie
- Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, China.
| | - Xuyang Yi
- Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, China.
| | - He Huang
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, China; State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, School of Pre-Clinical Medicine/ Second Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang, 830011, China.
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20
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Zhang ZM, Wang JS, Zulfiqar H, Lv H, Dao FY, Lin H. Early Diagnosis of Pancreatic Ductal Adenocarcinoma by Combining Relative Expression Orderings With Machine-Learning Method. Front Cell Dev Biol 2020; 8:582864. [PMID: 33178697 PMCID: PMC7593596 DOI: 10.3389/fcell.2020.582864] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 09/15/2020] [Indexed: 12/16/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal cancer deeply affecting human health. Diagnosing early-stage PDAC is the key point to PDAC patients' survival. However, the biomarkers for diagnosing early PDAC are inexact in most cases. Therefore, it is highly desirable to identify an effective PDAC diagnostic biomarker. In the current work, we designed a novel computational approach based on within-sample relative expression orderings (REOs). A feature selection technique called minimum redundancy maximum relevance was used to pick out optimal REOs. We then compared the performances of different classification algorithms for discriminating PDAC and its adjacent normal tissues from non-PDAC tissues. The support vector machine algorithm is the best one for identifying early PDAC diagnostic biomarker. At first, a signature composed of nine gene pairs was acquired from microarray gene expression data sets. These gene pairs could produce satisfactory classification accuracy up to 97.53% in fivefold cross-validation. Subsequently, two types of data from diverse platforms, namely, microarray and RNA-Seq, were used to validate this signature. For microarray data, all (100.00%) of 115 PDAC tissues and all (100.00%) of 31 PDAC adjacent normal tissues were correctly recognized as PDAC. In addition, 88.24% of 17 non-PDAC (normal or pancreatitis) tissues were correctly classified. For the RNA-Seq data, all (100.00%) of 177 PDAC tissues and all (100.00%) of 4 PDAC adjacent normal tissues were correctly recognized as PDAC. Validation results demonstrated that the signature had a good cross-platform effect for early detection of PDAC. This work developed a new robust signature that might be a promising biomarker for early PDAC diagnosis.
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Affiliation(s)
- Zi-Mei Zhang
- Key Laboratory for Neuro-Information of Ministry of Education, Center for Informational Biology, School of Life Sciences and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Jia-Shu Wang
- Key Laboratory for Neuro-Information of Ministry of Education, Center for Informational Biology, School of Life Sciences and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Hasan Zulfiqar
- Key Laboratory for Neuro-Information of Ministry of Education, Center for Informational Biology, School of Life Sciences and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Hao Lv
- Key Laboratory for Neuro-Information of Ministry of Education, Center for Informational Biology, School of Life Sciences and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Fu-Ying Dao
- Key Laboratory for Neuro-Information of Ministry of Education, Center for Informational Biology, School of Life Sciences and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Hao Lin
- Key Laboratory for Neuro-Information of Ministry of Education, Center for Informational Biology, School of Life Sciences and Technology, University of Electronic Science and Technology of China, Chengdu, China
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21
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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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22
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Ritter A, Hirschfeld M, Berner K, Rücker G, Jäger M, Weiss D, Medl M, Nöthling C, Gassner S, Asberger J, Erbes T. Circulating non‑coding RNA‑biomarker potential in neoadjuvant chemotherapy of triple negative breast cancer? Int J Oncol 2019; 56:47-68. [PMID: 31789396 PMCID: PMC6910196 DOI: 10.3892/ijo.2019.4920] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 09/26/2019] [Indexed: 12/11/2022] Open
Abstract
Due to the positive association between neoadjuvant chemotherapy (NACT) and the promising early response rates of patients with triple negative breast cancer (TNBC), including probabilities of pathological complete response, NACT is increasingly used in TNBC management. Liquid biopsy-based biomarkers with the power to diagnose the early response to NACT may support established monitoring tools, which are to a certain extent imprecise and costly. Simple serum- or urine-based analyses of non-coding RNA (ncRNA) expression may allow for fast, minimally-invasive testing and timely adjustment of the therapy regimen. The present study investigated breast cancer-related ncRNAs [microRNA (miR)-7, -9, -15a, -17, -18a, -19b, -21, -30b, -222 and -320c, PIWI-interacting RNA-36743 and GlyCCC2] in triple positive BT-474 cells and three TNBC cell lines (BT-20, HS-578T and MDA-MB-231) treated with various chemotherapeutic agents using reverse transcription-quantitative PCR. Intracellular and secreted microvesicular ncRNA expression levels were analysed using a multivariable statistical regression analysis. Chemotherapy-driven effects were investigated by analysing cell cycle determinants at the mRNA and protein levels. Serum and urine specimens from 8 patients with TNBC were compared with 10 healthy females using two-sample t-tests. Samples from the patients with TNBC were compared at two time points. Chemotherapeutic treatments induced distinct changes in ncRNA expression in TNBC cell lines and the BT-474 cell line in intra- and extracellular compartments. Serum and urine-based ncRNA expression analysis was able to discriminate between patients with TNBC and controls. Time point comparisons in the urine samples of patients with TNBC revealed a general rise in the level of ncRNA. Serum data suggested a potential association between piR-36743, miR-17, -19b and -30b expression levels and an NACT-driven complete clinical response. The present study highlighted the potential of ncRNAs as liquid biopsy-based biomarkers in TNBC chemotherapy treatment. The ncRNAs tested in the present study have been previously investigated for their involvement in BC or TNBC chemotherapy responses; however, these previous studies were restricted to patient tissue or in vitro models. The data from the present study offer novel insight into ncRNA expression in liquid samples from patients with TNBC, and the study serves as an initial step in the evaluation of ncRNAs as diagnostic biomarkers in the monitoring of TNBC therapy.
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Affiliation(s)
- Andrea Ritter
- Department of Obstetrics and Gynecology, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79106 Freiburg, Germany
| | - Marc Hirschfeld
- Department of Obstetrics and Gynecology, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79106 Freiburg, Germany
| | - Kai Berner
- Department of Obstetrics and Gynecology, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79106 Freiburg, Germany
| | - Gerta Rücker
- Institute of Medical Biometry and Statistics, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79104 Freiburg, Germany
| | - Markus Jäger
- Department of Obstetrics and Gynecology, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79106 Freiburg, Germany
| | - Daniela Weiss
- Department of Obstetrics and Gynecology, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79106 Freiburg, Germany
| | - Markus Medl
- Department of Obstetrics and Gynecology, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79106 Freiburg, Germany
| | - Claudia Nöthling
- Department of Obstetrics and Gynecology, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79106 Freiburg, Germany
| | - Sandra Gassner
- Department of Obstetrics and Gynecology, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79106 Freiburg, Germany
| | - Jasmin Asberger
- Department of Obstetrics and Gynecology, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79106 Freiburg, Germany
| | - Thalia Erbes
- Department of Obstetrics and Gynecology, Faculty of Medicine, Medical Center‑University of Freiburg, D‑79106 Freiburg, Germany
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23
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Distribution of SET/I2PP2A protein in gastrointestinal tissues. PLoS One 2019; 14:e0222845. [PMID: 31557212 PMCID: PMC6762106 DOI: 10.1371/journal.pone.0222845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 09/09/2019] [Indexed: 11/21/2022] Open
Abstract
SET (also called I2PP2A and TIF-1) is a multi-functional protein that regulates a variety of cell signaling including nucleosome assembly, histone binding, and tumorigenesis. Elevated SET protein levels are observed in various human tumors, and are correlated with poor prognosis and drug-resistance. We recently reported that SET protein levels in cancer cells were positively correlated with poor prognosis of gastric cancer patients. Using immunohistochemistry, SET protein was observed not only in cancer cells, but also in some interstitial cells. However, the tissue distribution of SET has not been investigated. Here we performed co-immunofluorescent staining to characterize SET protein distribution in gastrointestinal tissues. We found that even though the positive rate is much lower than epithelial cells, SET protein is also expressed in non-epithelial cells, such as monocytes/macrophages, neural cells, myofibroblasts, and smooth muscle cells. Our results indicate an extensive role of SET in a variety of cell types.
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24
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miRNA Predictors of Pancreatic Cancer Chemotherapeutic Response: A Systematic Review and Meta-Analysis. Cancers (Basel) 2019; 11:cancers11070900. [PMID: 31252688 PMCID: PMC6678460 DOI: 10.3390/cancers11070900] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 06/13/2019] [Accepted: 06/21/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND pancreatic cancer (PC) has increasing incidence and mortality in developing countries, and drug resistance is a significant hindrance to the efficacy of successful treatment. The objective of this systematic review and meta-analysis was to evaluate the association between miRNAs and response to chemotherapy in pancreatic cancer patients. METHODS the systematic review and meta-analysis was based on articles collected from a thorough search of PubMed and Science Direct databases for publications spanning from January 2008 to December 2018. The articles were screened via a set of inclusion and exclusion criteria based on the preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines. Data was extracted, collated and tabulated in MS Excel for further synthesis. Hazard ratio (HR) was selected as the effect size metric to be pooled across studies for the meta-analysis, with the random effects model being applied. Subgroup analysis was also conducted, and the presence of publication bias in the selected studies was assessed. Publication bias of the included studies was quantified. FINDINGS of the 169 articles screened, 43 studies were included in our systematic review and 13 articles were included in the meta-analysis. Gemcitabine was observed to be the principal drug used in a majority of the studies. A total of 48 miRNAs have been studied, and 18 were observed to have possible contributions to chemoresistance, while 15 were observed to have possible contributions to chemosensitivity. 41 drug-related genetic pathways have been identified, through which the highlighted miRNA may be affecting chemosensitivity/resistance. The pooled HR value for overall survival was 1.603; (95% Confidence Interval (CI) 1.2-2.143; p-value: 0.01), with the subgroup analysis for miR-21 showing HR for resistance of 2.061; 95% CI 1.195-3.556; p-value: 0.09. INTERPRETATION our results highlight multiple miRNAs that have possible associations with modulation of chemotherapy response in pancreatic cancer patients. Further studies are needed to discover the molecular mechanisms underlying these associations before they can be suggested for use as biomarkers of response to chemotherapeutic interventions in pancreatic cancer.
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MiR-20a-5p regulates gemcitabine chemosensitivity by targeting RRM2 in pancreatic cancer cells and serves as a predictor for gemcitabine-based chemotherapy. Biosci Rep 2019; 39:BSR20181374. [PMID: 30777929 PMCID: PMC6504660 DOI: 10.1042/bsr20181374] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 01/16/2019] [Accepted: 01/25/2019] [Indexed: 02/07/2023] Open
Abstract
Ribonucleotide reductase subunit M2 (RRM2) acts as an important gemcitabine resistance-related gene in pancreatic cancer (PC). Here, we aimed to investigate the potential microRNA that regulates gemcitabine chemosensitivity by targeting RRM2 and explores the clinical significance of candidate miRNA in PC. MTT assay and Western blot analysis revealed that long-time gemcitabine treatment in PC cells induced drug resistance and RRM2 increase, and silence of RRM2 blocked gemcitabine resistance. Among the predicted eight RRM2-related microRNAs, the expression of miR-20a-5p showed the most significant discrepancy between gemcitabine-resistant cells and parental cells. Furthermore, the Dual-Luciferase reporter gene assay indicated that miR-20a-5p directly targeted RRM2 3'UTR, thus inhibited expression of RRM2 and overcame gemcitabine resistance of PC cells. Retrospective study suggested that plasma miR-20a-5p level was correlated with gemcitabine resistance in PC patient. ROC curve showed that miR-20a-5p abundant level might predict gemcitabine resistance with an AUC of 89% (P<0.0001). Additionally, the PFS of patients with high and low expression levels miR-20a-5p was 2.8 and 4.5 months (P<0.001), respectively. Taken together, our results suggests that miR-20a-5p regulated gemcitabine chemosensitivity by targeting RRM2 in PC cells and could serve as a predictor for predicting the efficacy of gemcitabine-based chemotherapy in first-line treatment of PC patients.
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Sethi S, Sethi S, Bluth MH. Clinical Implication of MicroRNAs in Molecular Pathology: An Update for 2018. Clin Lab Med 2019; 38:237-251. [PMID: 29776629 DOI: 10.1016/j.cll.2018.02.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
MicroRNAs (miRNAs) are poised to provide diagnostic, prognostic, and therapeutic targets for several diseases including malignancies for precision medicine applications. The miRNAs have immense potential in the clinical arena because they can be detected in the blood, serum, tissues (fresh and formalin-fixed paraffin-embedded), and fine-needle aspirate specimens. The most attractive feature of miRNA-based therapy is that a single miRNA could be useful for targeting multiple genes that are deregulated in cancers, which can be further investigated through systems biology and network analysis that may provide cancer-specific personalized therapy.
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Affiliation(s)
- Seema Sethi
- Department of Pathology, University of Michigan and VA Hospital, E300, 2215 Fuller Road, Ann Arbor, MI 48105, USA.
| | - Sajiv Sethi
- Department of Gastroenterology, University of South Florida, 12901 Bruce B. Downs Boulevard, MDC 82, Tampa, FL 33612, USA
| | - Martin H Bluth
- Department of Pathology, Wayne State University, School of Medicine, 540 East Canfield Street, Detroit, MI 48201, USA; Pathology Laboratories, Michigan Surgical Hospital, 21230 Dequindre Road, Warren, MI 48091, USA
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27
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Zou Y, Li W, Zhou J, Zhang J, Huang Y, Wang Z. ERK Inhibitor Enhances Everolimus Efficacy through the Attenuation of dNTP Pools in Renal Cell Carcinoma. MOLECULAR THERAPY. NUCLEIC ACIDS 2019; 14:550-561. [PMID: 30771617 PMCID: PMC6374702 DOI: 10.1016/j.omtn.2019.01.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 01/01/2019] [Accepted: 01/01/2019] [Indexed: 01/10/2023]
Abstract
The clinical efficiency of everolimus, an mammalian target of rapamycin (mTOR) inhibitor, is palliative as sequential or second-line therapy for renal cell carcinoma (RCC). However, the limited response of everolimus in RCC remains uncertain. In the present study, everolimus-resistant RCC models were established to understand the mechanisms and to seek combination approaches. Consequently, the activation of ERK was found to contribute toward everolimus-acquired resistance and poor prognosis in patients with RCC. In addition, the efficacy and mechanism of combination treatment underlying RCC using everolimus and ERK inhibitors was investigated. The ERK inhibitor in combination with everolimus synergistically inhibited the proliferation of RCC cells by arresting the cell cycle in the G1 phase. The combination treatment markedly attenuated the deoxyribonucleoside triphosphate (dNTP) pools by downregulating the mRNA expression of RRM1 and RRM2 through E2F1. The overexpression of E2F1 or supplementation of dNTP rescued the anti-proliferation activity of the everolimus-SCH772984 combination. The antitumor efficacy of combination therapy was reiterated in RCC xenograft models. Thus, the current findings provided evidence that the everolimus-ERK inhibitor combination is a preclinical therapeutic strategy for RCC.
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Affiliation(s)
- Yun Zou
- Department of Urology and Andrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Wenzhi Li
- Department of Urology and Andrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Juan Zhou
- Department of Urology and Andrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Jin Zhang
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yiran Huang
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
| | - Zhong Wang
- Department of Urology and Andrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China.
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Liu JK, Liu HF, Ding Y, Gao GD. Predictive value of microRNA let-7a expression for efficacy and prognosis of radiotherapy in patients with lung cancer brain metastasis: A case-control study. Medicine (Baltimore) 2018; 97:e12847. [PMID: 30383637 PMCID: PMC6221706 DOI: 10.1097/md.0000000000012847] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND As a well-known cancer with high mortality, lung cancer has been implied to be closely associated with brain metastasis. Despite notable advances, effective treatment methods are still in urgent need. This study aims to investigate the value of serum microRNA-let-7a (miR-let-7a) expression in predicting efficacy and prognosis of radiotherapy in patients with lung cancer brain metastasis. METHODS To begin with, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed for better understand of the correlation between miR-let-7a and lung cancer. Afterwards, the relationship between serum miR-let-7a expression and radiotherapy efficacy was analyzed by receiver operating characteristic curve analysis. Following successful transfection, RT-qPCR and Western blot assay were utilized for evaluating the involvement of miR-let-7a in regulation of DICER1 expression in lung cancer cell line. Then, whether miR-let-7a was implicated in proliferation and cell cycle distribution of lung cancer cells were confirmed by cell counting kit-8 assay and flow cytometry respectively. RESULTS Initially, it was revealed that serum miR-let-7a expression was decreased in lung cancer. Later, we found that decreased miR-let-7a displayed an unfavorable role in radiotherapy efficacy and overall survival rate of patients with lung cancer brain metastasis. After the successful transfection, the inverse relationship between miR-let-7a and DICER1 expression was uncovered. Meanwhile, biological behaviors of lung cancer cells were presented to be limited after transfection of overexpressed miR-let-7a. CONCLUSION Our findings demonstrated that the lower expression of miR-let-7a in patients with lung cancer brain metastasis was closely related to unfavorable efficacy and prognosis of radiotherapy, and it may be an important predictive biomarker by regulation of DICER1.
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Affiliation(s)
- Ji-Kuan Liu
- Department of Thoracic Surgery, Jining No.1 People's Hospital, Jining
| | - Hong-Feng Liu
- Department of Thoracic Surgery, Jining No.1 People's Hospital, Jining
| | - Yong Ding
- Department of Surgery, Weishan People's Hospital, Weishan, Shandong Province, P.R. China
| | - Guo-Dong Gao
- Department of Thoracic Surgery, Jining No.1 People's Hospital, Jining
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Zhang QA, Yang XH, Chen D, Yan X, Jing FC, Liu HQ, Zhang R. miR-34 increases in vitro PANC-1 cell sensitivity to gemcitabine via targeting Slug/PUMA. Cancer Biomark 2018; 21:755-762. [PMID: 29355113 DOI: 10.3233/cbm-170289] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
miR-34 was deregulated in tumor tissues compared with corresponding noncancerous tissue samples. Furthermore, miR-34 may contribute to cancer-stromal interaction associated with cancer progression. However, whether miR-34 could decrease chemoresistance of cancer cells to chemotherapeutic agent remains unclear. In our study, we examined whether overexpression of miR-34 could sensitize gemcitabine -mediated apoptosis in human pancreatic cancer PANC-1 cells. We found that miR-34 markedly induced gemcitabine -mediated apoptosis in PANC-1 cells. miR-34 induced down-regulation of Slug expression and upregulation of p53 up-regulated modulator of apoptosis (PUMA) expression. The over-expression of Slug or downregulation of PUMA by Slug cDNA or PUMA siRNA transfection markedly blocked miR-34-induced gemcitabine sensitization. Furthermore, miR-34 induced PUMA expression by downregulation of Slug. Taken together, our study demonstrates that miR-34 enhances sensitization against gemcitabine-mediated apoptosis through the down-regulation of Slug expression, and up-regulation of Slug-dependent PUMA expression.
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Affiliation(s)
- Qing-An Zhang
- Department of Clinical Laboratory, The Central Hospital of Linyi, Yishui, Shandong, China.,Department of Clinical Laboratory, The Central Hospital of Linyi, Yishui, Shandong, China
| | - Xu-Hai Yang
- Department of Oncology, Yantaiyuhuangding Hospital, Yantai, Shandong, China
| | - Dong Chen
- Department of General Surgery, The Affiliated Hospital of Qingdao University, Qingdao,Shandong, China
| | - Xiang Yan
- Department of Oncology, Yantaiyuhuangding Hospital, Yantai, Shandong, China
| | - Fu-Chun Jing
- Department of Gastroenterology, Taian Central Hospital, Taian, Shandong, China
| | - Hong-Qian Liu
- Department Pharmacy, The Central Hospital of Linyi, Yishui, Shandong, China
| | - Ronghua Zhang
- Department of Clinical Laboratory, The Central Hospital of Linyi, Yishui, Shandong, China
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30
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Corrà F, Agnoletto C, Minotti L, Baldassari F, Volinia S. The Network of Non-coding RNAs in Cancer Drug Resistance. Front Oncol 2018; 8:327. [PMID: 30211115 PMCID: PMC6123370 DOI: 10.3389/fonc.2018.00327] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 07/31/2018] [Indexed: 12/12/2022] Open
Abstract
Non-coding RNAs (ncRNAs) have been implicated in most cellular functions. The disruption of their function through somatic mutations, genomic imprinting, transcriptional and post-transcriptional regulation, plays an ever-increasing role in cancer development. ncRNAs, including notorious microRNAs, have been thus proposed to function as tumor suppressors or oncogenes, often in a context-dependent fashion. In parallel, ncRNAs with altered expression in cancer have been reported to exert a key role in determining drug sensitivity or restoring drug responsiveness in resistant cells. Acquisition of resistance to anti-cancer drugs is a major hindrance to effective chemotherapy and is one of the most important causes of relapse and mortality in cancer patients. For these reasons, non-coding RNAs have become recent focuses as prognostic agents and modifiers of chemo-sensitivity. This review starts with a brief outline of the role of most studied non-coding RNAs in cancer and then highlights the modulation of cancer drug resistance via known ncRNAs based mechanisms. We identified from literature 388 ncRNA-drugs interactions and analyzed them using an unsupervised approach. Essentially, we performed a network analysis of the non-coding RNAs with direct relations with cancer drugs. Within such a machine-learning framework we detected the most representative ncRNAs-drug associations and groups. We finally discussed the higher integration of the drug-ncRNA clusters with the goal of disentangling effectors from downstream effects and further clarify the involvement of ncRNAs in the cellular mechanisms underlying resistance to cancer treatments.
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Affiliation(s)
- Fabio Corrà
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Chiara Agnoletto
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Linda Minotti
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Federica Baldassari
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Stefano Volinia
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
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31
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The Molecular Basis and Therapeutic Potential of Let-7 MicroRNAs against Colorectal Cancer. Can J Gastroenterol Hepatol 2018; 2018:5769591. [PMID: 30018946 PMCID: PMC6029494 DOI: 10.1155/2018/5769591] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 06/06/2018] [Indexed: 12/12/2022] Open
Abstract
Although a number of studies have revealed the underlying mechanisms which regulate the development of colorectal cancer (CRC), we have not completely overcome this disease yet. Accumulating evidence has shown that the posttranscriptional regulation by the noncoding RNAs such as microRNAs plays an important role in the development or progression of CRC. Among a number of microRNAs, the let-7 microRNA family that was first discovered in C. elegans and conserved from worms to humans has been linked with the development of many types of cancers including CRC. The expression level of let-7 microRNAs is temporally low during the normal developmental processes, while elevated in the differentiated tissues. The let-7 microRNAs regulate the cell proliferation, cell cycle, apoptosis, metabolism, and stemness. In CRC, expressions of let-7 microRNAs have been reported to be reduced, and so let-7 microRNAs are considered to be a tumor suppressor. In this review, we discuss the mechanisms regulating the let-7 microRNA expression and the downstream targets of let-7 in the context of intestinal tumorigenesis. The application of let-7 mimics is also highlighted as a novel therapeutic agent.
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32
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Hahne JC, Valeri N. Non-Coding RNAs and Resistance to Anticancer Drugs in Gastrointestinal Tumors. Front Oncol 2018; 8:226. [PMID: 29967761 PMCID: PMC6015885 DOI: 10.3389/fonc.2018.00226] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 05/31/2018] [Indexed: 12/12/2022] Open
Abstract
Non-coding RNAs are important regulators of gene expression and transcription. It is well established that impaired non-coding RNA expression especially the one of long non-coding RNAs and microRNAs is involved in a number of pathological conditions including cancer. Non-coding RNAs are responsible for the development of resistance to anticancer treatments as they regulate drug resistance-related genes, affect intracellular drug concentrations, induce alternative signaling pathways, alter drug efficiency via blocking cell cycle regulation, and DNA damage response. Furthermore, they can prevent therapeutic-induced cell death and promote epithelial-mesenchymal transition (EMT) and elicit non-cell autonomous mechanisms of resistance. In this review, we summarize the role of non-coding RNAs for different mechanisms resulting in drug resistance (e.g., drug transport, drug metabolism, cell cycle regulation, regulation of apoptotic pathways, cancer stem cells, and EMT) in the context of gastrointestinal cancers.
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Affiliation(s)
- Jens C. Hahne
- Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
| | - Nicola Valeri
- Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
- Department of Medicine, The Royal Marsden NHS Trust, London, United Kingdom
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33
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Mizuno R, Chatterji P, Andres S, Hamilton K, Simon L, Foley SW, Jeganathan A, Gregory BD, Madison B, Rustgi AK. Differential Regulation of LET-7 by LIN28B Isoform-Specific Functions. Mol Cancer Res 2018; 16:403-416. [PMID: 29330293 DOI: 10.1158/1541-7786.mcr-17-0514] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Revised: 11/07/2017] [Accepted: 11/29/2017] [Indexed: 12/30/2022]
Abstract
The RNA-binding protein LIN28B plays an important role in development, stem cell biology, and tumorigenesis. LIN28B has two isoforms: the LIN28B-long and -short isoforms. Although studies have revealed the functions of the LIN28B-long isoform in tumorigenesis, the role of the LIN28B-short isoform remains unclear and represents a major gap in the field. The LIN28B-long and -short isoforms are expressed in a subset of human colorectal cancers and adjacent normal colonic mucosa, respectively. To elucidate the functional and mechanistic aspects of these isoforms, colorectal cancer cells (Caco-2 and LoVo) were generated to either express no LIN28B or the -short or -long isoform. Interestingly, the long isoform suppressed LET-7 expression and activated canonical RAS/ERK signaling, whereas the short isoform did not. The LIN28B-long isoform-expressing cells demonstrated increased drug resistance to 5-fluorouracil and cisplatin through the upregulation of ERCC1, a DNA repair gene, in a LET-7-dependent manner. The LIN28B-short isoform preserved its ability to bind pre-let-7, without inhibiting the maturation of LET-7, and competed with the LIN28B-long isoform for binding to pre-let-7 Coexpression of the short isoform in the LIN28B-long isoform-expressing cells rescued the phenotypes induced by the LIN28B-long isoform.Implications: This study demonstrates the differential antagonistic functions of the LIN28B-short isoform against the LIN28B-long isoform through an inability to degrade LET-7, which leads to the novel premise that the short isoform may serve to counterbalance the long isoform during normal colonic epithelial homeostasis, but its downregulation during colonic carcinogenesis may reveal the protumorigenic effects of the long isoform. Mol Cancer Res; 16(3); 403-16. ©2018 AACR.
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Affiliation(s)
- Rei Mizuno
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Priya Chatterji
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sarah Andres
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kathryn Hamilton
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Lauren Simon
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Shawn W Foley
- Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Arjun Jeganathan
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Brian D Gregory
- Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Blair Madison
- Division of Gastroenterology, Department of Medicine, Washington University, St. Louis, Missouri
| | - Anil K Rustgi
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. .,Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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34
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Yan T, Li HY, Wu JS, Niu Q, Duan WH, Han QZ, Ji WM, Zhang T, Lv W. Astaxanthin inhibits gemcitabine-resistant human pancreatic cancer progression through EMT inhibition and gemcitabine resensitization. Oncol Lett 2017; 14:5400-5408. [PMID: 29098031 PMCID: PMC5652142 DOI: 10.3892/ol.2017.6836] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Accepted: 06/16/2017] [Indexed: 12/22/2022] Open
Abstract
Pancreatic cancer rapidly acquires resistance to chemotherapy resulting in its being difficult to treat. Gemcitabine is the current clinical chemotherapy strategy; however, owing to gemcitabine resistance, it is only able to prolong the life of patients with pancreatic cancer for a limited number of months. Understanding the underlying molecular mechanisms of gemcitabine resistance and selecting a suitable combination of agents for the treatment of pancreatic cancer is required. Astaxanthin (ASX) is able to resensitize gemcitabine-resistant human pancreatic cancer cells (GR-HPCCs) to gemcitabine. ASX was identified to upregulate human equilibrative nucleoside transporter 1 (hENT1) and downregulate ribonucleoside diphosphate reductase (RRM) 1 and 2 to enhance gemcitabine-induced cell death in GR-HPCCs treated with gemcitabine, and also downregulates TWIST1 and ZEB1 to inhibit the gemcitabine-induced epithelial-mesenchymal transition (EMT) phenotype in GR-HPCCs and to mediate hENT1, RRM1 and RRM2. Furthermore, ASX acts through the hypoxia-inducible factor 1α/signal transducer and activator of transcription 3 signaling pathway to mediate TWIST1, ZEB1, hENT1, RRM1 and RRM2, regulating the gemcitabine-induced EMT phenotype and gemcitabine-induced cell death. Co-treatment with ASX and gemcitabine in a tumor xenograft model induced by GR-HPCCs supported the in vitro results. The results of the present study provide a novel therapeutic strategy for the treatment of gemcitabine-resistant pancreatic cancer.
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Affiliation(s)
- Tao Yan
- Department of Hepatobiliary Surgery, The General Hospital of The PLA Rocket Force, Beijing 100088, P.R. China
| | - Hai-Ying Li
- Department of Hepatobiliary Surgery, The General Hospital of The PLA Rocket Force, Beijing 100088, P.R. China
| | - Jian-Song Wu
- Department of Hepatobiliary Surgery, The General Hospital of The PLA Rocket Force, Beijing 100088, P.R. China
| | - Qiang Niu
- Department of Hepatobiliary Surgery, The General Hospital of The PLA Rocket Force, Beijing 100088, P.R. China
| | - Wei-Hong Duan
- Department of Hepatobiliary Surgery, The General Hospital of The PLA Rocket Force, Beijing 100088, P.R. China
| | - Qing-Zeng Han
- Surgical Department, Qinghe County Central Hospital, Qinghe, Xingtai, Hebei 054800, P.R. China
| | - Wang-Ming Ji
- Department of Hepatobiliary Surgery, The General Hospital of The PLA Rocket Force, Beijing 100088, P.R. China
| | - Tao Zhang
- Department of Hepatobiliary Surgery, The General Hospital of The PLA Rocket Force, Beijing 100088, P.R. China
| | - Wei Lv
- Department of Hepatobiliary Surgery, The General Hospital of The PLA Rocket Force, Beijing 100088, P.R. China
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35
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Xia G, Wang H, Song Z, Meng Q, Huang X, Huang X. Gambogic acid sensitizes gemcitabine efficacy in pancreatic cancer by reducing the expression of ribonucleotide reductase subunit-M2 (RRM2). JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:107. [PMID: 28797284 PMCID: PMC5553806 DOI: 10.1186/s13046-017-0579-0] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2017] [Accepted: 08/08/2017] [Indexed: 12/12/2022]
Abstract
Background Pancreatic cancer is susceptible to gemcitabine resistance, and patients receive less benefit from gemcitabine chemotherapy. Previous studies report that gambogic acid possesses antineoplastic properties; however, to our knowledge, there have been no specific studies on its effects in pancreatic cancer. Therefore, the purpose of this study was to explore whether increases the sensitivity of pancreatic cancer to gemcitabine, and determine the synergistic effects of gambogic acid and gemcitabine against pancreatic cancer. Methods The effects of gambogic acid on cell viability, the cell cycle, and apoptosis were assessed using 4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) and flow cytometry in pancreatic cancer cell lines. Protein expression was detected by western blot analysis and mRNA expression was detected using q-PCR. A xenograft tumor model of pancreatic cancer was used to investigate the synergistic effects of gambogic acid and gemcitabine. Results Gambogic acid effectively inhibited the growth of pancreatic cancer cell lines by inducing S-phase cell cycle arrest and apoptosis. Synergistic activity of gambogic acid combined with gemcitabine was observed in PANC-1 and BxPC-3 cells based on the results of MTT, colony formation, and apoptosis assays. Western blot results demonstrated that gambogic acid sensitized gemcitabine-induced apoptosis by enhancing the expression of cleaved caspase-3, cleaved caspase-9, cleaved-PARP, and Bax, and reducing the expression of Bcl-2. In particular, gambogic acid reduced the expression of the ribonucleotide reductase subunit-M2 (RRM2) protein and mRNA, a trend that correlated with resistance to gemcitabine through inhibition of the extracellular signal-regulated kinase (ERK)/E2F1 signaling pathway. Treatment with gambogic acid and gemcitabine significantly repressed tumor growth in the xenograft pancreatic cancer model. Immunohistochemistry results demonstrated a downregulation of p-ERK, E2F1, and RRM2 in mice receiving gambogic acid treatment and combination treatment. Conclusions These results demonstrate that gambogic acid sensitizes pancreatic cancer cells to gemcitabine in vitro and in vivo by inhibiting the activation of the ERK/E2F1/RRM2 signaling pathway. The results also indicate that gambogic acid treatment combined with gemcitabine might be a promising chemotherapy strategy for pancreatic cancer. Electronic supplementary material The online version of this article (doi:10.1186/s13046-017-0579-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Guanggai Xia
- Department of general surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Rd, Shanghai, 200233, People's Republic of China
| | - Hongcheng Wang
- Department of general surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Rd, Shanghai, 200233, People's Republic of China
| | - Ziliang Song
- Department of general surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Rd, Shanghai, 200233, People's Republic of China
| | - Qingcai Meng
- Department of Pancreatic Surgery, Pancreatic Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, People's Republic of China
| | - Xiuyan Huang
- Department of general surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Rd, Shanghai, 200233, People's Republic of China.
| | - Xinyu Huang
- Department of general surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Rd, Shanghai, 200233, People's Republic of China.
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36
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Mody HR, Hung SW, Naidu K, Lee H, Gilbert CA, Hoang TT, Pathak RK, Manoharan R, Muruganandan S, Govindarajan R. SET contributes to the epithelial-mesenchymal transition of pancreatic cancer. Oncotarget 2017; 8:67966-67979. [PMID: 28978088 PMCID: PMC5620228 DOI: 10.18632/oncotarget.19067] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 05/22/2017] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer has a devastating prognosis due to 80-90% of diagnostic cases occurring when metastasis has already presented. Activation of the epithelial-mesenchymal transition (EMT) is a prerequisite for metastasis because it allows for the dissemination of tumor cells to blood stream and secondary organs. Here, we sought to determine the role of SET oncoprotein, an endogenous inhibitor of PP2A, in EMT and pancreatic tumor progression. Among the two major isoforms of SET (isoform 1 and isoform 2), higher protein levels of SET isoform 2 were identified in aggressive pancreatic cancer cell lines. Overexpressing SET isoform 2, and to a lesser extent SET isoform 1, in epithelial cell lines promoted EMT-like features by inducing mesenchymal characteristics and promoting cellular proliferation, migration, invasion, and colony formation. Consistently, knockdown of SET isoforms in the mesenchymal cell line partially resisted these characteristics and promoted epithelial features. SET-induced EMT was likely facilitated by increased N-cadherin overexpression, decreased PP2A activity and/or increased expression of key EMT-driving transcription factors. Additionally, SET overexpression activated the Rac1/JNK/c-Jun signaling pathway that induced transcriptional activation of N-cadherin expression. In vivo, SET isoform 2 overexpression significantly correlated with increased N-cadherin in human PDAC and to tumor burden and metastatic ability in an orthotopic mouse tumor model. These findings identify a new role for SET in cancer and have implications for the design and targeting of SET for intervening pancreatic tumor progression.
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Affiliation(s)
- Hardik R Mody
- Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, OH, USA.,Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, GA, USA
| | - Sau Wai Hung
- Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, GA, USA
| | - Kineta Naidu
- Department of Biochemistry and Molecular Biology, The University of Georgia, Athens, GA, USA
| | - Haesung Lee
- Department of Biochemistry and Molecular Biology, The University of Georgia, Athens, GA, USA
| | - Caitlin A Gilbert
- Department of Biochemistry and Molecular Biology, The University of Georgia, Athens, GA, USA
| | - Toan Thanh Hoang
- Department of Biochemistry and Molecular Biology, The University of Georgia, Athens, GA, USA
| | - Rakesh K Pathak
- Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, OH, USA
| | - Radhika Manoharan
- Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, OH, USA
| | - Shanmugam Muruganandan
- Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, OH, USA
| | - Rajgopal Govindarajan
- The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.,Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, OH, USA.,Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, GA, USA
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37
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Yuan X, Zhang T, Zheng X, Zhang Y, Feng T, Liu P, Sun Z, Qin S, Liu X, Zhang L, Song J, Liu Y. Overexpression of SET oncoprotein is associated with tumor progression and poor prognosis in human gastric cancer. Oncol Rep 2017; 38:1733-1741. [PMID: 28677734 DOI: 10.3892/or.2017.5788] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 06/22/2017] [Indexed: 11/05/2022] Open
Abstract
SE translocation (SET) oncoprotein, an inhibitor of protein phosphatase 2A, is abnormally expressed in many cancers. In this study, SET was aberrantly upregulated in gastric cancer (GC) compared with control tissues. Clinicopathological analysis showed that SET expression was significantly correlated with pathological grade (p=0.002), lymph node stage (p=0.014), and invasive depth (p=0.022). Kaplan-Meier analysis indicated that patients with high SET expression showed poorer overall survival rates than those with low SET expression. Moreover, SET knockdown downregulated GC cell proliferation, colony formation, tumorigenesis, and metastasis. The biological effect of SET on proliferation and invasion was mediated by inhibition of protein phosphatase 2, which in turn, activated Akt. Taken together, our results suggested that SET overexpression is associated with GC progression, and it might be a potential diagnostic marker for GC, thereby a possible target for GC drug development.
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Affiliation(s)
- Xiaoning Yuan
- Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Te Zhang
- Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Xin Zheng
- Department of Gastrointestinal Surgery, Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Yunfei Zhang
- Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Tingting Feng
- School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Pengfei Liu
- Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Zhiting Sun
- Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Shanshan Qin
- Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Xuewen Liu
- Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Liang Zhang
- Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Jie Song
- Department of Gastrointestinal Surgery, Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Ying Liu
- Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
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Khan MAA, Azim S, Zubair H, Bhardwaj A, Patel GK, Khushman M, Singh S, Singh AP. Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward. Int J Mol Sci 2017; 18:ijms18040779. [PMID: 28383487 PMCID: PMC5412363 DOI: 10.3390/ijms18040779] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 03/28/2017] [Accepted: 03/30/2017] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) continues to rank among the most lethal cancers. The consistent increase in incidence and mortality has made it the seventh leading cause of cancer-associated deaths globally and the third in the United States. The biggest challenge in combating PC is our insufficient understanding of the molecular mechanism(s) underlying its complex biology. Studies during the last several years have helped identify several putative factors and events, both genetic and epigenetic, as well as some deregulated signaling pathways, with implications in PC onset and progression. In this review article, we make an effort to summarize our current understanding of molecular and cellular events involved in the pathogenesis of pancreatic malignancy. Specifically, we provide up-to-date information on the genetic and epigenetic changes that occur during the initiation and progression of PC and their functional involvement in the pathogenic processes. We also discuss the impact of the tumor microenvironment on the molecular landscape of PC and its role in aggressive disease progression. It is envisioned that a better understanding of these molecular factors and the mechanisms of their actions can help unravel novel diagnostic and prognostic biomarkers and can also be exploited for future targeted therapies.
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Affiliation(s)
- Mohammad Aslam Aslam Khan
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Shafquat Azim
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Haseeb Zubair
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Arun Bhardwaj
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Girijesh Kumar Patel
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Moh'd Khushman
- Departments of Interdisciplinary Clinical Oncology, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Seema Singh
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
- Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36604, USA.
| | - Ajay Pratap Singh
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
- Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36604, USA.
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Mody HR, Hung SW, Pathak RK, Griffin J, Cruz-Monserrate Z, Govindarajan R. miR-202 Diminishes TGFβ Receptors and Attenuates TGFβ1-Induced EMT in Pancreatic Cancer. Mol Cancer Res 2017; 15:1029-1039. [PMID: 28373289 DOI: 10.1158/1541-7786.mcr-16-0327] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Revised: 10/24/2016] [Accepted: 03/29/2017] [Indexed: 12/15/2022]
Abstract
Previous studies in our laboratory identified that 3-deazaneplanocin A (DZNep), a carbocyclic adenosine analog and histone methyl transferase inhibitor, suppresses TGFβ-induced epithelial-to-mesenchymal (EMT) characteristics. In addition, DZNep epigenetically reprograms miRNAs to regulate endogenous TGFβ1 levels via miR-663/4787-mediated RNA interference (Mol Cancer Res. 2016 Sep 13. pii: molcanres.0083.2016) (1). Although DZNep also attenuates exogenous TGFβ-induced EMT response, the mechanism of this inhibition was unclear. Here, DZNep induced miR-202-5p to target both TGFβ receptors, TGFBR1 and TGFBR2, for RNA interference and thereby contributes to the suppression of exogenous TGFβ-induced EMT in pancreatic cancer cells. Lentiviral overexpression of miR-202 significantly reduced the protein levels of both TGFβ receptors and suppressed TGFβ signaling and EMT phenotypic characteristics of cultured parenchymal pancreatic cancer cells. Consistently, transfection of anti-miRNAs against miR-202-5p resulted in increased TGFBR1 and TGFBR2 protein expressions and induced EMT characteristics in these cells. In stellate pancreatic cells, miR-202 overexpression slowed growth as well as reduced stromal extracellular membrane matrix protein expression. In orthotopic pancreatic cancer mouse models, both immunodeficient and immunocompetent, miR-202 reduced tumor burden and metastasis. Together, these findings demonstrate an alternative mechanism of DZNep in suppressing TGFβ signaling at the receptor level and uncover the EMT-suppressing role of miR-202 in pancreatic cancer.Implications: These findings support the possibility of combining small molecule-based (e.g., DZNep analogs) or large molecule-based (e.g., miRNAs) epigenetic modifiers with conventional nucleoside analogs (e.g., gemcitabine, capecitabine) to improve the antimetastatic potential of current pancreatic cancer therapy. Mol Cancer Res; 15(8); 1029-39. ©2017 AACR.
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Affiliation(s)
- Hardik R Mody
- Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, Ohio.,Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia
| | - Sau Wai Hung
- Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia
| | - Rakesh K Pathak
- Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, Ohio
| | - Jazmine Griffin
- Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia
| | - Zobeida Cruz-Monserrate
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.,Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - Rajgopal Govindarajan
- Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, Ohio. .,Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia.,The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
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Balzeau J, Menezes MR, Cao S, Hagan JP. The LIN28/let-7 Pathway in Cancer. Front Genet 2017; 8:31. [PMID: 28400788 PMCID: PMC5368188 DOI: 10.3389/fgene.2017.00031] [Citation(s) in RCA: 344] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Accepted: 02/27/2017] [Indexed: 01/12/2023] Open
Abstract
Among all tumor suppressor microRNAs, reduced let-7 expression occurs most frequently in cancer and typically correlates with poor prognosis. Activation of either LIN28A or LIN28B, two highly related RNA binding proteins (RBPs) and proto-oncogenes, is responsible for the global post-transcriptional downregulation of the let-7 microRNA family observed in many cancers. Specifically, LIN28A binds the terminal loop of precursor let-7 and recruits the Terminal Uridylyl Transferase (TUTase) ZCCHC11 that polyuridylates pre-let-7, thereby blocking microRNA biogenesis and tumor suppressor function. For LIN28B, the precise mechanism responsible for let-7 inhibition remains controversial. Functionally, the decrease in let-7 microRNAs leads to overexpression of their oncogenic targets such as MYC, RAS, HMGA2, BLIMP1, among others. Furthermore, mouse models demonstrate that ectopic LIN28 expression is sufficient to drive and/or accelerate tumorigenesis via a let-7 dependent mechanism. In this review, the LIN28/let-7 pathway is discussed, emphasizing its role in tumorigenesis, cancer stem cell biology, metabolomics, metastasis, and resistance to ionizing radiation and several chemotherapies. Also, emerging evidence will be presented suggesting that molecular targeting of this pathway may provide therapeutic benefit in cancer.
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Affiliation(s)
- Julien Balzeau
- Department of Neurosurgery, University of Texas Health Science Center at Houston Houston, TX, USA
| | - Miriam R Menezes
- Department of Neurosurgery, University of Texas Health Science Center at Houston Houston, TX, USA
| | - Siyu Cao
- Department of Neurosurgery, University of Texas Health Science Center at Houston Houston, TX, USA
| | - John P Hagan
- Department of Neurosurgery, University of Texas Health Science Center at Houston Houston, TX, USA
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Ayers D, Vandesompele J. Influence of microRNAs and Long Non-Coding RNAs in Cancer Chemoresistance. Genes (Basel) 2017; 8:genes8030095. [PMID: 28273813 PMCID: PMC5368699 DOI: 10.3390/genes8030095] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 02/15/2017] [Accepted: 02/24/2017] [Indexed: 12/16/2022] Open
Abstract
Innate and acquired chemoresistance exhibited by most tumours exposed to conventional chemotherapeutic agents account for the majority of relapse cases in cancer patients. Such chemoresistance phenotypes are of a multi-factorial nature from multiple key molecular players. The discovery of the RNA interference pathway in 1998 and the widespread gene regulatory influences exerted by microRNAs (miRNAs) and other non-coding RNAs have certainly expanded the level of intricacy present for the development of any single physiological phenotype, including cancer chemoresistance. This review article focuses on the latest research efforts in identifying and validating specific key molecular players from the two main families of non-coding RNAs, namely miRNAs and long non-coding RNAs (lncRNAs), having direct or indirect influences in the development of cancer drug resistance properties and how such knowledge can be utilised for novel theranostics in oncology.
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Affiliation(s)
- Duncan Ayers
- Centre for Molecular Medicine and Biobanking, University of Malta, Msida MSD2080, Malta.
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M1 7DN, UK.
| | - Jo Vandesompele
- Center for Medical Genetics Ghent, Ghent University, Ghent 9000, Belgium.
- Cancer Research Institute Ghent (CRIG), Ghent University, Ghent 9000, Belgium.
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An X, Sarmiento C, Tan T, Zhu H. Regulation of multidrug resistance by microRNAs in anti-cancer therapy. Acta Pharm Sin B 2017; 7:38-51. [PMID: 28119807 PMCID: PMC5237711 DOI: 10.1016/j.apsb.2016.09.002] [Citation(s) in RCA: 151] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 05/30/2016] [Accepted: 07/06/2016] [Indexed: 12/31/2022] Open
Abstract
Multidrug resistance (MDR) remains a major clinical obstacle to successful cancer treatment. Although diverse mechanisms of MDR have been well elucidated, such as dysregulation of drugs transporters, defects of apoptosis and autophagy machinery, alterations of drug metabolism and drug targets, disrupti on of redox homeostasis, the exact mechanisms of MDR in a specific cancer patient and the cross-talk among these different mechanisms and how they are regulated are poorly understood. MicroRNAs (miRNAs) are a new class of small noncoding RNAs that could control the global activity of the cell by post-transcriptionally regulating a large variety of target genes and proteins expression. Accumulating evidence shows that miRNAs play a key regulatory role in MDR through modulating various drug resistant mechanisms mentioned above, thereby holding much promise for developing novel and more effective individualized therapies for cancer treatment. This review summarizes the various MDR mechanisms and mainly focuses on the role of miRNAs in regulating MDR in cancer treatment.
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Affiliation(s)
- Xin An
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Cesar Sarmiento
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Tao Tan
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
- Corresponding authors..
| | - Hua Zhu
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
- Corresponding authors..
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Mody HR, Hung SW, AlSaggar M, Griffin J, Govindarajan R. Inhibition of S-Adenosylmethionine-Dependent Methyltransferase Attenuates TGFβ1-Induced EMT and Metastasis in Pancreatic Cancer: Putative Roles of miR-663a and miR-4787-5p. Mol Cancer Res 2016; 14:1124-1135. [PMID: 27624777 PMCID: PMC5107158 DOI: 10.1158/1541-7786.mcr-16-0083] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 07/29/2016] [Accepted: 08/27/2016] [Indexed: 01/25/2023]
Abstract
The identification of epigenetic reversal agents for use in combination chemotherapies to treat human pancreatic ductal adenocarcinomas (PDAC) remains an unmet clinical need. Pharmacologic inhibitors of Enhancer of Zeste Homolog 2 (EZH2) are emerging as potential histone methylation reversal agents for the treatment of various solid tumors and leukemia; however, the surprisingly small set of mRNA targets identified with EZH2 knockdown suggests novel mechanisms contribute to their antitumorigenic effects. Here, 3-deazaneplanocin-A (DZNep), an inhibitor of S-adenosyl-L-homocysteine hydrolase and EZH2 histone lysine-N-methyltransferase, significantly reprograms noncoding microRNA (miRNA) expression and dampens TGFβ1-induced epithelial-to-mesenchymal (EMT) signals in pancreatic cancer. In particular, miR-663a and miR-4787-5p were identified as PDAC-downregulated miRNAs that were reactivated by DZNep to directly target TGFβ1 for RNA interference. Lentiviral overexpression of miR-663a and miR-4787-5p reduced TGFβ1 synthesis and secretion in PDAC cells and partially phenocopied DZNep's EMT-resisting effects, whereas locked nucleic acid (LNA) antagomiRNAs counteracted them. DZNep, miR-663a, and miR-4787-5p reduced tumor burden in vivo and metastases in an orthotopic mouse pancreatic tumor model. Taken together, these findings suggest the epigenetic reprogramming of miRNAs by synthetic histone methylation reversal agents as a viable approach to attenuate TGFβ1-induced EMT features in human PDAC and uncover putative miRNA targets involved in the process. IMPLICATIONS The findings support the potential for synthetic histone methylation reversal agents to be included in future epigenetic-chemotherapeutic combination therapies for pancreatic cancer. Mol Cancer Res; 14(11); 1124-35. ©2016 AACR.
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Affiliation(s)
- Hardik R Mody
- Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, Ohio
- Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia
| | - Sau Wai Hung
- Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia
| | - Mohammad AlSaggar
- Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia
| | - Jazmine Griffin
- Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia
| | - Rajgopal Govindarajan
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
- Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, Ohio
- Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia
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Grolmusz VK, Karászi K, Micsik T, Tóth EA, Mészáros K, Karvaly G, Barna G, Szabó PM, Baghy K, Matkó J, Kovalszky I, Tóth M, Rácz K, Igaz P, Patócs A. Cell cycle dependent RRM2 may serve as proliferation marker and pharmaceutical target in adrenocortical cancer. Am J Cancer Res 2016; 6:2041-2053. [PMID: 27725909 PMCID: PMC5043113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 06/06/2016] [Indexed: 06/06/2023] Open
Abstract
Adrenocortical cancer (ACC) is a rare, but agressive malignancy with poor prognosis. Histopathological diagnosis is challenging and pharmacological options for treatment are limited. By the comparative reanalysis of the transcriptional malignancy signature with the cell cycle dependent transcriptional program of ACC, we aimed to identify novel biomarkers which may be used in the histopathological diagnosis and for the prediction of therapeutical response of ACC. Comparative reanalysis of publicly available microarray datasets included three earlier studies comparing transcriptional differences between ACC and benign adrenocortical adenoma (ACA) and one study presenting the cell cycle dependent gene expressional program of human ACC cell line NCI-H295R. Immunohistochemical analysis was performed on ACC samples. In vitro effects of antineoplastic drugs including gemcitabine, mitotane and 9-cis-retinoic acid alone and in combination were tested in the NCI-H295R adrenocortical cell line. Upon the comparative reanalysis, ribonucleotide reductase subunit 2 (RRM2), responsible for the ribonucleotide dezoxyribonucleotide conversion during the S phase of the cell cycle has been validated as cell cycle dependently expressed. Moreover, its expression was associated with the malignancy signature, as well. Immunohistochemical analysis of RRM2 revealed a strong correlation with Ki67 index in ACC. Among the antiproliferative effects of the investigated compounds, gemcitabine showed a strong inhibition of proliferation and an increase of apoptotic events. Additionally, RRM2 has been upregulated upon gemcitabine treatment. Upon our results, RRM2 might be used as a proliferation marker in ACC. RRM2 upregulation upon gemcitabine treatment might contribute to an emerging chemoresistance against gemcitabine, which is in line with its limited therapeutical efficacy in ACC, and which should be overcome for successful clinical applications.
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Affiliation(s)
- Vince Kornél Grolmusz
- 2 Department of Medicine, Semmelweis UniversityBudapest, Hungary
- “Lendület” Hereditary Endocrine Tumours Research Group, Hungarian Academy of Sciences, Semmelweis UniversityBudapest, Hungary
| | - Katalin Karászi
- 1 Department of Pathology and Experimental Cancer Research, Semmelweis UniversityBudapest, Hungary
| | - Tamás Micsik
- 1 Department of Pathology and Experimental Cancer Research, Semmelweis UniversityBudapest, Hungary
| | | | - Katalin Mészáros
- “Lendület” Hereditary Endocrine Tumours Research Group, Hungarian Academy of Sciences, Semmelweis UniversityBudapest, Hungary
- Department of Laboratory Medicine, Semmelweis UniversityBudapest, Hungary
| | - Gellért Karvaly
- “Lendület” Hereditary Endocrine Tumours Research Group, Hungarian Academy of Sciences, Semmelweis UniversityBudapest, Hungary
- Department of Laboratory Medicine, Semmelweis UniversityBudapest, Hungary
- Bionics Innovation CenterBudapest, Hungary
| | - Gábor Barna
- 1 Department of Pathology and Experimental Cancer Research, Semmelweis UniversityBudapest, Hungary
| | - Péter Márton Szabó
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Semmelweis UniversityBudapest, Hungary
| | - Kornélia Baghy
- 1 Department of Pathology and Experimental Cancer Research, Semmelweis UniversityBudapest, Hungary
| | - János Matkó
- Department of Immunology, Eötvös Loránd UniversityBudapest, Hungary
| | - Ilona Kovalszky
- 1 Department of Pathology and Experimental Cancer Research, Semmelweis UniversityBudapest, Hungary
| | - Miklós Tóth
- 2 Department of Medicine, Semmelweis UniversityBudapest, Hungary
| | - Károly Rácz
- 2 Department of Medicine, Semmelweis UniversityBudapest, Hungary
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Semmelweis UniversityBudapest, Hungary
| | - Péter Igaz
- 2 Department of Medicine, Semmelweis UniversityBudapest, Hungary
| | - Attila Patócs
- “Lendület” Hereditary Endocrine Tumours Research Group, Hungarian Academy of Sciences, Semmelweis UniversityBudapest, Hungary
- Department of Laboratory Medicine, Semmelweis UniversityBudapest, Hungary
- Bionics Innovation CenterBudapest, Hungary
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Taucher V, Mangge H, Haybaeck J. Non-coding RNAs in pancreatic cancer: challenges and opportunities for clinical application. Cell Oncol (Dordr) 2016; 39:295-318. [DOI: 10.1007/s13402-016-0275-7] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2016] [Indexed: 01/17/2023] Open
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Yao J, Li Z, Wang X, Xu P, Zhao L, Qian J. MiR-125a regulates chemo-sensitivity to gemcitabine in human pancreatic cancer cells through targeting A20. Acta Biochim Biophys Sin (Shanghai) 2016; 48:202-8. [PMID: 26758190 DOI: 10.1093/abbs/gmv129] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 09/29/2015] [Indexed: 12/17/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly human malignant diseases and the sixth leading cause of cancer-related deaths in China. Gemcitabine is the only first-line chemotherapeutic agent used for the palliative treatment of patients with PDAC, but chemo-resistance limits their efficacy. Here, we showed that miR-125a was up-regulated in chemo-resistant SW1990GZ cells when compared with SW1990 cells. Over-expression of miR-125a increased the chemo-resistance to gemcitabine in SW1990 cells, while down-regulation of miR-125a in SW1990GZ cells increased chemo-sensitivity to gemcitabine. By using bioinformatics analysis tool (Targetscan), the 3' untranslated region (3'UTR) of A20 gene was found to be a target of miR-125a. Luciferase reporter assay further confirmed that A20 3'UTR is a direct target of miR-125a. Over-expression of A20 in SW1990 cells increased chemo-sensitivity to gemcitabine, while knockdown of A20 in SW1990 cells promoted the chemo-resistance to gemcitabine. Finally, the expression level of miR-125a in pancreatic cancer tissues from chemo-sensitive patients was significantly lower than that from chemo-resistant patients, and was inversely correlated with the A20 mRNA levels. In conclusion, our results suggest that miR-125a promotes chemo-resistance to gemcitabine in pancreatic cells through targeting A20, which may provide novel therapeutic targets or molecular biomarkers for cancer therapy and improve tumor diagnosis or predictions of therapeutic responses.
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Affiliation(s)
- Jie Yao
- Department of Hepatobiliary and Pancreatic Surgery, the Northern Jiangsu People's Hospital, Clinic Medical College of Yangzhou University, Yangzhou 225001, China
| | - Zhennan Li
- Department of Hepatobiliary and Pancreatic Surgery, the Northern Jiangsu People's Hospital, Clinic Medical College of Yangzhou University, Yangzhou 225001, China
| | - Xiaodong Wang
- Department of Hepatobiliary and Pancreatic Surgery, the Northern Jiangsu People's Hospital, Clinic Medical College of Yangzhou University, Yangzhou 225001, China
| | - Peng Xu
- Department of Hepatobiliary and Pancreatic Surgery, the Northern Jiangsu People's Hospital, Clinic Medical College of Yangzhou University, Yangzhou 225001, China
| | - Long Zhao
- Department of Hepatobiliary and Pancreatic Surgery, the Northern Jiangsu People's Hospital, Clinic Medical College of Yangzhou University, Yangzhou 225001, China
| | - Jianjun Qian
- Department of Hepatobiliary and Pancreatic Surgery, the Northern Jiangsu People's Hospital, Clinic Medical College of Yangzhou University, Yangzhou 225001, China
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Sun L, Lu J, Niu Z, Ding K, Bi D, Liu S, Li J, Wu F, Zhang H, Zhao Z, Ding S. A Potent Chemotherapeutic Strategy with Eg5 Inhibitor against Gemcitabine Resistant Bladder Cancer. PLoS One 2015; 10:e0144484. [PMID: 26658059 PMCID: PMC4675549 DOI: 10.1371/journal.pone.0144484] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 11/19/2015] [Indexed: 11/30/2022] Open
Abstract
Development of resistance to gemcitabine is a major concern in bladder cancer therapy, and the mechanism remains unclear. Eg5 has been recently identified as an attractive target in cancer chemotherapy, so novel targeted chemotherapy with Eg5 inhibitor is expected to improve the anticancer effect in gemcitabine-resistant bladder cancer. In this research, RT112-Gr cells were 350-fold less sensitive to gemcitabine than the parental cell lines, while KU7-Gr cells were 15-fold less sensitive to gemcitabine than the parental cell lines. Human OneArray Microarray analysis was performed to obtain broad spectrum information about the genes differentially expressed in RT112 and RT112-Gr cells. The anti-proliferative activity of S(MeO)TLC, an Eg5 inhibitor, was analyzed in RT112-Gr cell lines using a cell viability assay. Furthermore, the inhibitory effect was evaluated in vivo using subcutaneous xenograft tumor model. According to the result of Human OneArray GeneChip, RRM1 and RRM2 were up-regulated, while there was no significant change in Eg5. Trypan blue staining confirmed that in S(MeO)TLC and Gemcitabine combining S(MeO)TLC group cell viability were significantly decreased in RT112-Gr cells as compared with other groups. S(MeO)TLC and S(MeO)TLC+gemcitabine groups prominently suppressed tumor growth in comparison with other groups' in vivo. There were no significant differences in S(MeO)TLC and gemcitabine+S(MeO)TLC group in the effect of inhibition of bladder cancer in vivo and in vitro. Our data collectively demonstrated that S(MeO)TLC represents a novel strategy for the treatment of gemcitabine resistant bladder cancer.
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Affiliation(s)
- Liang Sun
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
- Department of Cardiac Surgery, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, ShanDong, China
| | - Jiaju Lu
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
| | - Zhihong Niu
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
| | - Kejia Ding
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
| | - Dongbin Bi
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
| | - Shuai Liu
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
| | - Jiamei Li
- Department of pathology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
| | - Fei Wu
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
| | - Hui Zhang
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
| | - Zuohui Zhao
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
| | - Sentai Ding
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, ShanDong, China
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Nagy Z, Baghy K, Hunyadi-Gulyás É, Micsik T, Nyírő G, Rácz G, Butz H, Perge P, Kovalszky I, Medzihradszky KF, Rácz K, Patócs A, Igaz P. Evaluation of 9-cis retinoic acid and mitotane as antitumoral agents in an adrenocortical xenograft model. Am J Cancer Res 2015; 5:3645-3658. [PMID: 26885453 PMCID: PMC4731638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2015] [Accepted: 11/07/2015] [Indexed: 06/05/2023] Open
Abstract
The available drug treatment options for adrenocortical carcinoma (ACC) are limited. In our previous studies, the in vitro activity of 9-cis retinoic acid (9-cisRA) on adrenocortical NCI-H295R cells was shown along with its antitumoral effects in a small pilot xenograft study. Our aim was to dissect the antitumoral effects of 9-cisRA on ACC in a large-scale xenograft study involving mitotane, 9-cisRA and their combination. 43 male SCID mice inoculated with NCI-H295R cells were treated in four groups (i. control, ii. 9-cisRA, iii. mitotane, iv. 9-cisRA + mitotane) for 28 days. Tumor size follow-up, histological and immunohistochemical (Ki-67) analysis, tissue gene expression microarray, quantitative real-time-PCR for the validation of microarray results and to detect circulating microRNAs were performed. Protein expression was studied by proteomics and Western-blot validation. Only mitotane alone and the combination of 9-cisRA and mitotane resulted in significant tumor size reduction. The Ki-67 index was significantly reduced in both 9-cisRA and 9-cisRA+mitotane groups. Only modest changes at the mRNA level were found: the 9-cisRA-induced overexpression of apolipoprotein A4 and down-regulation of phosphodiesterase 4A was validated. The expression of circulating hsa-miR-483-5p was significantly reduced in the combined treatment group. The SET protein was validated as being significantly down-regulated in the combined mitotane+9-cisRA group. 9-cisRA might be a helpful additive agent in the treatment of ACC in combination with mitotane. Circulating hsa-miR-483-5p could be utilized for monitoring the treatment efficacy in ACC patients, and the treatment-induced reduction in protein SET expression might raise its relevance in ACC biology.
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Affiliation(s)
- Zoltán Nagy
- The 2 Department of Medicine, Faculty of Medicine, Semmelweis UniversityH-1088 Budapest, Szentkirályi Str. 46., Hungary
| | - Kornélia Baghy
- The 1 Department of Pathology and Experimental Cancer Research, Faculty of Medicine, Semmelweis UniversityH-1088 Budapest, Üllői Str. 26., Hungary
| | - Éva Hunyadi-Gulyás
- Laboratory of Proteomics, Biological Research CentreH-6726 Szeged, Temesvári Krt. 62., Hungary
| | - Tamás Micsik
- The 1 Department of Pathology and Experimental Cancer Research, Faculty of Medicine, Semmelweis UniversityH-1088 Budapest, Üllői Str. 26., Hungary
| | - Gábor Nyírő
- Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis UniversitySzentkirályi Str. 46., H-1088 Budapest, Hungary
| | - Gergely Rácz
- The 1 Department of Pathology and Experimental Cancer Research, Faculty of Medicine, Semmelweis UniversityH-1088 Budapest, Üllői Str. 26., Hungary
| | - Henriett Butz
- Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis UniversitySzentkirályi Str. 46., H-1088 Budapest, Hungary
| | - Pál Perge
- The 2 Department of Medicine, Faculty of Medicine, Semmelweis UniversityH-1088 Budapest, Szentkirályi Str. 46., Hungary
| | - Ilona Kovalszky
- The 1 Department of Pathology and Experimental Cancer Research, Faculty of Medicine, Semmelweis UniversityH-1088 Budapest, Üllői Str. 26., Hungary
| | - Katalin F Medzihradszky
- Laboratory of Proteomics, Biological Research CentreH-6726 Szeged, Temesvári Krt. 62., Hungary
| | - Károly Rácz
- The 2 Department of Medicine, Faculty of Medicine, Semmelweis UniversityH-1088 Budapest, Szentkirályi Str. 46., Hungary
- Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis UniversitySzentkirályi Str. 46., H-1088 Budapest, Hungary
| | - Attila Patócs
- Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis UniversitySzentkirályi Str. 46., H-1088 Budapest, Hungary
- “Lendület-2013” Research Group, Hungarian Academy of Sciences and Semmelweis UniversitySzentkirályi Str. 46., H-1088 Budapest, Hungary
| | - Peter Igaz
- The 2 Department of Medicine, Faculty of Medicine, Semmelweis UniversityH-1088 Budapest, Szentkirályi Str. 46., Hungary
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Huang YK, Yu JC. Circulating microRNAs and long non-coding RNAs in gastric cancer diagnosis: An update and review. World J Gastroenterol 2015; 21:9863-9886. [PMID: 26379393 PMCID: PMC4566381 DOI: 10.3748/wjg.v21.i34.9863] [Citation(s) in RCA: 94] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Revised: 05/15/2015] [Accepted: 07/18/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is the fourth most common cancer and the third leading cause of cancer mortality worldwide. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are the most popular non-coding RNAs in cancer research. To date, the roles of miRNAs and lncRNAs have been extensively studied in GC, suggesting that miRNAs and lncRNAs represent a vital component of tumor biology. Furthermore, circulating miRNAs and lncRNAs are found to be dysregulated in patients with GC compared with healthy individuals. Circulating miRNAs and lncRNAs may function as promising biomarkers to improve the early detection of GC. Multiple possibilities for miRNA secretion have been elucidated, including active secretion by microvesicles, exosomes, apoptotic bodies, high-density lipoproteins and protein complexes as well as passive leakage from cells. However, the mechanism underlying lncRNA secretion and the functions of circulating miRNAs and lncRNAs have not been fully illuminated. Concurrently, to standardize results of global investigations of circulating miRNAs and lncRNAs biomarker studies, several recommendations for pre-analytic considerations are put forward. In this review, we summarize the known circulating miRNAs and lncRNAs for GC diagnosis. The possible mechanism of miRNA and lncRNA secretion as well as methodologies for identification of circulating miRNAs and lncRNAs are also discussed. The topics covered here highlight new insights into GC diagnosis and screening.
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Kwon MS, Kim Y, Lee S, Namkung J, Yun T, Yi SG, Han S, Kang M, Kim SW, Jang JY, Park T. Integrative analysis of multi-omics data for identifying multi-markers for diagnosing pancreatic cancer. BMC Genomics 2015; 16 Suppl 9:S4. [PMID: 26328610 PMCID: PMC4547403 DOI: 10.1186/1471-2164-16-s9-s4] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background microRNA (miRNA) expression plays an influential role in cancer classification and malignancy, and miRNAs are feasible as alternative diagnostic markers for pancreatic cancer, a highly aggressive neoplasm with silent early symptoms, high metastatic potential, and resistance to conventional therapies. Methods In this study, we evaluated the benefits of multi-omics data analysis by integrating miRNA and mRNA expression data in pancreatic cancer. Using support vector machine (SVM) modelling and leave-one-out cross validation (LOOCV), we evaluated the diagnostic performance of single- or multi-markers based on miRNA and mRNA expression profiles from 104 PDAC tissues and 17 benign pancreatic tissues. For selecting even more reliable and robust markers, we performed validation by independent datasets from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) data depositories. For validation, miRNA activity was estimated by miRNA-target gene interaction and mRNA expression datasets in pancreatic cancer. Results Using a comprehensive identification approach, we successfully identified 705 multi-markers having powerful diagnostic performance for PDAC. In addition, these marker candidates annotated with cancer pathways using gene ontology analysis. Conclusions Our prediction models have strong potential for the diagnosis of pancreatic cancer.
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