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Yang Z, Tang Y, Wu X, Wang J, Yao W. MicroRNA-130b Suppresses Malignant Behaviours and Inhibits the Activation of the PI3K/Akt Signaling Pathway by Targeting MET in Pancreatic Cancer. Biochem Genet 2025; 63:1660-1685. [PMID: 38607540 PMCID: PMC11929638 DOI: 10.1007/s10528-024-10696-7] [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: 10/19/2023] [Accepted: 01/10/2024] [Indexed: 04/13/2024]
Abstract
There has been interested in the microRNAs' roles in pancreatic cancer (PC) cell biology, particularly in regulating pathways related to tumorigenesis. The study aimed to explore the hub miRNAs in PC and underlying mechanisms by bioinformatics and fundamental experiments. RNA datasets collected from the Gene Expression Omnibus were analysed to find out differentially expressed RNAs (DERNAs). The miRNA-mRNA and protein-protein interaction (PPI) networks were built. The clinicopathological features and expressions of hub miRNAs and hub mRNAs were explored. Dual-luciferase reporter gene assay was performed to assess the interaction between microRNA and target gene. RT-qPCR and western blot were employed to explore RNA expression. The roles of RNA were detected by CCK-8 test, wound healing, transwell, and flow cytometry experiment. We verified 40 DEmiRNAs and 1613 DEmRNAs, then detected a total of 69 final functional mRNAs (FmRNAs) and 23 DEmiRNAs. In the miRNA-mRNA networks, microRNA-130b (miR-130b) was the hub RNA with highest degrees. Clinical analysis revealed that miR-130b was considerably lower expressed in cancerous tissues than in healthy ones, and patients with higher-expressed miR-130b had a better prognosis. Mechanically, miR-130b directly targeted MET in PC cells. Cell functional experiments verified that miR-130b suppressed cell proliferation, migration, promoted apoptosis, and inhibited the PI3K/Akt pathway by targeting MET in PC cells. Our findings illustrated the specific molecular mechanism of miR-130b regulating PC progress. The miR-130b/MET axis may be an alternative target in the therapeutic intervention of PC and provide an opportunity to deepen our understanding of the pathogenesis of PC.
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Affiliation(s)
- Zilin Yang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yuming Tang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xuejiao Wu
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jiancheng Wang
- Department of General Surgery, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Weiyan Yao
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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Ankill J, Zhao Z, Tekpli X, Kure EH, Kristensen VN, Mathelier A, Fleischer T. Integrative pan-cancer analysis reveals a common architecture of dysregulated transcriptional networks characterized by loss of enhancer methylation. PLoS Comput Biol 2024; 20:e1012565. [PMID: 39556603 DOI: 10.1371/journal.pcbi.1012565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 10/16/2024] [Indexed: 11/20/2024] Open
Abstract
Aberrant DNA methylation contributes to gene expression deregulation in cancer. However, these alterations' precise regulatory role and clinical implications are still not fully understood. In this study, we performed expression-methylation Quantitative Trait Loci (emQTL) analysis to identify deregulated cancer-driving transcriptional networks linked to CpG demethylation pan-cancer. By analyzing 33 cancer types from The Cancer Genome Atlas, we identified and confirmed significant correlations between CpG methylation and gene expression (emQTL) in cis and trans, both across and within cancer types. Bipartite network analysis of the emQTL revealed groups of CpGs and genes related to important biological processes involved in carcinogenesis including proliferation, metabolism and hormone-signaling. These bipartite communities were characterized by loss of enhancer methylation in specific transcription factor binding regions (TFBRs) and the CpGs were topologically linked to upregulated genes through chromatin loops. Penalized Cox regression analysis showed a significant prognostic impact of the pan-cancer emQTL in many cancer types. Taken together, our integrative pan-cancer analysis reveals a common architecture where hallmark cancer-driving functions are affected by the loss of enhancer methylation and may be epigenetically regulated.
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Affiliation(s)
- Jørgen Ankill
- Department of Cancer Genetics, Institute of Cancer Research, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Zhi Zhao
- Department of Cancer Genetics, Institute of Cancer Research, Oslo University Hospital, Oslo, Norway
- Oslo Centre for Biostatistics and Epidemiology (OCBE), Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Xavier Tekpli
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Elin H Kure
- Department of Cancer Genetics, Institute of Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Vessela N Kristensen
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Anthony Mathelier
- Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
- Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Norway, Oslo, Norway
| | - Thomas Fleischer
- Department of Cancer Genetics, Institute of Cancer Research, Oslo University Hospital, Oslo, Norway
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Fenu G, Griñán-Lisón C, Pisano A, González-Titos A, Farace C, Fiorito G, Etzi F, Perra T, Sabalic A, Toledo B, Perán M, Solinas MG, Porcu A, Marchal JA, Madeddu R. Unveiling the microRNA landscape in pancreatic ductal adenocarcinoma patients and cancer cell models. BMC Cancer 2024; 24:1308. [PMID: 39448959 PMCID: PMC11515555 DOI: 10.1186/s12885-024-13007-w] [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: 03/07/2024] [Accepted: 09/27/2024] [Indexed: 10/26/2024] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to late-stage diagnoses resulting from nonspecific early symptoms and the absence of early diagnostic biomarkers. MicroRNAs (miRNAs) play a crucial role in regulating diverse biological processes, and their abnormal expression is observed in various diseases, including cancer. Cancer stem cells (CSCs) are thought to act as a driving force in PDAC spread and recurrence. In pursuing the goal of unravelling the complexities of PDAC and its underlying molecular mechanisms, our study aimed to identify PDAC-associated miRNAs and relate them to disease progression, focusing on their involvement in various PDAC stages in patients and in reliable in vitro models, including pancreatic CSC (PaCSC) models. METHODS The miRNA profiling datasets of serum and solid biopsies of PDAC patients deposited in GEO DataSets were analyzed by REML-based meta-analysis. The panel was then investigated by Real Time PCR in serum and solid biopsies of 37 PDAC patients enrolled in the study, as well as on BxPC-3 and AsPC-1 PDAC cell lines. We extended our focus towards a possible role of PDAC-associated miRNAs in the CSC phenotype, by inducing CSC-enriched pancreatospheres from BxPC-3 and AsPC-1 PDAC cell lines and performed differential miRNA expression analysis between PaCSCs and monolayer-grown PDAC cell lines. RESULTS Meta-analysis showed differentially expressed miRNAs in blood samples and cancerous tissues of PDAC patients, allowing the identification of a panel of 9 PDAC-associated miRNAs. The results emerging from our patients fully confirmed the meta-analysis for the majority of miRNAs under investigation. In vitro tasks confirmed the aberrant expression of the panel of PDAC-associated miRNAs, with a dramatic dysregulation in PaCSC models. Notably, PaCSCs have shown significant overexpression of miR-4486, miR-216a-5p, and miR-216b-5p compared to PDAC cell lines, suggesting the recruitment of such miRNAs in stemness-related molecular mechanisms. Globally, our results showed a dual behaviour of miR-216a-5p and miR-216b-5p in PDAC while miR-4486, miR-361-3p, miR-125a-5p, miR-320d expression changes during the disease suggest they could promote PDAC initiation and progression. CONCLUSIONS This study contributed to an enhanced comprehension of the role of miRNAs in the development and progression of PDAC, shedding new light on the miRNA landscape in PDAC and its intricate interplay with CSCs, and providing specific insights useful in the development of miRNA-based diagnostic biomarkers and therapeutic targets.
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Affiliation(s)
- Grazia Fenu
- Department of Biomedical Science, University of Sassari, Sassari, 07100, Italy
| | - Carmen Griñán-Lisón
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, 18016, Spain
- Instituto de Investigación Biosanitaria Ibs.GRANADA, University of Granada, Granada, 18071, Spain
- Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, 18016, Spain
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, 18071, Spain
| | - Andrea Pisano
- Department of Biomedical Science, University of Sassari, Sassari, 07100, Italy
| | - Aitor González-Titos
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, 18016, Spain
- Instituto de Investigación Biosanitaria Ibs.GRANADA, University of Granada, Granada, 18071, Spain
| | - Cristiano Farace
- Department of Biomedical Science, University of Sassari, Sassari, 07100, Italy.
- National Institute of Biostructures and Biosystems, Rome, 00136, Italy.
| | - Giovanni Fiorito
- Clinical Bioinformatics Unit, IRCSS Istituto Giannina Gaslini, Genoa, 16147, Italy
| | - Federica Etzi
- Department of Biomedical Science, University of Sassari, Sassari, 07100, Italy
| | - Teresa Perra
- Department of Medicine, Surgery and Pharmacy - Unit of General Surgery, University of Sassari, Sassari, 07100, Italy
| | - Angela Sabalic
- Department of Biomedical Science, University of Sassari, Sassari, 07100, Italy
| | - Belén Toledo
- Instituto de Investigación Biosanitaria Ibs.GRANADA, University of Granada, Granada, 18071, Spain
- Department of Health Sciences, University of Jaén, Jaén, 23071, Spain
| | - Macarena Perán
- Department of Health Sciences, University of Jaén, Jaén, 23071, Spain
| | | | - Alberto Porcu
- Department of Medicine, Surgery and Pharmacy - Unit of General Surgery, University of Sassari, Sassari, 07100, Italy
| | - Juan Antonio Marchal
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, 18016, Spain.
- Instituto de Investigación Biosanitaria Ibs.GRANADA, University of Granada, Granada, 18071, Spain.
- Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, 18016, Spain.
- Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, 18016, Spain.
| | - Roberto Madeddu
- Department of Biomedical Science, University of Sassari, Sassari, 07100, Italy
- National Institute of Biostructures and Biosystems, Rome, 00136, Italy
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Menadi S, Kucuk B, Cacan E. Promoter Hypomethylation Upregulates ANXA2 Expression in Pancreatic Cancer and is Associated with Poor Prognosis. Biochem Genet 2024; 62:2721-2742. [PMID: 38001391 DOI: 10.1007/s10528-023-10577-5] [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: 11/23/2022] [Accepted: 10/26/2023] [Indexed: 11/26/2023]
Abstract
Pancreatic cancer (PC) is one of the world's most aggressive and deadly cancers, owing to non-specific early clinical symptoms, late-stage diagnosis, and poor survival. Therefore, it is critical to identify specific biomarkers for its early diagnosis. Annexin A2 (ANXA2) is a calcium-dependent phospholipid-binding protein that has been reported to be upregulated in several cancer types, making it an emerging biomarker and potential cancer therapeutic target. However, the mechanism underlying the regulation of ANXA2 overexpression is still unclear. It is well established that genetic and epigenetic alterations may lead to widespread dysregulation of gene expression. Hence, in this study, we focused on exploring the regulatory mechanism of ANXA2 by investigating the transcriptional profile, methylation pattern, somatic mutation, and prognostic value of ANXA2 in PC using several bioinformatics databases. Our results revealed that the expression levels of ANXA2 were remarkably increased in PC tissues comparing to normal tissues. Furthermore, the high expression of ANXA2 was significantly related to the poor prognosis of PC patients. More importantly, we demonstrated for the first time that the ANXA2 promoter is hypomethylated in PC tissues compared to normal tissues which may result in ANXA2 overexpression in PC. However, more experimental research is required to corroborate our findings.
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Affiliation(s)
- Soumaya Menadi
- Department of Molecular Biology and Genetics, Tokat Gaziosmanpasa University, 60250, Tokat, Turkey
| | - Burak Kucuk
- Department of Molecular Biology and Genetics, Tokat Gaziosmanpasa University, 60250, Tokat, Turkey
| | - Ercan Cacan
- Department of Molecular Biology and Genetics, Tokat Gaziosmanpasa University, 60250, Tokat, Turkey.
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Wen H, Ni X, Qian S, Abdul S, Lv H, Chen Y. Construction of a gene signature associated with anoikis to evaluate the prognosis and immune infiltration in patients with colorectal cancer. Transl Cancer Res 2024; 13:1904-1923. [PMID: 38737694 PMCID: PMC11082817 DOI: 10.21037/tcr-23-1221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 02/08/2024] [Indexed: 05/14/2024]
Abstract
Background Colorectal cancer (CRC) is characterized by a high metastasis rate, leading to poor prognosis and increased mortality. Anoikis, a physiological process, serves as a crucial barrier against metastasis. The objective of this research is to construct a prognostic model for CRC based on genes associated with anoikis. Methods The study involved differential analysis and univariate Cox analysis of anoikis-related genes (ARGs), resulting in the selection of 47 genes closely associated with prognosis. Subsequently, unsupervised k-means clustering analysis was conducted on all patients to identify distinct clusters. Survival analysis, principal component analysis (PCA), and t-distributed stochastic neighbor embedding (t-SNE) analysis were performed on the different clusters to investigate associations within the clusters. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) were utilized to assess metabolic pathway enrichment between the identified clusters. Furthermore, single-sample GSEA (ssGSEA) was applied to explore variations in immune infiltration. Multivariable Cox regression and least absolute shrinkage and selection operator (LASSO) analyses were conducted to construct a risk model based on ten signatures, which enabled the grouping of all samples according to their risk scores. The prognostic value of the model was validated using receiver operating characteristic (ROC) curves, area under the curve (AUC) calculations, and survival curves. Additionally, the expression of candidate genes was validated using quantitative real-time polymerase chain reaction (qRT-PCR). Results Forty-seven survival-related ARGs were screened out. Somatic mutation analysis showed that these genes revealed a high mutation rate. Based on their expression, two clusters were identified. Cluster B patients exhibited a shortened overall survival and higher immune infiltration. A risk scoring model including ten genes was subsequently developed, which exhibited excellent prognostic predictive ability for CRC, as evidenced by the survival curve, ROC curve, and AUC curve. In addition, a nomogram was developed for predicting 3- and 5-year survival probabilities. The qRT-PCR results indicated the dissimilarities among the ten signatures in the tumor tissues and adjacent tissues of patients with CRC were fundamentally consistent with the analytical findings. Conclusions This study comprehensively evaluated the prognostic significance of ARGs in CRC. It identified two distinct anoikis-related clusters and examined their respective immune microenvironments. Furthermore, an ARGs signature was developed to effectively predict the prognosis of CRC, thereby establishing a solid foundation for investigating the clinical prognostic role of anoikis in CRC.
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Affiliation(s)
- Hang Wen
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xixian Ni
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Sicheng Qian
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Sammad Abdul
- International Education College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Hang Lv
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yitao Chen
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, China
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Nalbant MO, Oner O, Akinci O, Hocaoglu E, Inci E. Analysis of Pancreatobiliary and Intestinal Type Periampullary Carcinomas Using Volumetric Apparent Diffusion Coefficient Histograms. Acad Radiol 2023; 30 Suppl 1:S238-S245. [PMID: 37211479 DOI: 10.1016/j.acra.2023.04.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 04/21/2023] [Accepted: 04/22/2023] [Indexed: 05/23/2023]
Abstract
RATIONALE AND OBJECTIVES Magnetic resonance imaging plays an important role in the evaluation of patients with known or suspected periampullary masses. The utilization of volumetric apparent diffusion coefficient (ADC) histogram evaluation for the entire lesion eradicates the potential for subjectivity in the region of interest placement, thus guaranteeing the accuracy of computation and repeatability. PURPOSE To investigate the value of volumetric ADC histogram analysis in the differentiation of intestinal-type (IPAC) and pancreatobiliary-type periampullary adenocarcinomas (PPAC). MATERIALS AND METHODS This retrospective study included 69 patients with histopathologically confirmed periampullary adenocarcinoma (54 PPAC and 15 IPAC). Diffusion-weighted imaging was obtained at b values of 1000 mm²/s. The histogram parameters of ADC values, comprising the mean, minimum, maximum, 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles, as well as skewness, kurtosis, and variance, were calculated independently by two radiologists. Using the interclass correlation coefficient, the interobserver agreement was evaluated. RESULTS The ADC parameters for the PPAC group were all lower than those of the IPAC group. The PPAC group had higher variance, skewness, and kurtosis than the IPAC group. However, the difference between the kurtosis (P = .003), the 5th (P = .032), 10th (P = .043), and 25th (P = .037) percentiles of ADC values was statistically significant. The area under the curve (AUC) of the kurtosis was the highest (AUC=0.752; cut-off value=-0.235; sensitivity=61.1%; specificity=80.0%). CONCLUSION Volumetric ADC histogram analysis with b values of 1000 mm²/s can discriminate subtypes noninvasively before surgery.
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Affiliation(s)
- Mustafa Orhan Nalbant
- University of Health Sciences, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Radiology Department, Tevfik Saglam Cad. No: 11, Zuhuratbaba, 34147 Bakırkoy, Istanbul, Turkey.
| | - Ozkan Oner
- University of Health Sciences, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Radiology Department, Tevfik Saglam Cad. No: 11, Zuhuratbaba, 34147 Bakırkoy, Istanbul, Turkey
| | - Ozlem Akinci
- University of Health Sciences, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Radiology Department, Tevfik Saglam Cad. No: 11, Zuhuratbaba, 34147 Bakırkoy, Istanbul, Turkey
| | - Elif Hocaoglu
- University of Health Sciences, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Radiology Department, Tevfik Saglam Cad. No: 11, Zuhuratbaba, 34147 Bakırkoy, Istanbul, Turkey
| | - Ercan Inci
- University of Health Sciences, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Radiology Department, Tevfik Saglam Cad. No: 11, Zuhuratbaba, 34147 Bakırkoy, Istanbul, Turkey
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Gregório C, Thakur S, Camara Rivero R, Márcia Dos Santos Machado S, Cuenin C, Carreira C, White V, Cree IA, Vukojevic K, Glavina Durdov M, Bersch Osvaldt A, Ashton-Prolla P, Herceg Z, Talukdar FR. Telomere length assessment and molecular characterization of TERT gene promoter in periampullary carcinomas. Gene 2023; 873:147460. [PMID: 37150235 DOI: 10.1016/j.gene.2023.147460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 04/14/2023] [Accepted: 05/01/2023] [Indexed: 05/09/2023]
Abstract
Genetic and epigenetic alterations of the telomere maintenance machinery like telomere length and telomerase reverse transcriptase (encoded by TERT gene) are reported in several human malignancies. However, there is limited knowledge on the status of the telomere machinery in periampullary carcinomas (PAC) which are rare and heterogeneous groups of cancers arising from different anatomic sites around the ampulla of Vater. In the current study, we investigated the relative telomere length (RTL) and the most frequent genetic and epigenetic alterations in the TERT promoter in PAC and compared it with tumor-adjacent nonpathological duodenum (NDu). We found shorter RTLs (1.27 vs 1.33, P = 0.01) and lower TERT protein expression (p = 0.04) in PAC tissues as compared to the NDu. Although we did not find any mutation at two reactivating hotspot mutation sites of the TERT promoter, we detected polymorphism in 45% (9/20) of the cases at rs2853669 (T > C). Also, we found a hypermethylated region in the TERT promoter of PACs consisting of four CpGs (cg10896616 with Δβ 7%; cg02545192 with Δβ 9%; cg03323598 with Δβ 19%; and cg07285213 with Δβ 15%). In conclusion, we identified shorter telomeres with DNA hypermethylation in the TERT promoter region and lower TERT protein expression in PAC tissues. These results could be used further to investigate molecular pathology and develop theranostics for PAC.
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Affiliation(s)
- Cleandra Gregório
- Departamento de Genética, Programa de Pós-graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Laboratório de Medicina Genômica, Centro de Pesquisa Experimental - Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, Brazil
| | - Shefali Thakur
- International Agency for Research on Cancer, Lyon, France; Faculty of Science, Charles University, Prague, Czech Republic
| | - Raquel Camara Rivero
- Departamento de Patologia, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Serviço de Patologia- Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - Simone Márcia Dos Santos Machado
- Grupo de Vias Biliares e Pâncreas - Cirurgia do Aparelho Digestivo, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - Cyrille Cuenin
- International Agency for Research on Cancer, Lyon, France
| | | | - Valerie White
- International Agency for Research on Cancer, Lyon, France
| | - Ian A Cree
- International Agency for Research on Cancer, Lyon, France
| | - Katarina Vukojevic
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, Split, Croatia
| | | | - Alessandro Bersch Osvaldt
- Serviço de Patologia- Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil; Programa de Pós-graduação em Medicina: Ciências Cirúrgicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Patricia Ashton-Prolla
- Departamento de Genética, Programa de Pós-graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Laboratório de Medicina Genômica, Centro de Pesquisa Experimental - Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, Brazil; Serviço de Patologia- Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - Zdenko Herceg
- International Agency for Research on Cancer, Lyon, France
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Apurva, Abdul Sattar RS, Ali A, Nimisha, Kumar Sharma A, Kumar A, Santoshi S, Saluja SS. Molecular pathways in periampullary cancer: An overview. Cell Signal 2022; 100:110461. [PMID: 36096460 DOI: 10.1016/j.cellsig.2022.110461] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 08/19/2022] [Accepted: 08/29/2022] [Indexed: 11/22/2022]
Abstract
Molecular alterations in oncogenes and tumor suppressors in various signaling pathways are basis for personalized therapy in cancer. Periampullary carcinoma behaves differently from pancreatic carcinoma both in prognosis and outcome, therefore it needs special attention. Pancreatic cancer have higher incidence of nodal spread and perineural &lymphovascular invasion suggesting it biologically more aggressive tumor compared to periampullary cancer. Since PAC tumors consist of heterogenous tissue of origin, they might contain different mutations in tumor associated genes and other changes in tissue composition among different subgroups clubbed together. Significant progress has been made in understanding the molecular nature of PAC in the previous two decades, and a large number of mutations and other genetic changes have been identified as being responsible for the disease. This review article targets to collate and discuss the molecular evolution of PAC and their implication in its outcome. As per literature, mitogen-activated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), and Wnt signaling are the most common pathways involved in PAC. Mutations in KRAS, TP53, CTNNB1, SMAD4 and APC genes were the most frequently reported. I-subtype resembles colorectal cancer while the morphology of PB-type shows close resemblance to pancreatic tumors. The frequency of driver gene mutations is higher in I-type compared to PB-type of PAC indicating I-type to be genetically more unstable. The genetic landscape of PAC obtained from WES data highlighted PI3/AKT pathway to be a primary target in I-type and RAS/RAF in PB-type.
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Affiliation(s)
- Apurva
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; Amity University, Noida, India
| | - Real Sumayya Abdul Sattar
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Asgar Ali
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Nimisha
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Abhay Kumar Sharma
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Arun Kumar
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | | | - Sundeep Singh Saluja
- Central Molecular Lab, GovindBallabhPant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; Department of GI Surgery, GovindBallabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India.
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Silwal-Pandit L, Stålberg SM, Johansson HJ, Mermelekas G, Lothe IMB, Skrede ML, Dalsgaard AM, Nebdal DJH, Helland Å, Lingjærde OC, Labori KJ, Skålhegg BS, Lehtiö J, Kure EH. Proteome Analysis of Pancreatic Tumors Implicates Extracellular Matrix in Patient Outcome. CANCER RESEARCH COMMUNICATIONS 2022; 2:434-446. [PMID: 36923555 PMCID: PMC10010336 DOI: 10.1158/2767-9764.crc-21-0100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 02/23/2022] [Accepted: 05/18/2022] [Indexed: 11/16/2022]
Abstract
Pancreatic cancer remains a disease with unmet clinical needs and inadequate diagnostic, prognostic, and predictive biomarkers. In-depth characterization of the disease proteome is limited. This study thus aims to define and describe protein networks underlying pancreatic cancer and identify protein centric subtypes with clinical relevance. Mass spectrometry-based proteomics was used to identify and quantify the proteome in tumor tissue, tumor-adjacent tissue, and patient-derived xenografts (PDX)-derived cell lines from patients with pancreatic cancer, and tissues from patients with chronic pancreatitis. We identified, quantified, and characterized 11,634 proteins from 72 pancreatic tissue samples. Network focused analysis of the proteomics data led to identification of a tumor epithelium-specific module and an extracellular matrix (ECM)-associated module that discriminated pancreatic tumor tissue from both tumor adjacent tissue and pancreatitis tissue. On the basis of the ECM module, we defined an ECM-high and an ECM-low subgroup, where the ECM-high subgroup was associated with poor prognosis (median survival months: 15.3 vs. 22.9 months; log-rank test, P = 0.02). The ECM-high tumors were characterized by elevated epithelial-mesenchymal transition and glycolytic activities, and low oxidative phosphorylation, E2F, and DNA repair pathway activities. This study offers novel insights into the protein network underlying pancreatic cancer opening up for proteome precision medicine development. Significance Pancreatic cancer lacks reliable biomarkers for prognostication and treatment of patients. We analyzed the proteome of pancreatic tumors, nonmalignant tissues of the pancreas and PDX-derived cell lines, and identified proteins that discriminate between patients with good and poor survival. The proteomics data also unraveled potential novel drug targets.
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Affiliation(s)
- Laxmi Silwal-Pandit
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Stina M Stålberg
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,Department of Natural Sciences and Environmental Health, University of South-Eastern Norway, Bø i Telemark, Norway
| | - Henrik J Johansson
- Department of Oncology-Pathology, Karolinska Institutet, Science for Life Laboratory, Solna, Sweden
| | - Georgios Mermelekas
- Department of Oncology-Pathology, Karolinska Institutet, Science for Life Laboratory, Solna, Sweden
| | - Inger Marie B Lothe
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Martina L Skrede
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Astrid Marie Dalsgaard
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Daniel J H Nebdal
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Åslaug Helland
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Ole Christian Lingjærde
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,Department of Computer Science, University of Oslo, Oslo, Norway
| | - Knut Jørgen Labori
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - Bjørn S Skålhegg
- Division of Molecular Nutrition, University of Oslo, Oslo, Norway
| | - Janne Lehtiö
- Department of Oncology-Pathology, Karolinska Institutet, Science for Life Laboratory, Solna, Sweden
| | - Elin H Kure
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,Department of Natural Sciences and Environmental Health, University of South-Eastern Norway, Bø i Telemark, Norway
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10
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Ke X, He L, Wang R, Shen J, Wang Z, Shen Y, Fan L, Shao J, Qi H. miR-377-3p-Mediated EGR1 Downregulation Promotes B[a]P-Induced Lung Tumorigenesis by Wnt/Beta-Catenin Transduction. Front Oncol 2021; 11:699004. [PMID: 34497759 PMCID: PMC8419355 DOI: 10.3389/fonc.2021.699004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 07/26/2021] [Indexed: 12/24/2022] Open
Abstract
Polycyclic aromatic hydrocarbons (PAHs), particularly benzo[a]pyrene (B[a]P), found in cigarette smoke and air pollution, is an important carcinogen. Nevertheless, early molecular events and related regulatory effects of B[a]P-mediated cell transformation and tumor initiation remain unclear. This study found that EGR1 was significantly downregulated during human bronchial epithelial cell transformation and mice lung carcinogenesis upon exposure to B[a]P and its active form BPDE, respectively. In contrast, overexpression of EGR1 inhibited the BPDE-induced cell malignant transformation. Moreover, miR-377-3p was strongly enhanced by BPDE/B[a]P exposure and crucial for the inhibition of EGR1 expression by targeting the 3'UTR of EGR1. MiR-377-3p antagomir reversed the effect of EGR1 downregulation in cell malignant transformation and tumor initiation models. Furthermore, the B[a]P-induced molecular changes were evaluated by IHC in clinical lung cancer tissues and examined with a clinic database. Mechanistically, EGR1 inhibition was also involved in the regulation of Wnt/β-catenin transduction, promoting lung tumorigenesis following B[a]P/BPDE exposure. Taken together, the results demonstrated that bBenzo[a]pyrene exposure might induce lung tumorigenesis through miR-377-3p-mediated reduction of EGR1 expression, suggesting an important role of EGR1 in PAHs-induced lung carcinogenesis.
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Affiliation(s)
- Xinxin Ke
- Department of Pathology and Pathophysiology, and Department of Radiation Oncology of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lulu He
- Department of Pathology and Pathophysiology, and Department of Radiation Oncology of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Runan Wang
- Department of Pathology and Pathophysiology, and Department of Radiation Oncology of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jing Shen
- Department of Pathology and Pathophysiology, and Department of Medical Oncology of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhengyang Wang
- Department of Pulmonary and Critical Care Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yifei Shen
- Institute of Crop Science and Institute of Bioinformatics, Zhejiang University, Hangzhou, China
| | - Longjiang Fan
- Institute of Crop Science and Institute of Bioinformatics, Zhejiang University, Hangzhou, China
| | - Jimin Shao
- Department of Pathology and Pathophysiology, and Department of Radiation Oncology of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Disease Proteomics of Zhejiang Province, Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, and Research Center for Air Pollution and Health, School of Medicine, Zhejiang University, Hangzhou, China
| | - Hongyan Qi
- Department of Pathology and Pathophysiology, and Department of Radiation Oncology of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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11
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Mishra SK, Kumari N, Krishnani N, Singh RK, Mohindra S. Identification and prevalence of potentially therapeutic targetable variants of major cancer driver genes in ampullary cancer patients in India through deep sequencing. Cancer Genet 2021; 258-259:41-48. [PMID: 34455261 DOI: 10.1016/j.cancergen.2021.08.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 07/19/2021] [Accepted: 08/13/2021] [Indexed: 12/26/2022]
Abstract
Ampulla is a complex region located at the confluence of pancreatic and common bile duct and intestinal epithelium. Tumors arising in this region are anatomically and morphologically heterogenous, however they show unique as well as overlapping molecular features. Cancers of both these anatomic sites share morphological as well as genetic profile despite having few unique differences. Targeted therapies are currently emerging as one of the demanding approaches for treatment in most cancer types especially for malignant epithelial tumors and therefore genetic profiling of cancers is the key for identification of potentially therapeutic targetable mutations to know their prevalence and prognostic impact. We studied 97 resected cases of formalin fixed paraffin-embedded AC by deep targeted sequencing using Ampliseq cancer hotspot panel comprising of 50 oncogenes and tumor suppressor genes. Potentially therapeutic targetable mutations were observed in 58/83 (70%) cases. Fourteen patients did not show any pathogenic mutation. TP53 (48.1%), KRAS (37.3%), APC (25.3%), SMAD4 (22.8%), MET (16.8%), CTNNB1 (15.6%) and PIK3CA (10.8%) were the major mutated potential therapeutic targets. KRAS mutation (43.2 Vs. 32.6%) was more prevalent in pancreatobiliary subtype, while TP53 (58.6 Vs 35.1), APC (36.9 Vs 10.8), SMAD4 (28.2 Vs 16.2), MET (21.7 Vs 10.8) and CTNNB1 (19.5 Vs 10.8) were more prevalent in intestinal subtype. WNT signaling pathway was the major altered pathway in intestinal subtype. These mutated genes and pathways may be targeted with currently available drugs and may be explored for future development of targetable agents to improve the disease course in patients of AC.
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Affiliation(s)
- Shravan Kumar Mishra
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, UP, India
| | - Niraj Kumari
- Department of Pathology and Laboratory Medicine, All India Institute of Medical Sciences, Raebareli, UP, India.
| | - Narendra Krishnani
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, UP, India
| | - Rajneesh Kumar Singh
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, UP, India
| | - Samir Mohindra
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, UP, India
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12
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Zhu P, Lu J, Zhi X, Zhou Y, Wang X, Wang C, Gao Y, Zhang X, Yu J, Sun YB, Zhou P. tRNA-derived fragment tRF Lys-CTT-010 promotes triple-negative breast cancer progression by regulating glucose metabolism via G6PC. Carcinogenesis 2021; 42:1196-1207. [PMID: 34216208 DOI: 10.1093/carcin/bgab058] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 06/09/2021] [Accepted: 07/01/2021] [Indexed: 12/28/2022] Open
Abstract
tRNA-derived fragments (tRFs) are a novel class of small non-coding RNAs (sncRNAs) whose biological roles are not well defined. Here, using multiple approaches, we investigated its role in human triple-negative breast cancer (TNBC). Our genome-wide transcriptome analysis of sncRNAs revealed that tRF Lys-CTT-010 was significantly increased in human TNBC. It promoted TNBC proliferation and migration. It also closely associated with starch and sucrose metabolism pathways (KEGG analysis) and positively regulated the expression of glucose-6-phosphatase catalytic subunit (G6PC), one of the related genes in the pathway. G6PC, a complex of glucose-6-phosphatase in gluconeogenesis and glycogenolysis, is upregulated in human TNBC samples. Further studies demonstrated that overexpression of G6PC in tRF Lys-CTT-010 inhibitor transfected TNBC cell lines can reverse malignant biological behavior and knockdown of G6PC in TNBC cell lines inhibited tumor progression and reversed the oncogenic function of tRF Lys-CTT-010. In addition, tRF Lys-CTT-010 interacted with G6PC to regulate cellular lactate production and glycogen consumption, resulting in cell survival and proliferation. Thus, fine-tuneing glucose metabolism and the tRF Lys-CTT-010 /G6PC axis may provide a therapeutic target for TNBC treatment.
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Affiliation(s)
- Ping Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Jingjing Lu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Clinical medical research Center, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Xiuling Zhi
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yue Zhou
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xue Wang
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chaofu Wang
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yabiao Gao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xiufen Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Jerry Yu
- Department of Medicine, University of Louisville, Louisville, Kentucky, USA
| | - Yang Bai Sun
- Department of Pathology and Musculoskeletal Oncology of Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Ping Zhou
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
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13
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Recouvreux MV, Moldenhauer MR, Galenkamp KMO, Jung M, James B, Zhang Y, Lowy A, Bagchi A, Commisso C. Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer. J Exp Med 2021; 217:151843. [PMID: 32510550 PMCID: PMC7478719 DOI: 10.1084/jem.20200388] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/10/2020] [Accepted: 05/06/2020] [Indexed: 12/12/2022] Open
Abstract
Tumor cells rely on glutamine to fulfill their metabolic demands and sustain proliferation. The elevated consumption of glutamine can lead to intratumoral nutrient depletion, causing metabolic stress that has the potential to impact tumor progression. Here, we show that nutrient stress caused by glutamine deprivation leads to the induction of epithelial–mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, we demonstrate that glutamine deficiency regulates EMT through the up-regulation of the EMT master regulator Slug, a process that is dependent on both MEK/ERK signaling and ATF4. We find that Slug is required in PDAC cells for glutamine deprivation–induced EMT, cell motility, and nutrient stress survival. Importantly, we decipher that Slug is associated with nutrient stress in PDAC tumors and is required for metastasis. These results delineate a novel role for Slug in the nutrient stress response and provide insight into how nutrient depletion might influence PDAC progression.
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Affiliation(s)
- Maria Victoria Recouvreux
- National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
| | - Matthew R Moldenhauer
- National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
| | - Koen M O Galenkamp
- National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
| | - Michael Jung
- National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
| | - Brian James
- National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
| | - Yijuan Zhang
- National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
| | - Andrew Lowy
- Moores Cancer Center, University of California, San Diego, La Jolla, CA.,Division of Surgical Oncology, Department of Surgery, University of California, San Diego, La Jolla, CA
| | - Anindya Bagchi
- National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
| | - Cosimo Commisso
- National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
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14
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Palmeri M, Funel N, Franco GD, Furbetta N, Gianardi D, Guadagni S, Bianchini M, Pollina LE, Ricci C, Chiaro MD, Candio GD, Morelli L. Tissue microarray-chip featuring computerized immunophenotypical characterization more accurately subtypes ampullary adenocarcinoma than routine histology. World J Gastroenterol 2020; 26:6822-6836. [PMID: 33268964 PMCID: PMC7684454 DOI: 10.3748/wjg.v26.i43.6822] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/24/2020] [Accepted: 08/27/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Ampullary adenocarcinomas (AACs) are heterogeneous tumors currently classified into three important sub-classes (SC): Intestinal (INT), Pancreato-Biliary (PB) and Mixed-Type (MT). The different subgroups have similar clinical presentation and are treated by pancreatoduodenectomy with curative intent. However, they respond differently to chemotherapy and have different prognostic outcomes. The SC are often difficult to identify with conventional histology alone. The clinical outcome of all three remains unclear, particularly for MT. AIM To identify two main subtypes of AACs, using an immunohistochemical (IHC) score based on CDX2, CK7 and CK20. METHODS Tissue samples from 21 patients who had undergone resection of AAC were classified by HE histology and IHC expression of CDX2, CK7 and CK 20. An IHC score was obtained for each marker by counting the number of positive cells (0 = no stained cells; 1 < 25%; 2 < 50% and 3 > 50%) and their intensity (1 = weak; 2 = moderate and 3 = strong). A global score (GS) was then obtained by summation of the IHC scores of each marker. The MT tumors were grouped either with the INT or PB group based on the predominant immuno-molecular phenotype, obtaining only two AACs subtypes. The overall survival in INT and PB patients was obtained by Kaplan-Meier methods. RESULTS Histological parameters defined the AACs subtypes as follows: 15% INT, 45% PB and 40% MT. Using IHC expression and the GS, 75% and 25% of MT samples were assigned to either the INT or the PB group. The mean value of the GS was 9.5 (range 4-16). All INT samples had a GS above the average, distinct from the PB samples which had a GS score significantly below the average (P = 0.0011). The INT samples were identified by high expression of CDX2 and CK20, whereas PB samples exhibited high expression of CK7 and no expression of CK20 (P = 0.0008). The INT group had a statistically significant higher overall survival than in the PB group (85.7 mo vs 20.3 mo, HR: 8.39; 95%CI: 1.38 to 18.90; P = 0.0152). CONCLUSION The combination of histopathological and molecular criteria enables the classification of AACs into two clinically relevant histo-molecular phenotypes, which appear to represent distinct disorders with potentially significant changes to the current therapeutic strategies.
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Affiliation(s)
- Matteo Palmeri
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56124, Italy
| | - Niccola Funel
- Division of Surgical Pathology, University-Hospital of Pisa, Pisa 56124, Italy
| | - Gregorio Di Franco
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56124, Italy
| | - Niccolò Furbetta
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56124, Italy
| | - Desirée Gianardi
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56124, Italy
| | - Simone Guadagni
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56124, Italy
| | - Matteo Bianchini
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56124, Italy
| | - Luca E Pollina
- Division of Surgical Pathology, University-Hospital of Pisa, Pisa 56124, Italy
| | - Claudio Ricci
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa 56124, Italy
| | - Marco Del Chiaro
- Department of Surgery, University of Colorado, Denver, CO 80045, United States
| | - Giulio Di Candio
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56124, Italy
| | - Luca Morelli
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa 56124, Italy
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15
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Luo G, He K, Xia Z, Liu S, Liu H, Xiang G. Regulation of microRNA-497 expression in human cancer. Oncol Lett 2020; 21:23. [PMID: 33240429 PMCID: PMC7681205 DOI: 10.3892/ol.2020.12284] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 08/28/2020] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs/miRs) are a type of non-coding single-stranded RNA, with a length of ~22 nt, which are encoded by endogenous genes and are involved in the post-transcriptional regulation of gene expression in animals and plants. Studies have demonstrated that miRNAs play an important role in the occurrence, development, metastasis, diagnosis and treatment of cancer. In recent years, miR-497 has been identified as one of the key miRNAs in a variety of cancer types and has been shown to be downregulated in a variety of solid tumors. However, the regulation of miR-497 expression involves a complex network, which is affected by several factors. The aim of the present review was to summarize the mechanism of regulation of miR-497 expression at the pre-transcriptional and transcriptional levels in cancer, as well as the role of miR-497 expression imbalance in cancer diagnosis, treatment and prognosis. The regulatory mechanisms of miR-497 expression may aid in our understanding of the causes of miR-497 expression imbalance and provide a reference value for further research on the diagnosis and treatment of cancer.
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Affiliation(s)
- Guanshui Luo
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China.,Department of Postgraduate Studies, The Second Clinical College of Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Ke He
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| | - Zhenglin Xia
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| | - Shuai Liu
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| | - Hong Liu
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| | - Guoan Xiang
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
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16
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Vicentini C, Calore F, Nigita G, Fadda P, Simbolo M, Sperandio N, Luchini C, Lawlor RT, Croce CM, Corbo V, Fassan M, Scarpa A. Exosomal miRNA signatures of pancreatic lesions. BMC Gastroenterol 2020; 20:137. [PMID: 32375666 PMCID: PMC7204029 DOI: 10.1186/s12876-020-01287-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 04/29/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Pancreatic and peri-pancreatic neoplasms encompass a variety of histotypes characterized by a heterogeneous prognostic impact. miRNAs are considered efficient candidate biomarkers due to their high stability in tissues and body fluids. We applied Nanostring profiling of circulating exosomal miRNAs to distinct pancreatic lesions in order to establish a source for biomarker development. METHODS A series of 140 plasma samples obtained from patients affected by pancreatic ductal adenocarcinoma (PDAC, n = 58), pancreatic neuroendocrine tumors (PanNET, n = 42), intraductal papillary mucinous neoplasms (IPMN, n = 20), and ampulla of Vater carcinomas (AVC, n = 20) were analyzed. Comprehensive miRNA profiling was performed on plasma-derived exosomes. Relevant miRNAs were validated by qRT-PCR and in situ hybridization (ISH). RESULTS Lesion specific miRNAs were identified through multiple disease comparisons. Selected miRNAs were validated in the plasma by qRT-PCR and at tissue level by ISH. We leveraged the presence of clinical subtypes with each disease cohort to identify miRNAs that are differentially enriched in aggressive phenotypes. CONCLUSIONS This study shows that pancreatic lesions are characterized by specific exosomal-miRNA signatures. We also provide the basis for further explorations in order to better understand the relevance of these signatures in pancreatic neoplasms.
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Affiliation(s)
| | - Federica Calore
- Department of Cancer Biology and Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA
| | - Giovanni Nigita
- Department of Cancer Biology and Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA
| | - Paolo Fadda
- Department of Cancer Biology and Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA
| | - Michele Simbolo
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy
| | | | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Rita T Lawlor
- ARC-NET Research Centre, University of Verona, Verona, Italy
| | - Carlo Maria Croce
- Department of Cancer Biology and Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA
| | - Vincenzo Corbo
- ARC-NET Research Centre, University of Verona, Verona, Italy
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Matteo Fassan
- ARC-NET Research Centre, University of Verona, Verona, Italy.
- Department of Medicine (DIMED), Surgical Pathology and Cytopathology Unit, University of Padua, Via Aristide Gabelli 61, 35121, Padua, PD, Italy.
| | - Aldo Scarpa
- ARC-NET Research Centre, University of Verona, Verona, Italy
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy
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17
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Almeida PP, Cardoso CP, de Freitas LM. PDAC-ANN: an artificial neural network to predict pancreatic ductal adenocarcinoma based on gene expression. BMC Cancer 2020; 20:82. [PMID: 32005189 PMCID: PMC6995241 DOI: 10.1186/s12885-020-6533-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 01/13/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Although the pancreatic ductal adenocarcinoma (PDAC) presents high mortality and metastatic potential, there is a lack of effective therapies and a low survival rate for this disease. This PDAC scenario urges new strategies for diagnosis, drug targets, and treatment. METHODS We performed a gene expression microarray meta-analysis of the tumor against normal tissues in order to identify differentially expressed genes (DEG) shared among all datasets, named core-genes (CG). We confirmed the CG protein expression in pancreatic tissue through The Human Protein Atlas. It was selected five genes with the highest area under the curve (AUC) among these proteins with expression confirmed in the tumor group to train an artificial neural network (ANN) to classify samples. RESULTS This microarray included 461 tumor and 187 normal samples. We identified a CG composed of 40 genes, 39 upregulated, and one downregulated. The upregulated CG included proteins and extracellular matrix receptors linked to actin cytoskeleton reorganization. With the Human Protein Atlas, we verified that fourteen genes of the CG are translated, with high or medium expression in most of the pancreatic tumor samples. To train our ANN, we selected the best genes (AHNAK2, KRT19, LAMB3, LAMC2, and S100P) to classify the samples based on AUC using mRNA expression. The network classified tumor samples with an f1-score of 0.83 for the normal samples and 0.88 for the PDAC samples, with an average of 0.86. The PDAC-ANN could classify the test samples with a sensitivity of 87.6 and specificity of 83.1. CONCLUSION The gene expression meta-analysis and confirmation of the protein expression allow us to select five genes highly expressed PDAC samples. We could build a python script to classify the samples based on RNA expression. This software can be useful in the PDAC diagnosis.
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Affiliation(s)
- Palloma Porto Almeida
- Núcleo de Biointegração, Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista, Brazil
| | - Cristina Padre Cardoso
- Núcleo de Biointegração, Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista, Brazil
- Faculdade Santo Agostinho, Vitória da Conquista, Brazil
| | - Leandro Martins de Freitas
- Núcleo de Biointegração, Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista, Brazil.
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Sandhu V, Labori KJ, Borgida A, Lungu I, Bartlett J, Hafezi-Bakhtiari S, Denroche RE, Jang GH, Pasternack D, Mbaabali F, Watson M, Wilson J, Kure EH, Gallinger S, Haibe-Kains B. Meta-Analysis of 1,200 Transcriptomic Profiles Identifies a Prognostic Model for Pancreatic Ductal Adenocarcinoma. JCO Clin Cancer Inform 2019; 3:1-16. [DOI: 10.1200/cci.18.00102] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
PURPOSE With a dismal 8% median 5-year overall survival, pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy. Only 10% to 20% of patients are eligible for surgery, and more than 50% of these patients will die within 1 year of surgery. Building a molecular predictor of early death would enable the selection of patients with PDAC who are at high risk. MATERIALS AND METHODS We developed the Pancreatic Cancer Overall Survival Predictor (PCOSP), a prognostic model built from a unique set of 89 PDAC tumors in which gene expression was profiled using both microarray and sequencing platforms. We used a meta-analysis framework that was based on the binary gene pair method to create gene expression barcodes that were robust to biases arising from heterogeneous profiling platforms and batch effects. Leveraging the largest compendium of PDAC transcriptomic data sets to date, we show that PCOSP is a robust single-sample predictor of early death—1 year or less—after surgery in a subset of 823 samples with available transcriptomics and survival data. RESULTS The PCOSP model was strongly and significantly prognostic, with a meta-estimate of the area under the receiver operating curve of 0.70 ( P = 2.6E−22) and d-index (robust hazard ratio) of 1.9 (range, 1.6 to 2.3; ( = 1.4E−04) for binary and survival predictions, respectively. The prognostic value of PCOSP was independent of clinicopathologic parameters and molecular subtypes. Over-representation analysis of the PCOSP 2,619 gene pairs—1,070 unique genes—unveiled pathways associated with Hedgehog signaling, epithelial–mesenchymal transition, and extracellular matrix signaling. CONCLUSION PCOSP could improve treatment decisions by identifying patients who will not benefit from standard surgery/chemotherapy but who may benefit from a more aggressive treatment approach or enrollment in a clinical trial.
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Affiliation(s)
- Vandana Sandhu
- University Health Network, Toronto, Ontario, Canada
- Oslo University Hospital, Institute for Cancer Research, Oslo, Norway
| | | | | | - Ilinca Lungu
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - John Bartlett
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | | | | | - Gun Ho Jang
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | | | | | - Matthew Watson
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Julie Wilson
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Elin H. Kure
- Oslo University Hospital, Institute for Cancer Research, Oslo, Norway
- University of South-Eastern Norway, Bø in Telemark, Norway
| | - Steven Gallinger
- University Health Network, Toronto, Ontario, Canada
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Benjamin Haibe-Kains
- University Health Network, Toronto, Ontario, Canada
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
- University of Toronto, Toronto, Ontario, Canada
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19
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Lu JY, Yu H, Zou XL, Li Z, Hu XM, Shen YQ, Hu DY. Apparent diffusion coefficient-based histogram analysis differentiates histological subtypes of periampullary adenocarcinoma. World J Gastroenterol 2019; 25:6116-6128. [PMID: 31686767 PMCID: PMC6824280 DOI: 10.3748/wjg.v25.i40.6116] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 09/17/2019] [Accepted: 09/28/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND For periampullary adenocarcinoma, the histological subtype is a better prognostic predictor than the site of tumor origin. Intestinal-type periampullary adenocarcinoma (IPAC) is reported to have a better prognosis than the pan-creatobiliary-type periampullary adenocarcinoma (PPAC). However, the classification of histological subtypes is difficult to determine before surgery. Apparent diffusion coefficient (ADC) histogram analysis is a noninvasive, non-enhanced method with high reproducibility that could help differentiate the two subtypes.
AIM To investigate whether volumetric ADC histogram analysis is helpful for distinguishing IPAC from PPAC.
METHODS Between January 2015 and October 2018, 476 consecutive patients who were suspected of having a periampullary tumor and underwent magnetic resonance imaging (MRI) were reviewed in this retrospective study. Only patients who underwent MRI at 3.0 T with different diffusion-weighted images (b-values = 800 and 1000 s/mm2) and who were confirmed with a periampullary adenocarcinoma were further analyzed. Then, the mean, 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles of ADC values and ADCmin, ADCmax, kurtosis, skewness, and entropy were obtained from the volumetric histogram analysis. Comparisons were made by an independent Student's t-test or Mann-Whitney U test. Multiple-class receiver operating characteristic curve analysis was performed to determine and compare the diagnostic value of each significant parameter.
RESULTS In total, 40 patients with histopathologically confirmed IPAC (n = 17) or PPAC (n = 23) were enrolled. The mean, 5th, 25th, 50th, 75th, 90th, and 95th percentiles and ADCmax derived from ADC1000 were significantly lower in the PPAC group than in the IPAC group (P < 0.05). However, values derived from ADC800 showed no significant difference between the two groups. The 75th percentile of ADC1000 values achieved the highest area under the curve (AUC) for differentiating IPAC from PPAC (AUC = 0.781; sensitivity, 91%; specificity, 59%; cut-off value, 1.50 × 10-3 mm2/s).
CONCLUSION Volumetric ADC histogram analysis at a b-value of 1000 s/mm2 might be helpful for differentiating the histological subtypes of periampullary adenocarcinoma before surgery.
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Affiliation(s)
- Jing-Yu Lu
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
- Department of Radiology, the First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Hao Yu
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Xian-Lun Zou
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Zhen Li
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Xue-Mei Hu
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Ya-Qi Shen
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Dao-Yu Hu
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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20
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Wu HY, Xia S, Liu AG, Wei MD, Chen ZB, Li YX, He Y, Liao MJ, Hu QP, Pan SL. Upregulation of miR‑132‑3p in cholangiocarcinoma tissues: A study based on RT‑qPCR, The Cancer Genome Atlas miRNA sequencing, Gene Expression Omnibus microarray data and bioinformatics analyses. Mol Med Rep 2019; 20:5002-5020. [PMID: 31638221 PMCID: PMC6854587 DOI: 10.3892/mmr.2019.10730] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 04/05/2019] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs/miRs) have been reported to be closely associated with numerous human diseases, including cholangiocarcinoma (CCA). However, the number of miRNAs known to be involved in CCA is limited, and the association between miR-132-3p and CCA remains unknown. In the present study, the clinical role of miR-132-3p and its potential signaling pathways were investigated by multiple approaches. Reverse transcription-quantitative PCR (RT-qPCR), CCA-associated Gene Expression Omnibus (GEO), ArrayExpress and Sequence Read Archive (SRA) miRNA-microarray or miRNA-sequencing data were screened, and meta-analyses were conducted, in order to calculate the receiver operating characteristic (ROC) curve and standardized mean difference (SMD). The predicted target genes of miR-132-3p were obtained from 12 online databases and were combined with the downregulated differentially expressed genes identified in the RNA-sequencing data of CCA. Gene Ontology annotation and pathway analysis were performed in WebGestalt. Protein-protein interaction analyses were conducted in STRING. The Cancer Genome Atlas (TCGA) mRNA expression profiles were used to validate the expression levels of hub genes at the mRNA level. The Human Protein Atlas was used to identify the protein expression levels of hub genes in CCA tissues and non-tumor biliary epithelium. The meta-analyses comprised 10 groups of RT-qPCR data, eight GEO microarray datasets and one TCGA miRNA-sequencing dataset. The SMD of miR-132-3p in CCA was 0.75 (95% CI: 0.25, 1.24), which indicated that miR-132-3p was overexpressed in CCA tissues. This finding was supported by a summary ROC value of 0.80 (95% CI: 0.76, 0.83). The pooled sensitivity and specificity were 0.81 (95% CI: 0.59, 0.93) and 0.71 (95% CI: 0.58, 0.81), respectively. The relative expression level of miR-132-3p in the early stage of CCA (stages I–II) was 6.8754±0.5279, which was markedly lower than that in the advanced stage (stages III–IVB), 7.3034±0.3267 (P=0.003). Consistently, the miR-132-3p level in low-grade CCA (grades G1-G2) was 6.7581±0.5297, whereas it was 7.1191±0.4651 in patients with high-grade CCA (grades G3-G4) (P=0.037). Furthermore, 555 potential target genes of miR-132-3p in CCA were mainly enriched in the ‘Focal Adhesion-PI3K-Akt-mTOR-signaling pathway’. In conclusion, upregulation of miR-132-3p may serve a pivotal role in the tumorigenesis and progression of CCA by targeting different pathways. Further in vitro and in vivo studies are required to support the current findings.
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Affiliation(s)
- Hua-Yu Wu
- Department of Pathophysiology, School of Pre‑clinical Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Shuang Xia
- Department of Human Anatomy, School of Pre‑clinical Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - An-Gui Liu
- Department of Pathophysiology, School of Pre‑clinical Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Min-Da Wei
- Department of Pathophysiology, School of Pre‑clinical Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Zhong-Biao Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yu-Xin Li
- Department of Pathophysiology, School of Pre‑clinical Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yu He
- Department of Pathophysiology, School of Pre‑clinical Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Min-Jun Liao
- Department of Pathophysiology, School of Pre‑clinical Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Qi-Ping Hu
- Department of Cell Biology and Genetics, School of Pre‑clinical Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Shang-Ling Pan
- Department of Pathophysiology, School of Pre‑clinical Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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Bowitz Lothe IM, Kleive D, Pomianowska E, Cvancarova M, Kure E, Dueland S, Gladhaug IP, Labori KJ. Clinical relevance of pancreatobiliary and intestinal subtypes of ampullary and duodenal adenocarcinoma: Pattern of recurrence, chemotherapy, and survival after pancreatoduodenectomy. Pancreatology 2019; 19:316-324. [PMID: 30713128 DOI: 10.1016/j.pan.2019.01.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 11/07/2018] [Accepted: 01/24/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND The clinical relevance of the classification of ampullary adenocarcinoma (AC) into pancreatobiliary (PB) or intestinal (Int) subtypes has not been resolved. METHODS Clinicopathological factors, survival, and localization and treatment of recurrence were investigated for patients with AC and duodenal adenocarcinoma (DC) treated by pancreatoduodenectomy from 2000 to 2015. RESULTS A total of 109 AC (45 PB, 64 Int) and 71 DC (all Int) were identified. Median overall survival (OS) for ACPB vs DC vs ACInt was 43.6 vs 51 vs 75 months, respectively. ACPB had significantly shorter OS than ACInt (p = 0.036). However, for AC stage (HR = 2.39; 95 %CI 1.23-4.64, p = 0.010) was the only factor associated with mortality risk in multivariate analysis. Localization of recurrence (n = 88) was predominantly distant (ACPB 81.5%; ACInt 92%; DC 91.7%, p = 0.371). Post-recurrence survival (PRS) for ACPB, ACInt and DC did not differ (6.9 vs 9.2 vs 7.5 months, p = 0.755). Best supportive care or palliative chemotherapy were offered for recurrent disease to 44.5%/48.1% for ACPB, 40%/56% for ACInt, and 41.7%/52.8% for DC (p = 0.947). The choice of chemotherapy regimen varied considerably. Five patients underwent surgical resection or ablation with curative intent. All deaths among ACPB were caused by recurrent disease, whereas 29.4% of ACInt and 23.1% of DC deaths was non-cancer related or caused by other specific cancer. CONCLUSION ACPB, ACInt and DC have similar recurrence patterns and PRS. The difference in survival between ACPB and ACInt was not statistically significant when stratified by stage. The optimal chemotherapy in patients with recurrent AC remains undefined.
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Affiliation(s)
- Inger Marie Bowitz Lothe
- Department of Pathology, Oslo University Hospital, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Dyre Kleive
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Norway
| | - Ewa Pomianowska
- Department of Surgery, Baerum Hospital, Vestre Viken Hospital Trust, Norway
| | - Milada Cvancarova
- Faculty of Health Sciences, Department of Nursing and Health Promotion, Oslo Metropolitan University, Oslo, Norway
| | - Elin Kure
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Svein Dueland
- Department of Oncology, Oslo University Hospital, Norway
| | - Ivar P Gladhaug
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Norway
| | - Knut Jørgen Labori
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Norway.
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22
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Pang C, Gu Y, Ding Y, Ma C, Yv W, Wang Q, Meng B. Several genes involved in the JAK-STAT pathway may act as prognostic markers in pancreatic cancer identified by microarray data analysis. Medicine (Baltimore) 2018; 97:e13297. [PMID: 30557977 PMCID: PMC6320066 DOI: 10.1097/md.0000000000013297] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
PURPOSE This study aimed to identify the underlying mechanisms in pancreatic cancer (PC) carcinogenesis and those as potential prognostic biomarkers, which can also be served as new therapeutic targets of PC. METHODS Differentially expressed genes (DEGs) were identified between PC tumor tissues and adjacent normal tissue samples from a public GSE62452 dataset, followed by functional and pathway enrichment analysis. Then, protein-protein interaction (PPI) network was constructed and prognosis-related genes were screened based on genes in the PPI network, before which prognostic gene-related miRNA regulatory network was constructed. Functions of the prognostic gene in the network were enriched before which Kaplan-Meier plots were calculated for significant genes. Moreover, we predicted related drug molecules based on target genes in the miRNA regulatory network. Furthermore, another independent GSE60979 dataset was downloaded to validate the potentially significant genes. RESULTS In the GSE62452 dataset, 1017 significant DEGs were identified. Twenty-six important prognostic-related genes were found using multivariate Cox regression analysis. Through pathway enrichment analysis and miRNA regulatory analysis, we found that the 5 genes, such as Interleukin 22 Receptor Subunit Alpha 1 (IL22RA1), BCL2 Like 1 (BCL2L1), STAT1, MYC Proto-Oncogene (MYC), and Signal Transducer And Activator Of Transcription 2 (STAT2), involved in the Jak-STAT signaling pathway were significantly associated with prognosis. Moreover, the expression change of these 5 genes was further validated using another microarray dataset. Additionally, we identified camptothecin as an effective drug for PC. CONCLUSION IL22RA1, BCL2L1, STAT1, MYC, and STAT2 involved in the Jak-STAT signaling pathway may be significantly associated with prognosis of PC.
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23
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Jayaramayya K, Balachandar V, Santhy KS. Ampullary carcinoma-A genetic perspective. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2018; 776:10-22. [PMID: 29807574 DOI: 10.1016/j.mrrev.2018.03.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 03/14/2018] [Accepted: 03/14/2018] [Indexed: 12/19/2022]
Abstract
Ampulla of vater carcinoma (AVC) is a rare gastrointestinal tumour that is associated with a high mortality rate and it's often diagnosed at later stages due to lack of clinical symptoms. Early diagnosis of this condition is essential to effectively treat patients for better prognosis. A significant amount of advancement has been made in understanding the molecular nature of cancer in the past decade. A substantial number of mutations and alterations have been detected in various tumors. Despite the occurrence of AVC across the globe, the number of studies conducted on this tumor type remains low; this is largely due to its rare occurrence. Moreover, AVC tissues are complex and contain mutations in oncogenes, tumour suppressors, apoptotic proteins, cell proliferation proteins, cell signaling proteins, transcription factors, chromosomal abnormalities and cellular adhesion proteins. The frequently mutated genes included KRAS, TP53 and SMAD4 and are associated with prognosis. Several molecules of the PI3K, Wnt signaling, TGF-beta pathway and cell cycle have also been altered in AVCs. This review comprises of all the genetic mutations, associated pathways and related prognosis that are involved in AVCs from the year 1989 to 2017. This report can be used as a stepping-stone to establish biomarkers for early diagnosis of AVC and to discover molecular targets for drug therapy.
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Affiliation(s)
- Kaavya Jayaramayya
- Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women - Avinashilingam University for Women, Coimbatore 641 043, Tamil Nadu, India.
| | - Vellingiri Balachandar
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India
| | - Kumaran Sivanandan Santhy
- Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women - Avinashilingam University for Women, Coimbatore 641 043, Tamil Nadu, India
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24
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El Baroudi M, Machiels JP, Schmitz S. Expression of SESN1, UHRF1BP1, and miR-377-3p as prognostic markers in mutated TP53 squamous cell carcinoma of the head and neck. Cancer Biol Ther 2017; 18:775-782. [PMID: 28886272 DOI: 10.1080/15384047.2017.1373212] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
The tumor suppressor gene TP53 is the most frequently mutated gene in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). It represents a known transcription factor that controls different microRNAs (miRNA) and target genes involved in the regulation of cellular stress, apoptosis and response to DNA damage. We used The Cancer Genome Atlas database to investigate the difference in transcriptome and proteome levels between mutated and wild-type TP53 HPV-negative HNSCC. Using different databases and an extensive literature review, we built the transcriptional and post-transcriptional network regulated by TP53. TP53 mutation was associated with poor overall survival in 203 HPV-negative patients compared to 40 patients with TP53 wild-type tumors. Using the enrichment analysis, we found that UHRF1BP1 and SESN1 mRNA were linked to prognosis in the TP53 mutated group. This is also the case for miR-377-3p, an important miRNA regulator of SESN1. Our study shows that SESN1 mRNA, UHRF1BP11 mRNA and miRNA-377-3p levels are prognostically relevant in HPV-negative HNSCC patients. This finding may help with patient stratification and the development of potential new therapeutic targets to treat patients with HNSCC.
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Affiliation(s)
- Mariama El Baroudi
- a Department of Medical Oncology, Institut de Recherche Expérimentale et Clinique (IREC)-Pole MIRO , Université Catholique de Louvain , Brussels , Belgium
| | - Jean-Pascal Machiels
- a Department of Medical Oncology, Institut de Recherche Expérimentale et Clinique (IREC)-Pole MIRO , Université Catholique de Louvain , Brussels , Belgium.,b Institut Roi Albert II, Department of Medical Oncology and Head and Neck Surgery , Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université catholique de Louvain , Brussels , Belgium
| | - Sandra Schmitz
- a Department of Medical Oncology, Institut de Recherche Expérimentale et Clinique (IREC)-Pole MIRO , Université Catholique de Louvain , Brussels , Belgium.,b Institut Roi Albert II, Department of Medical Oncology and Head and Neck Surgery , Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université catholique de Louvain , Brussels , Belgium
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25
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Murali Manohar K, Sasikala M, Kvsrr Y, Sunil V, Talukdar R, Murthy H, Ramji C, Rao GV, Pradeep R, Reddy DN. Plasma microRNA192 in combination with serum CA19-9 as non-invasive prognostic biomarker in periampullary carcinoma. Tumour Biol 2017; 39:1010428317695018. [PMID: 28351309 DOI: 10.1177/1010428317695018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
In this study, circulating microRNAs (miRNAs) are being investigated as non-invasive biomarkers for early diagnosis and prognosis of human cancers. Since the prognosis for pancreatobiliary subtype of periampullary carcinoma is poor, we assessed the prognostic relevance of miRNAs in combination with CA19-9 as noninvasive biomarker in periampullary carcinoma. Circulating miRNAs in plasma and serum CA19-9 were evaluated in periampullary carcinoma patients (n = 109) undergoing Whipple's pancreaticoduodenectomy and in healthy volunteers (n = 92). Tumour tissues were subjected to staging and subtyping prior to determining differentially expressed miRNAs in them by quantitative real-time polymerase chain reaction (qRT-PCR). Statistical analysis involved correlation, receiver operating characteristic, logistic regression, survival analyses and Cox-proportional regression. Of the three differentially expressed circulating miRNA, miRNA192 was significantly increased both in circulation and in tumour tissue and correlated with tumour stage and aggressiveness (r = 0.96, P < 0.0001). Area under the curve of circulating miRNA192 + CA19-9 combination was 0.877 (95% confidence interval, 0.72 to 0.96) for stage III and 0.92 (95% confidence interval, 0.77 to 0.88) for tumour aggressiveness. The combination was associated with poor survival (median: 22 months, P = 0.0008) in stage III patients. Cox-proportional regression analysis revealed prognostic importance of combination of circulating miR192 and CA19-9 (HR = 1.005, P = 0.0001) in periampullary carcinoma. In conclusion, combination of circulating miRNA192 with serum CA19-9 is a better prognostic biomarker than CA19-9 alone.
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Affiliation(s)
- K Murali Manohar
- 1 Institute of Basic Sciences and Translational Research, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, India
| | - Mitnala Sasikala
- 1 Institute of Basic Sciences and Translational Research, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, India
| | - Yesaswini Kvsrr
- 1 Institute of Basic Sciences and Translational Research, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, India
| | - V Sunil
- 2 Asian Institute of Gastroenterology, Hyderabad, India
| | - Rupjyoti Talukdar
- 1 Institute of Basic Sciences and Translational Research, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, India
- 2 Asian Institute of Gastroenterology, Hyderabad, India
| | - Hvv Murthy
- 1 Institute of Basic Sciences and Translational Research, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, India
| | - C Ramji
- 1 Institute of Basic Sciences and Translational Research, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, India
| | - G V Rao
- 1 Institute of Basic Sciences and Translational Research, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, India
- 2 Asian Institute of Gastroenterology, Hyderabad, India
| | - R Pradeep
- 2 Asian Institute of Gastroenterology, Hyderabad, India
| | - D Nageshwar Reddy
- 1 Institute of Basic Sciences and Translational Research, Asian Healthcare Foundation, Asian Institute of Gastroenterology, Hyderabad, India
- 2 Asian Institute of Gastroenterology, Hyderabad, India
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Buanes TA. Updated therapeutic outcome for patients with periampullary and pancreatic cancer related to recent translational research. World J Gastroenterol 2016; 22:10502-10511. [PMID: 28082802 PMCID: PMC5192261 DOI: 10.3748/wjg.v22.i48.10502] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 10/14/2016] [Accepted: 11/23/2016] [Indexed: 02/06/2023] Open
Abstract
Chemotherapy with improved effect in patients with metastatic pancreatic cancer has recently been established, launching a new era for patients with this very aggressive disease. FOLFIRINOX and gemcitabine plus nab-paclitaxel are different regimens, both capable of stabilizing the disease, thus increasing the number of patients who can reach second line and even third line of treatment. Concurrently, new windows of opportunity open for nutritional support and other therapeutic interventions, improving quality of life. Also pancreatic surgery has changed significantly during the latest years. Extended operations, including vascular/multivisceral resections are frequently performed in specialized centers, pushing borders of resectability. Potentially curative treatment including neoadjuvant and adjuvant chemotherapy is offered new patient groups. Translational research is the basis for the essential understanding of the ongoing development. Even thou biomarkers for clinical management of patients with periampullary tumors have almost been lacking, biomarker driven trials are now in progress. New insight is constantly made available for clinicians; one recent example is selection of patients for gemcitabine treatment based on the expression level of the human equilibrium nucleoside transporter 1. An example of new diagnostic tools is identification of early pancreatic cancer patients by a three-biomarker panel in urine: The proteins lymphatic vessel endothelial hyaluronan receptor 1, regenerating gene 1 alpha and translation elongation factor 1 alpha. Requirement of treatment guideline revisions is intensifying, as combined chemotherapy regimens result in unexpected advantages. The European Study Group for Pancreatic Cancer 4 trial outcome is an illustration: Addition of capecitabine in the adjuvant setting improved overall survival more than expected from the effect in advanced disease. Rapid implementation of new treatment options is mandatory when progress finally extends to patients with this serious disease.
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Sandhu V, Wedge DC, Bowitz Lothe IM, Labori KJ, Dentro SC, Buanes T, Skrede ML, Dalsgaard AM, Munthe E, Myklebost O, Lingjærde OC, Børresen-Dale AL, Ikdahl T, Van Loo P, Nord S, Kure EH. The Genomic Landscape of Pancreatic and Periampullary Adenocarcinoma. Cancer Res 2016; 76:5092-5102. [PMID: 27488532 DOI: 10.1158/0008-5472.can-16-0658] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 06/21/2016] [Indexed: 02/05/2023]
Abstract
Despite advances in diagnostics, less than 5% of patients with periampullary tumors experience an overall survival of five years or more. Periampullary tumors are neoplasms that arise in the vicinity of the ampulla of Vater, an enlargement of liver and pancreas ducts where they join and enter the small intestine. In this study, we analyzed copy number aberrations using Affymetrix SNP 6.0 arrays in 60 periampullary adenocarcinomas from Oslo University Hospital to identify genome-wide copy number aberrations, putative driver genes, deregulated pathways, and potential prognostic markers. Results were validated in a separate cohort derived from The Cancer Genome Atlas Consortium (n = 127). In contrast to many other solid tumors, periampullary adenocarcinomas exhibited more frequent genomic deletions than gains. Genes in the frequently codeleted region 17p13 and 18q21/22 were associated with cell cycle, apoptosis, and p53 and Wnt signaling. By integrating genomics and transcriptomics data from the same patients, we identified CCNE1 and ERBB2 as candidate driver genes. Morphologic subtypes of periampullary adenocarcinomas (i.e., pancreatobiliary or intestinal) harbor many common genomic aberrations. However, gain of 13q and 3q, and deletions of 5q were found specific to the intestinal subtype. Our study also implicated the use of the PAM50 classifier in identifying a subgroup of patients with a high proliferation rate, which had impaired survival. Furthermore, gain of 18p11 (18p11.21-23, 18p11.31-32) and 19q13 (19q13.2, 19q13.31-32) and subsequent overexpression of the genes in these loci were associated with impaired survival. Our work identifies potential prognostic markers for periampullary tumors, the genetic characterization of which has lagged. Cancer Res; 76(17); 5092-102. ©2016 AACR.
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Affiliation(s)
- Vandana Sandhu
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. Department for Environmental Health and Science, University College of Southeast Norway, Bø, Norway
| | - David C Wedge
- Wellcome Trust Sanger Institute, Hinxton, United Kingdom. Department of Cancer Genomics, Big Data Institute, University of Oxford, Oxford, United Kingdom
| | - Inger Marie Bowitz Lothe
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Knut Jørgen Labori
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - Stefan C Dentro
- Wellcome Trust Sanger Institute, Hinxton, United Kingdom. Department of Cancer Genomics, Big Data Institute, University of Oxford, Oxford, United Kingdom
| | - Trond Buanes
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway. Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Martina L Skrede
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Astrid M Dalsgaard
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Else Munthe
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Ola Myklebost
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | | | - Anne-Lise Børresen-Dale
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Tone Ikdahl
- Department of Oncology, Oslo University Hospital, Oslo, Norway. Akershus University Hospital, Nordbyhagen, Norway
| | - Peter Van Loo
- The Francis Crick Institute, London, United Kingdom. Department of Human Genetics, University of Leuven, Leuven, Belgium
| | - Silje Nord
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Elin H Kure
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. Department for Environmental Health and Science, University College of Southeast Norway, Bø, Norway.
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28
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Miller HC, Frampton AE, Malczewska A, Ottaviani S, Stronach EA, Flora R, Kaemmerer D, Schwach G, Pfragner R, Faiz O, Kos-Kudła B, Hanna GB, Stebbing J, Castellano L, Frilling A. MicroRNAs associated with small bowel neuroendocrine tumours and their metastases. Endocr Relat Cancer 2016; 23:711-26. [PMID: 27353039 DOI: 10.1530/erc-16-0044] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Accepted: 06/27/2016] [Indexed: 12/17/2022]
Abstract
Novel molecular analytes are needed in small bowel neuroendocrine tumours (SBNETs) to better determine disease aggressiveness and predict treatment response. In this study, we aimed to profile the global miRNome of SBNETs, and identify microRNAs (miRNAs) involved in tumour progression for use as potential biomarkers. Two independent miRNA profiling experiments were performed (n=90), including primary SBNETs (n=28), adjacent normal small bowel (NSB; n=14), matched lymph node (LN) metastases (n=24), normal LNs (n=7), normal liver (n=2) and liver metastases (n=15). We then evaluated potentially targeted genes by performing integrated computational analyses. We discovered 39 miRNAs significantly deregulated in SBNETs compared with adjacent NSB. The most upregulated (miR-204-5p, miR-7-5p and miR-375) were confirmed by qRT-PCR. Two miRNAs (miR-1 and miR-143-3p) were significantly downregulated in LN and liver metastases compared with primary tumours. Furthermore, we identified upregulated gene targets for miR-1 and miR-143-3p in an existing SBNET dataset, which could contribute to disease progression, and show that these miRNAs directly regulate FOSB and NUAK2 oncogenes. Our study represents the largest global miRNA profiling of SBNETs using matched primary tumour and metastatic samples. We revealed novel miRNAs deregulated during SBNET disease progression, and important miRNA-mRNA interactions. These miRNAs have the potential to act as biomarkers for patient stratification and may also be able to guide treatment decisions. Further experiments to define molecular mechanisms and validate these miRNAs in larger tissue cohorts and in biofluids are now warranted.
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Affiliation(s)
- Helen C Miller
- Department of Surgery and CancerImperial College, Hammersmith Hospital Campus, London, UK
| | - Adam E Frampton
- Department of Surgery and CancerImperial College, Hammersmith Hospital Campus, London, UK
| | - Anna Malczewska
- Department of Surgery and CancerImperial College, Hammersmith Hospital Campus, London, UK Department of Pathophysiology and EndocrinologySchool of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Silvia Ottaviani
- Department of Surgery and CancerImperial College, Hammersmith Hospital Campus, London, UK
| | - Euan A Stronach
- Department of Surgery and CancerImperial College, Hammersmith Hospital Campus, London, UK
| | - Rashpal Flora
- Department of HistopathologyImperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK
| | - Daniel Kaemmerer
- Zentralklinik Bad Berka GmbHRobert-Koch-Allee, Bad Berka, Germany
| | - Gert Schwach
- Institute of PathophysiologyCenter for Molecular Medicine, Medical University of Graz, Graz, Austria
| | - Roswitha Pfragner
- Institute of PathophysiologyCenter for Molecular Medicine, Medical University of Graz, Graz, Austria
| | | | - Beata Kos-Kudła
- Department of Pathophysiology and EndocrinologySchool of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
| | - George B Hanna
- Academic Surgical UnitDepartment of Surgery and Cancer, Imperial College, St Mary's Campus, London, UK
| | - Justin Stebbing
- Department of Pathophysiology and EndocrinologySchool of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Leandro Castellano
- Department of Pathophysiology and EndocrinologySchool of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Andrea Frilling
- Department of Surgery and CancerImperial College, Hammersmith Hospital Campus, London, UK
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29
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Chellappa S, Hugenschmidt H, Hagness M, Line PD, Labori KJ, Wiedswang G, Taskén K, Aandahl EM. Regulatory T cells that co-express RORγt and FOXP3 are pro-inflammatory and immunosuppressive and expand in human pancreatic cancer. Oncoimmunology 2016; 5:e1102828. [PMID: 27141387 PMCID: PMC4839385 DOI: 10.1080/2162402x.2015.1102828] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 09/21/2015] [Accepted: 09/26/2015] [Indexed: 12/20/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is highly infiltrated by CD4+T cells that express RORγt and IL-17 (TH17). Compelling evidence from the tumor microenvironment suggest that regulatory T cells (Treg) contribute to TH17 mediated inflammation. Concurrently, PDAC patients have elevated levels of pro-inflammatory cytokines that may lead to TH17 associated functional plasticity in Treg. In this study, we investigated the phenotype and functional properties of Treg in patients with PDAC. We report that PDAC patients have elevated frequency of FOXP3+Treg, which exclusively occurred within the FOXP3+RORγt+Treg compartment. The FOXP3+RORγt+Treg retained FOXP3+Treg markers and represented an activated subset. The expression of RORγt in Treg may indicate a phenotypic switch toward TH17 cells. However, the FOXP3+RORγt+Treg produced both TH17 and TH2 associated pro-inflammatory cytokines, which corresponded with elevated TH17 and TH2 immune responses in PDAC patients. Both the FOXP3+Treg and FOXP3+RORγt+Treg from PDAC patients strongly suppressed T cell immune responses, but they had impaired anti-inflammatory properties. We conclude that FOXP3+RORγt+Treg have a dual phenotype with combined pro-inflammatory and immunosuppressive activity, which may be involved in the pathogenesis of PDAC.
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Affiliation(s)
- Stalin Chellappa
- Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway
- Biotechnology Center, University of Oslo, Oslo, Norway
- K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway
- K.G. Jebsen Center for Cancer Immunotherapy, University of Oslo, Oslo, Norway
| | - Harald Hugenschmidt
- Section for Transplantation Surgery, Oslo University Hospital, Oslo, Norway
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - Morten Hagness
- Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway
- Biotechnology Center, University of Oslo, Oslo, Norway
- K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway
- Section for Transplantation Surgery, Oslo University Hospital, Oslo, Norway
| | - Pål D. Line
- Section for Transplantation Surgery, Oslo University Hospital, Oslo, Norway
| | - Knut J. Labori
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - Gro Wiedswang
- Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway
| | - Kjetil Taskén
- Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway
- Biotechnology Center, University of Oslo, Oslo, Norway
- K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway
- K.G. Jebsen Center for Cancer Immunotherapy, University of Oslo, Oslo, Norway
- Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway
| | - Einar M. Aandahl
- Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway
- Biotechnology Center, University of Oslo, Oslo, Norway
- K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway
- Section for Transplantation Surgery, Oslo University Hospital, Oslo, Norway
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30
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Sandhu V, Bowitz Lothe IM, Labori KJ, Skrede ML, Hamfjord J, Dalsgaard AM, Buanes T, Dube G, Kale MM, Sawant S, Kulkarni-Kale U, Børresen-Dale AL, Lingjærde OC, Kure EH. Differential expression of miRNAs in pancreatobiliary type of periampullary adenocarcinoma and its associated stroma. Mol Oncol 2016; 10:303-316. [PMID: 26590090 PMCID: PMC5528959 DOI: 10.1016/j.molonc.2015.10.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 09/22/2015] [Accepted: 10/08/2015] [Indexed: 02/08/2023] Open
Abstract
Periampullary adenocarcinomas can be of two histological subtypes, intestinal or pancreatobiliary. The latter is more frequent and aggressive, and characterized by a prominent desmoplastic stroma, which is tightly related to the biology of the cancer, including its poor response to chemotherapy. Whereas miRNAs are known to regulate various cellular processes and interactions between cells, their exact role in periampullary carcinoma remains to be characterized, especially with respect to the prominent stromal component of pancreatobiliary type cancers. The present study aimed at elucidating this role by miRNA expression profiling of the carcinomatous and stromal component in twenty periampullary adenocarcinomas of pancreatobiliary type. miRNA expression profiles were compared between carcinoma cells, stromal cells and normal tissue samples. A total of 43 miRNAs were found to be differentially expressed between carcinoma and stroma of which 11 belong to three miRNA families (miR-17, miR-15 and miR-515). The levels of expression of miRNAs miR-17, miR-20a, miR-20b, miR-223, miR-10b, miR-2964a and miR-342 were observed to be higher and miR-519e to be lower in the stromal component compared to the carcinomatous and normal components. They follow a trend where expression in stroma is highest followed by carcinoma and then normal tissue. Pathway analysis revealed that pathways regulating tumor-stroma interactions such as ECM interaction remodeling, epithelial-mesenchymal transition, focal adhesion pathway, TGF-beta, MAPK signaling, axon guidance and endocytosis were differently regulated. The miRNA-mRNA mediated interactions between carcinoma and stromal cells add new knowledge regarding tumor-stroma interactions.
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Affiliation(s)
- V Sandhu
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Department for Environmental Health and Science, Telemark University College, Bø in Telemark, Norway
| | - I M Bowitz Lothe
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - K J Labori
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - M L Skrede
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - J Hamfjord
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - A M Dalsgaard
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - T Buanes
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - G Dube
- Bioinformatics Centre, Savitribai Phule Pune University (Formerly University of Pune), Pune, India
| | - M M Kale
- Department of Statistics, Savitribai Phule Pune University (Formerly University of Pune), Pune, India
| | - S Sawant
- Bioinformatics Centre, Savitribai Phule Pune University (Formerly University of Pune), Pune, India
| | - U Kulkarni-Kale
- Bioinformatics Centre, Savitribai Phule Pune University (Formerly University of Pune), Pune, India
| | - A-L Børresen-Dale
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - O C Lingjærde
- K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Computer Science, University of Oslo, Oslo, Norway
| | - E H Kure
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Department for Environmental Health and Science, Telemark University College, Bø in Telemark, Norway.
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31
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Peng JF, Zhuang YY, Huang FT, Zhang SN. Noncoding RNAs and pancreatic cancer. World J Gastroenterol 2016; 22:801-814. [PMID: 26811626 PMCID: PMC4716078 DOI: 10.3748/wjg.v22.i2.801] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 12/01/2015] [Indexed: 02/06/2023] Open
Abstract
Noncoding RNAs (ncRNAs) represent a class of RNA molecules that typically do not code for proteins. Emerging data suggest that ncRNAs play an important role in several physiological and pathological conditions such as cancer. The best-characterized ncRNAs are the microRNAs (miRNAs), which are short, approximately 22-nucleotide sequences of RNA of approximately 22-nucleotide in length that regulate gene expression at the posttranscriptional level, through transcript degradation or translational repression. MiRNAs can function as master gene regulators, impacting a variety of cellular pathways important to normal cellular functions as well as cancer development and progression. In addition to miRNAs, long ncRNAs, which are transcripts longer than 200 nucleotides, have recently emerged as novel drivers of tumorigenesis. However, the molecular mechanisms of their regulation and function, and the significance of other ncRNAs such as piwi-interacting RNAs in pancreas carcinogenesis are largely unknown. This review summarizes the growing body of evidence supporting the vital roles of ncRNAs in pancreatic cancer, focusing on their dysregulation through both genetic and epigenetic mechanisms, and highlighting the promise of ncRNAs in diagnostic and therapeutic applications of pancreatic cancer.
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MESH Headings
- Animals
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Epigenesis, Genetic
- Gene Expression Regulation, Neoplastic
- Humans
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/therapy
- Predictive Value of Tests
- Prognosis
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- RNA, Small Interfering/genetics
- RNA, Small Interfering/metabolism
- RNA, Untranslated/genetics
- RNA, Untranslated/metabolism
- RNA, Untranslated/therapeutic use
- Transcription, Genetic
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32
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Hamfjord J, Saldova R, Stöckmann H, Sandhu V, Bowitz Lothe IM, Buanes T, Lingjærde OC, Labori KJ, Rudd PM, Kure EH. Serum N-Glycome Characterization in Patients with Resectable Periampullary Adenocarcinoma. J Proteome Res 2015; 14:5144-5156. [PMID: 26515733 DOI: 10.1021/acs.jproteome.5b00395] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Serum N-glycans are promising biomarkers for systemic disease states. Better understanding of the serum N-glycome of patients with resectable periampullary adenocarcinoma may identify novel prognostic markers for this disease. Serum N-glycans in 70 patients with resectable periampullary adenocarcinoma, 15 patients with benign periampullary tumor, and 129 healthy individuals were quantified using ultra performance liquid chromatography. High-sensitivity C-reactive protein (hsCRP) was analyzed for all samples using an immunoturbidimetric method. The N-glycome was compared to clinical and histopathological data, and to the acute phase response as measured by hsCRP. Whole-genome tumor tissue mRNA expression data were used for correlation and enrichment analysis to investigate underlying biological processes giving rise to changes in the serum N-glycome. Significant changes were found in the serum N-glycome of patients with periampullary adenocarcinoma (n = 70) compared to healthy individuals (n = 129). No significant differences were found between patients with benign (n = 15) and malignant periampullary tumors (n = 70). Many alterations in the N-glycome correlated with systemic acute phase response as measured by hsCRP. Enrichment analysis indicated that immunologic pathways of the cancer microenvironment correlate with specific features of the serum N-glycome. Certain glycans were associated with poor overall and disease free survival in patients with pancreatobiliary type of periampullary adenocarcinoma. Our study supports the hypothesis that certain factors secreted by the tumor affect liver and plasma cells to orchestrate the changes in the serum N-glycome observed. The serum N-glycome could potentially reflect modified phenotypes of the host and/or tumor microenvironment. The prognostic impact of the serum N-glycome should be evaluated in larger, prospective studies.
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Affiliation(s)
| | - Radka Saldova
- NIBRT GlycoScience Group, The National Institute for Bioprocessing Research and Training , Dublin, Ireland
| | - Henning Stöckmann
- NIBRT GlycoScience Group, The National Institute for Bioprocessing Research and Training , Dublin, Ireland
| | - Vandana Sandhu
- Department of Environmental and Health Studies, Faculty of Arts and Sciences, Telemark University College , 3800 Bo in Telemark, Norway
| | | | | | | | | | - Pauline M Rudd
- NIBRT GlycoScience Group, The National Institute for Bioprocessing Research and Training , Dublin, Ireland
| | - Elin H Kure
- Department of Environmental and Health Studies, Faculty of Arts and Sciences, Telemark University College , 3800 Bo in Telemark, Norway
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33
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Sandhu V, Bowitz Lothe IM, Labori KJ, Lingjærde OC, Buanes T, Dalsgaard AM, Skrede ML, Hamfjord J, Haaland T, Eide TJ, Børresen-Dale AL, Ikdahl T, Kure EH. Molecular signatures of mRNAs and miRNAs as prognostic biomarkers in pancreatobiliary and intestinal types of periampullary adenocarcinomas. Mol Oncol 2015; 9:758-771. [PMID: 25579086 PMCID: PMC5528780 DOI: 10.1016/j.molonc.2014.12.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Revised: 12/02/2014] [Accepted: 12/08/2014] [Indexed: 02/08/2023] Open
Abstract
Periampullary adenocarcinomas include four anatomical sites of origin (the pancreatic duct, bile duct, ampulla and duodenum) and most of them fall into two histological subgroups (pancreatobiliary and intestinal). Determining the exact origin of the tumor is sometimes difficult, due to overlapping histopathological characteristics. The prognosis depends on the histological subtype, as well as on the anatomical site of origin, the former being the more important. The molecular basis for these differences in prognosis is poorly understood. Whole-genome analyses were used to investigate the association between molecular tumor profiles, pathogenesis and prognosis. A total of 85 periampullary adenocarcinomas were characterized by mRNA and miRNA expressions profiling. Molecular profiles of the tumors from the different anatomical sites of origin as well as of the different histological subtypes were compared. Differentially expressed mRNAs and miRNAs between the two histopathological subtypes were linked to specific molecular pathways. Six miRNA families were downregulated and four were upregulated in the pancreatobiliary type as compared to the intestinal type (P < 0.05). miRNAs and mRNAs associated with improved overall and recurrence free survival for the two histopathological subtypes were identified. For the pancreatobiliary type the genes ATM, PTEN, RB1 and the miRNAs miR-592 and miR-497, and for the intestinal type the genes PDPK1, PIK3R2, G6PC and the miRNAs miR-127-3p, miR-377* were linked to enriched pathways and identified as prognostic markers. The molecular signatures identified may in the future guide the clinicians in the therapeutic decision making to an individualized treatment, if confirmed in other larger datasets.
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Affiliation(s)
- V Sandhu
- Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Department of Environmental and Health Studies, Faculty of Arts and Sciences, Telemark University College, Telemark, Norway
| | - I M Bowitz Lothe
- Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - K J Labori
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - O C Lingjærde
- Department of Informatics, University of Oslo, Oslo, Norway
| | - T Buanes
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway
| | - A M Dalsgaard
- Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - M L Skrede
- Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - J Hamfjord
- Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - T Haaland
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - T J Eide
- Department of Pathology, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway
| | - A-L Børresen-Dale
- Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway
| | - T Ikdahl
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - E H Kure
- Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Department of Environmental and Health Studies, Faculty of Arts and Sciences, Telemark University College, Telemark, Norway.
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