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miRNA profiling of small intestinal neuroendocrine tumors defines novel molecular subtypes and identifies miR-375 as a biomarker of patient survival

Artikel i vetenskaplig tidskrift
Författare Yvonne Arvidsson
Anna Rehammar
Anders Bergström
Ellinor Andersson
Gülay Altiparmak
Christina Swärd
Bo Wängberg
Erik Kristiansson
Ola Nilsson
Publicerad i Modern Pathology
Volym 31
Sidor 1302-1317
ISSN 0893-3952
Publiceringsår 2018
Publicerad vid Institutionen för matematiska vetenskaper
Institutionen för kliniska vetenskaper, Avdelningen för kirurgi
Sahlgrenska Cancer Center
Institutionen för biomedicin, avdelningen för patologi
Sidor 1302-1317
Språk en
Länkar https://doi.org/10.1038/s41379-018-...
Ämnesord CONSENSUS GUIDELINES UPDATE; WNT/BETA-CATENIN ACTIVATION; CELL-LIKE PHENOTYPE; COLON-CANCER CELLS; MICRORNA EXPRESSION; LUNG-CANCER; COLORECTAL-CANCER; GASTRIC-CANCER; LIVER METASTASES; DOWN-REGULATION
Ämneskategorier Cancer och onkologi, Patologi

Sammanfattning

© 2018, United States & Canadian Academy of Pathology. The aim of this study was to define the miRNA profile of small intestinal neuroendocrine tumors and to search for novel molecular subgroups and prognostic biomarkers. miRNA profiling was conducted on 42 tumors from 37 patients who underwent surgery for small intestinal neuroendocrine tumors. Unsupervised hierarchical clustering analysis of miRNA profiles identified two groups of tumor metastases, denoted cluster M1 and M2. The smaller cluster M1 was associated with shorter overall survival and contained tumors with higher grade (WHO grade G2/3) and multiple chromosomal gains including gain of chromosome 14. Tumors of cluster M1 had elevated expression of miR-1246 and miR-663a, and reduced levels of miR-488-3p. Pathway analysis predicted Wnt signaling to be the most significantly altered signaling pathway between clusters M1 and M2. Analysis of miRNA expression in relation to tumor proliferation rate showed significant alterations including downregulation of miR-137 and miR-204-5p in tumors with Ki67 index above 3%. Similarly, tumor progression was associated with significant alterations in miRNA expression, e.g. higher expression of miR-95 and miR-210, and lower expression of miR-378a-3p in metastases. Pathway analysis predicted Wnt signaling to be altered during tumor progression, which was supported by decreased nuclear translocation of β-catenin in metastases. Survival analysis revealed that downregulation of miR-375 was associated with shorter overall survival. We performed in situ hybridization on biopsies from an independent cohort of small intestinal neuroendocrine tumors using tissue microarrays. Expression of miR-375 was found in 578/635 (91%) biopsies and survival analysis confirmed that there was a correlation between downregulation of miR-375 in tumor metastases and shorter patient survival. We conclude that miRNA profiling defines novel molecular subgroups of metastatic small intestinal neuroendocrine tumors and identifies miRNAs associated with tumor proliferation rate and progression. miR-375 is highly expressed in small intestinal neuroendocrine tumors and may be used as a prognostic biomarker.

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