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The Role of MicroRNA-200 in Progression of Human Colorectal and Breast Cancer
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
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2013 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 8, no 12, 84815- p.Article in journal (Refereed) Published
Abstract [en]

The role of the epithelial-mesenchymal transition (EMT) in cancer has been studied extensively in vitro, but involvement of the EMT in tumorigenesis in vivo is largely unknown. We investigated the potential of microRNAs as clinical markers and analyzed participation of the EMT-associated microRNA-200 ZEB E-cadherin pathway in cancer progression. Expression of the microRNA-200 family was quantified by real-time RT-PCR analysis of fresh-frozen and microdissected formalin-fixed paraffin-embedded primary colorectal tumors, normal colon mucosa, and matched liver metastases. MicroRNA expression was validated by in situ hybridization and after in vitro culture of the malignant cells. To assess EMT as a predictive marker, factors considered relevant in colorectal cancer were investigated in 98 primary breast tumors from a treatment-randomized study. Associations between the studied EMTmarkers were found in primary breast tumors and in colorectal liver metastases. MicroRNA-200 expression in epithelial cells was lower in malignant mucosa than in normal mucosa, and was also decreased in metastatic compared to non-metastatic colorectal cancer. Low microRNA-200 expression in colorectal liver metastases was associated with bad prognosis. In breast cancer, low levels of microRNA-200 were related to reduced survival and high expression of microRNA-200 was predictive of benefit from radiotheraphy. MicroRNA-200 was associated with ER positive status, and inversely correlated to HER2 and overactivation of the PI3K/AKT pathway, that was associated with high ZEB1 mRNA expression. Our findings suggest that the stability of microRNAs makes them suitable as clinical markers and that the EMT-related microRNA-200 - ZEB - E-cadherin signaling pathway is connected to established clinical characteristics and can give useful prognostic and treatment-predictive information in progressive breast and colorectal cancers.

Place, publisher, year, edition, pages
Public Library of Science , 2013. Vol. 8, no 12, 84815- p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-103717DOI: 10.1371/journal.pone.0084815ISI: 000328745100188OAI: diva2:690708
Available from: 2014-01-24 Created: 2014-01-24 Last updated: 2015-11-26
In thesis
1. Metastatic Mechanisms in Malignant Tumors
Open this publication in new window or tab >>Metastatic Mechanisms in Malignant Tumors
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The ultimate cause of cancer related deaths is metastasis. This thesis is about three of the main human cancers; breast, colorectal and pancreatic cancer, that together account for more than 25% of the cancer-related deaths worldwide. The focus of the thesis is the spread of cancer, metastasis, and the aim was to investigate mechanisms that can be of importance for this process. We analyzed patient samples to validate the role of epithelialto-mesenchymal transition in vivo and found regulations of many related factors. However, these changes tend to fluctuate along the metastatic process, something which makes targeting complicated. We, moreover, focused on the influence of the tumor microenvironment for metastatic spread. In pancreatic cancer, the stroma constitutes the main part of many tumors. We analyzed the crosstalk between tumor and stromal cell and focused on the mediating inflammatory factor interleukin-1 (IL-1) and regulation of microRNAs. The results showed that the most commonly mutated factor in pancreatic cancer, KRAS, associates with the expression of IL-1 and subsequent activation of stromal cells. Blocking KRAS signaling together with IL-1 blockage give a more pronounced effect on in vitro proliferation and migration of cancer cells and suggests the use of a combination therapy. The cancer-associated activation of the stroma was found to be related to changes in microRNA expression. microRNA was analyzed separately in epithelial cells and stromal cells after microdissection of matched samples of primary and secondary tumors of breast and colorectal cancers. miR-214 and miR-199a were upregulated in stroma associated with progressive tumors and in pancreatic cancer stroma we could show that their expression alters the activation of stromal cells and thereby the growth and migratory ability of associated pancreatic tumor cells. In  breast and colorectal cancers we found several common microRNAs to be up- or downregulated in line with progression. We could show that one of these candidates, miR-18a, had a prognostic value in metastatic breast cancer. To further develop these studies we analyzed this microRNA in circulating microvesicles, i.e. exosomes, and investigated their role in the preparation of a pre-metastatic niche. MicroRNAs are stable biomarkers in the circulation, especially protected in exosomes, which can moreover specifically deliver their message to recipient cells. These studies facilitate the understanding of metastatic behavior and suggest new targets to stop cancer metastasis.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 91 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1487
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cancer and Oncology Cell and Molecular Biology
urn:nbn:se:liu:diva-122830 (URN)978-91-7685-934-6 (print) (ISBN)
Public defence
2015-12-18, Hasselqvistsalen, Ingång 76, Hus 511, Campus US, Linköping, 09:00 (Swedish)

The ISBN 987-91-7685-934-6 in the printed version is incorrect. The correct ISBN is  978-91-7685-934-6.

Available from: 2015-11-26 Created: 2015-11-26 Last updated: 2015-12-18Bibliographically approved

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Bojmar, LindaKarlsson, ElinOlsson, HansBjörnsson, BergthorHallböök, OlofLarsson, MarieStål, OlleSandström, Per
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Division of Clinical SciencesFaculty of Health SciencesOncologyMolecular and Immunological PathologyDepartment of Clinical Pathology and Clinical GeneticsDepartment of Surgery in LinköpingDivision of Microbiology and Molecular MedicineDepartment of Oncology
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