title: The role of microRNA-200 in progression of human colorectal and breast cancer.
abstract: 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 EMT-markers 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.
authors.affiliation: Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Department of Surgery in Östergötland, County Council of Östergötland, Linköping, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Bojmar
authors.affiliation: Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Department of Oncology, County Council of Östergötland, Linköping, Sweden.
authors.forename: Elin
authors.initials: E
authors.lastname: Karlsson
authors.affiliation: Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Department of Oncology, County Council of Östergötland, Linköping, Sweden.
authors.forename: Sander
authors.initials: S
authors.lastname: Ellegård
authors.affiliation: Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Department of Pathology in Östergötland, County Council of Östergötland, Linköping, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Olsson
authors.affiliation: Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Department of Surgery in Östergötland, County Council of Östergötland, Linköping, Sweden.
authors.forename: Bergthor
authors.initials: B
authors.lastname: Björnsson
authors.affiliation: Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Department of Surgery in Östergötland, County Council of Östergötland, Linköping, Sweden.
authors.forename: Olof
authors.initials: O
authors.lastname: Hallböök
authors.affiliation: Molecular Virology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Larsson
authors.affiliation: Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Department of Oncology, County Council of Östergötland, Linköping, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Stål
authors.affiliation: Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Department of Surgery in Östergötland, County Council of Östergötland, Linköping, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Sandström
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D015820:Cadherins / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D061346:Laser Capture Microdissection; D008113:Liver Neoplasms / Q000378:metabolism* / Q000556:secondary; D035683:MicroRNAs / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1