title: A Comprehensive MicroRNA Expression Profile of Liver and Lung Metastases of Colorectal Cancer with Their Corresponding Host Tissue and Its Prognostic Impact on Survival.
abstract: MicroRNAs are small non-coding RNAs with a length of 18-25 nucleotides. They can regulate tumor invasion and metastasis by changing the expression and translation of their target mRNAs. Their expression is substantially altered in colorectal cancer cells as well as in the adjacent tumor-associated stroma. Both of these compartments have a mutual influence on tumor progression. In the development of metastases, cancer cells initially interact with the host tissue. Therefore, compartment-specific expression signatures of these three locations-tumor, associated stroma, and host tissue-can provide new insights into the complex tumor biology of colorectal cancer. Frozen tissue samples of colorectal liver (n= 25) and lung metastases (n= 24) were laser microdissected to separate tumor cells and the adjacent tumor-associated stroma cells. Additionally, normal lung and liver tissue was collected from the same patients. We performed a microarray analysis in four randomly selected liver metastases and four randomly selected lung metastases, analyzing a total of 939 human miRNAs. miRNAs with a significant change >2-fold between the tumor, tumor stroma, and host tissue were analyzed in all samples using RT-qPCR (11 miRNAs) and correlated with the clinical data. We found a differential expression of several miRNAs between the tumor, the tumor-associated stroma, and the host tissue compartment. When comparing liver and lung metastases, miR-194 showed a 1.5-fold; miR-125, miR-127, and miR-192 showed a 2.5-fold; miR-19 and miR-215 a 3-fold; miR-145, miR-199-3, and miR-429 a 5-fold; miR-21 a 7-fold; and, finally, miR-199-5 a 12.5-fold downregulation in liver metastases compared to lung metastases. Furthermore miR-19, miR-125, miR-127, miR-192, miR-194, miR-199-5, and miR-215 showed a significant upregulation in the normal liver tissue compared to the normal lung tissue. Univariate analysis identified an association of poor survival with the expression of miR-125 (p= 0.05), miR-127 (p= 0.001), miR-145 (p= 0.005), miR-192 (p= 0.015), miR-194 (0.003), miR-199-5 (p= 0.008), miR-215 (p< 0.001), and miR-429 (p= 0.03) in the host liver tissue of the liver metastases. Colorectal liver and lung metastases have a unique miRNA expression profile. miRNA expression in the host tissue of colorectal liver metastases seems to be able to influence tumor progression and survival. These findings can be used in the development of tailored therapies.
authors: Department of General, Visceral and Thoracic Surgery, University of Dresden, Fetscherstraße 74, 01307 Dresden, Germany. Mathieu.Pecqueux@uniklinikum-dresden.de.
authors: Mathieu
authors: M
authors: Pecqueux
authors: ALB Fils clinic, Eybstr. 16, 73312 Geislingen, Germany. liebetrau.isabell@gmx.de.
authors: Isabell
authors: I
authors: Liebetrau
authors: German Cancer Research Center, Division of Biostatistics, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. w.werft@hs-mannheim.de.
authors: Wiebke
authors: W
authors: Werft
authors: Department of Thoracic Surgery, Thoraxklinik am Universitätsklinikum Heidelberg, Amalienstrasse 5, 69126 Heidelberg, Germany. hendrik.dienemann@med.uni-heidelberg.de.
authors: Hendrik
authors: H
authors: Dienemann
authors: Department of Thoracic Surgery, Thoraxklinik am Universitätsklinikum Heidelberg, Amalienstrasse 5, 69126 Heidelberg, Germany. Thomas.muley@med.uni-heidelberg.de.
authors: Thomas
authors: T
authors: Muley
authors: Department of Thoracic Surgery, Helios Clinic Emil von Behring, Walterhöferstraße 11, 14165 Berlin, Germany. joachim.pfannschmidt@helios-kliniken.de.
authors: Joachim
authors: J
authors: Pfannschmidt
authors: Department of General, Visceral and Thoracic Surgery, University of Dresden, Fetscherstraße 74, 01307 Dresden, Germany. Benjamin.Muessle@uniklinikum-dresden.de.
authors: Benjamin
authors: B
authors: Müssle
authors: Department of General, Visceral and Thoracic Surgery, University of Dresden, Fetscherstraße 74, 01307 Dresden, Germany. Nuh.Rahbari@uniklinikum-dresden.de.
authors: Nuh
authors: N
authors: Rahbari
authors: Department of General, Visceral and Thoracic Surgery, University of Dresden, Fetscherstraße 74, 01307 Dresden, Germany. Sebastian.Schoelch@uniklinikum-dresden.de.
authors: Sebastian
authors: S
authors: Schölch
authors: Department of Surgery at Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. Markus.Buechler@med.uni-heidelberg.de.
authors: Markus W
authors: MW
authors: Büchler
authors: Department of General, Visceral and Thoracic Surgery, University of Dresden, Fetscherstraße 74, 01307 Dresden, Germany. Juergen.Weitz@uniklinikum-dresden.de.
authors: Jürgen
authors: J
authors: Weitz
authors: Department of General, Visceral and Thoracic Surgery, University of Dresden, Fetscherstraße 74, 01307 Dresden, Germany. Christoph.Reissfelder@uniklinikum-dresden.de.
authors: Christoph
authors: C
authors: Reissfelder
authors: Department of General, Visceral and Thoracic Surgery, University of Dresden, Fetscherstraße 74, 01307 Dresden, Germany. Christoph.Kahlert@uniklinikum-dresden.de.
authors: Christoph
authors: C
authors: Kahlert
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics* / Q000556:secondary; D008175:Lung Neoplasms / Q000235:genetics* / Q000556:secondary; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D035683:MicroRNAs
keywords: colorectal; expression; metastases; metastasis; miRNA; survival