Colorectal cancer (CRC) is one of the main causes of death of neoplasia. Demand for predictive and prognostic markers to reverse this trend is increasing. Long non-coding RNA HOTAIR (Homeobox Transcript Antisense Intergenic RNA) overexpression in tumors was previously associated with poor prognosis and higher mortality in different carcinomas. We analyzed HOTAIR expression levels in tumor and blood of incident sporadic CRC patients in relation to their overall survival with the aim to evaluate surrogate prognostic marker for CRC. Tissue donor group consisted of 73 CRC patients sampled for tumor and normal tissue. Blood donor group was represented by 84 CRC patients compared with 40 healthy controls. Patients were characterized for tumor-node-metastasis stage, tumor grade, microsatellite instability and tumor penetration by stromal cells. HOTAIR levels were assessed by real-time quantitative PCR. CRC patients had higher HOTAIR expression in blood than healthy controls (P = 0.0001), whereas there was no difference in HOTAIR levels between tumor and adjacent mucosa of CRC patients. HOTAIR levels positively correlated between blood and tumor (R = 0.43, P = 0.03). High HOTAIR levels in tumors were associated with higher mortality of patients [Cox's proportional hazard, hazard ratio = 4.4, 95% confidence interval: 1.0-19.2, P = 0.046]. The hazard ratio was even higher when blood HOTAIR levels were taken into account (hazard ratio = 5.9, 95% confidence interval: 1.3-26.1, P = 0.019). Upregulated HOTAIR relative expression in primary tumors and in blood of CRC patients is associated with unfavorable prognosis. Our data suggest that HOTAIR blood levels may serve as potential surrogate prognostic marker in sporadic CRC.

Department of Internal Medicine Haematology and Oncology University Hospital Brno and Masaryk University Brno 62500 Czech Republic

Department of Surgery and

Department of Surgery General University Hospital Prague 1st Medical Faculty Charles University Prague 12111 Czech Republic

Department of Surgery Medical School and Teaching Hospital Plzen Charles University Plzen 30606 Czech Republic and Biomedical Centre Medical School Plzen Charles University Prague Plzen 30605 Czech Republic

Department of Surgery Thomayer Hospital and 1st Faculty of Medicine Prague 14200 Czech Republic

Department of Veterinary Sciences Czech University of Life Sciences Prague 16521 Czech Republic

Institute of Biology and Medical Genetics 1st Medical Faculty Charles University Prague 12000 Czech Republic

Institute of Experimental Medicine ASCR Prague 14220 Czech Republic Institute of Biology and Medical Genetics 1st Medical Faculty Charles University Prague 12000 Czech Republic

Institute of Experimental Medicine ASCR Prague 14220 Czech Republic Institute of Biology and Medical Genetics 1st Medical Faculty Charles University Prague 12000 Czech Republic Faculty of Science Charles University Prague 12800 Czech Republic

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$a HOTAIR long non-coding RNA is a negative prognostic factor not only in primary tumors, but also in the blood of colorectal cancer patients / $c M. Svoboda, J. Slyskova, M. Schneiderova, P. Makovicky, L. Bielik, M. Levy, L. Lipska, B. Hemmelova, Z. Kala, M. Protivankova, O. Vycital, V. Liska, L. Schwarzova, L. Vodickova, P. Vodicka,

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$a Colorectal cancer (CRC) is one of the main causes of death of neoplasia. Demand for predictive and prognostic markers to reverse this trend is increasing. Long non-coding RNA HOTAIR (Homeobox Transcript Antisense Intergenic RNA) overexpression in tumors was previously associated with poor prognosis and higher mortality in different carcinomas. We analyzed HOTAIR expression levels in tumor and blood of incident sporadic CRC patients in relation to their overall survival with the aim to evaluate surrogate prognostic marker for CRC. Tissue donor group consisted of 73 CRC patients sampled for tumor and normal tissue. Blood donor group was represented by 84 CRC patients compared with 40 healthy controls. Patients were characterized for tumor-node-metastasis stage, tumor grade, microsatellite instability and tumor penetration by stromal cells. HOTAIR levels were assessed by real-time quantitative PCR. CRC patients had higher HOTAIR expression in blood than healthy controls (P = 0.0001), whereas there was no difference in HOTAIR levels between tumor and adjacent mucosa of CRC patients. HOTAIR levels positively correlated between blood and tumor (R = 0.43, P = 0.03). High HOTAIR levels in tumors were associated with higher mortality of patients [Cox's proportional hazard, hazard ratio = 4.4, 95% confidence interval: 1.0-19.2, P = 0.046]. The hazard ratio was even higher when blood HOTAIR levels were taken into account (hazard ratio = 5.9, 95% confidence interval: 1.3-26.1, P = 0.019). Upregulated HOTAIR relative expression in primary tumors and in blood of CRC patients is associated with unfavorable prognosis. Our data suggest that HOTAIR blood levels may serve as potential surrogate prognostic marker in sporadic CRC.

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