Brief Article
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World J Gastroenterol. Jul 21, 2013; 19(27): 4363-4373
Published online Jul 21, 2013. doi: 10.3748/wjg.v19.i27.4363
Underexpression of LATS1 TSG in colorectal cancer is associated with promoter hypermethylation
Piotr M Wierzbicki, Krystian Adrych, Dorota Kartanowicz, Marcin Stanislawowski, Anna Kowalczyk, Janusz Godlewski, Iwona Skwierz-Bogdanska, Krzysztof Celinski, Tomasz Gach, Jan Kulig, Bartlomiej Korybalski, Zbigniew Kmiec
Piotr M Wierzbicki, Dorota Kartanowicz, Marcin Stanislawowski, Zbigniew Kmiec, Department of Histology, Faculty of Medicine, Medical University of Gdansk, 80210 Gdansk, Poland
Krystian Adrych, Department of Hepatology and Gastroenterology, Faculty of Medicine, Medical University of Gdansk, 80210 Gdansk, Poland
Anna Kowalczyk, Janusz Godlewski, Department of Human Histology and Embryology, Faculty of Medical Sciences, University of Varmia and Masuria, 10082 Olsztyn, Poland
Iwona Skwierz-Bogdanska, Department of General Surgery, Hospital Ministry Internal Affairs, 80104 Gdansk, Poland
Krzysztof Celinski, Department of Gastroenterology, Medical University of Lublin, 20059 Lublin, Poland
Tomasz Gach, Jan Kulig, 1st Department of General Surgery, Jagiellonian University, 31008 Cracow, Poland
Bartlomiej Korybalski, Endoscopy Unit, St. Adalbert Hospital, 80462 Gdansk, Poland
Author contributions: Kartanowicz D and Stanislawowski M performed the majority of the molecular experiments; Adrych K, Godlewski J, Skwierz-Bogdanska I, Gach T and Korybalski B collected tissue specimens; Celinski K and Kulig J coordinated and provided tissue collection; Kowalczyk A helped with tissue processing and writing the manuscript; Wierzbicki PM designed the study and molecular assays and wrote the manuscript; Kmiec Z coordinated collaboration among clinics and laboratories and was involved in editing the manuscript.
Supported by Polish Ministry of Science, No. N N402 683940
Correspondence to: Dr. Piotr M Wierzbicki, Department of Histology, Faculty of Medicine, Medical University of Gdansk, 1 Debinki Str., 80210 Gdansk, Poland. pwierzb@gumed.edu.pl
Telephone: +48-58-3491431 Fax: +48-58-3491419
Received: August 3, 2012
Revised: March 4, 2013
Accepted: March 15, 2013
Published online: July 21, 2013
Processing time: 351 Days and 19.9 Hours
Abstract

AIM: To investigate large tumor suppressor 1 (LATS1) expression, promoter hypermethylation, and microsatellite instability in colorectal cancer (CRC).

METHODS: RNA was isolated from tumor tissue of 142 CRC patients and 40 colon mucosal biopsies of healthy controls. After reverse transcription, quantitative polymerase chain reaction (PCR) was performed, and LATS1 expression was normalized to expression of the ACTB and RPL32 housekeeping genes. To analyze hypermethylation, genomic DNA was isolated from 44 tumor CRC biopsies, and methylation-specific PCR was performed. Microsatellite instability (MSI) status was checked with PCR using BAT26, BAT25, and BAT40 markers in the genomic DNA of 84 CRC patients, followed by denaturing gel electrophoresis.

RESULTS: Decreased LATS1 expression was found in 127/142 (89.4%) CRC cases with the average ratio of the LATS1 level 10.33 ± 32.64 in CRC patients vs 32.85 ± 33.56 in healthy controls. The lowest expression was found in Dukes’ B stage tumors and G1 (well-differentiated) cells. Hypermethylation of the LATS1 promoter was present in 25/44 (57%) CRC cases analyzed. LATS1 promoter hypermethylation was strongly associated with decreased gene expression; methylated cases showed 162× lower expression of LATS1 than unmethylated cases. Although high-grade MSI (mutation in all three markers) was found in 14/84 (17%) cases and low-grade MSI (mutation in 1-2 markers) was found in 30/84 (36%) cases, we found no association with LATS1 expression.

CONCLUSION: Decreased expression of LATS1 in CRC was associated with promoter hypermethylation, but not MSI status. Such reduced expression may promote progression of CRC.

Keywords: Large tumor suppressor 1; Colorectal cancer; Quantitative polymerase chain reaction; Reduced expression; Promoter hypermethylation; Microsatellite instability; Salvador-Warts-Hippo pathway

Core tip: Searching for new colorectal cancer (CRC) molecular markers is a very important objective, because CRC is one of the most common malignancies in the world and one of the most fatal of human neoplasms. Decreased expression of large tumor suppressor 1 in CRC was associated with promoter hypermethylation, but not microsatellite instability status. Such reduced expression may promote progression of CRC.