Expression of tyrosine and threonine protein kinase in carcinogenic process of colorectal cancer and its relationship with prognosis

Objective To investigate the expression of TTK (tyrosine and threonine protein kinase) in the process of colorectal cancer (CRC) development and its relationship to prognosis in CRC patients. Methods Colitis-associated colon cancer model was induced by azoxymethane (AOM) and dextran sulfate sodium (DSS) in C57BL/6 mice. Mice at four different stages of colon cancer development were obtained, named AD1 (inflammation of the recovery), AD2 (mild dysplasia), AD3 (adenoma) and AD4 (adenocarcinoma), as well as negative control (no treatment). The expression of TTK was measured by real time fluorescent quantitative PCR (qPCR) and immunohistochemical staining in mouse colon tissues and 24 pairs of CRC specimens. The relationship between TTK and prognosis was analyzed in a set of CRC genome-wide gene expression microarray data that was obtained from Gene Expression Omnibus (GEO) of National Center for Biotechnology Information (NCBI). Results The genome-wide microarray data from mouse AOM-DSS model indicated that the expression of TTK mRNA was gradually elevated during the development of colon cancer. The subsequent qPCR results showed that TTK mRNA levels in negative control, AD1, AD2, AD3 and AD4 groups were 1.05±0.42, 1.10±0.03, 1.38±0.15, 1.33±0.17 and 2.12±0.22, respectively. And TTK expression in AD2, AD3 and AD4 groups were significantly higher than that in negative control (P<0.05). The protein expression of TTK showed by immunohistochemical staining had similar tendency as the results of TTK mRNA. Besides that, the TTK mRNA levels in tumor tissues (0.71±0.10) from 24 CRC patients were significantly higher than those in paired adjacent normal tissues (0.18±0.04; P<0.001). The positive expression rate of TTK protein in 5 pairs of CRC clinical samples was 80.0%, and it was significantly higher than that in adjacent normal tissues (30.8%, P=0.014). Furthermore, according to a public transcriptomic data (GSE17536), the high levels of TTK were associated with poor prognosis in CRC patients. Conclusions Elevated expression of TTK is related to colonic carcinogenesis in both of mouse model and human CRC samples. TTK is a poor prognostic factor in CRC. Key words: Tyrosine and threonine protein kinase; Colorectal neoplasms; AOM/DSS model of colitis-associated colon cancer; Prognosis