DICER1 and PRKRA in Colon Adenocarcinoma

Abstract

Differential microRNA expression in colon adenocarcinoma (CA) was previously reported. MicroRNA biogenesis and function requires a set of proteins designated as the microRNA machinery, which includes DICER1 and PRKRA. Loss of heterozygosity at 14q32.13 DICER1 locus was detected in up to 60% of CA cases. The in silico gene array analysis of CA showed down-regulation of DICER1 and an up-regulation of PRKRA. Immunohistochemically, DICER1 expression was abnormal in 65% of CA (95 of 147 cases). PRKRA was deregulated in 70% of CA (32 of 46 cases). Expression of DICER1 and PRKRA was correlated with clinicopathologic features of CA. DICER1 up-regulation was seen more commonly in women. Only 10 of 46 cases immunostained for both DICER1 and PRKRA showed normal levels of both DICER1 and PRKRA. Microsatellite status of 32 cases was determined. Microsatellite instable cases showed DICER1 up-regulation more commonly when compared to microsatellite stable cases; however, this trend was not statistically significant. Abnormal DICER1 and/or PRKRA expression might explain the observed changes in microRNA profile. The status of the endogenous DICER1 and PRKRA in CA may help to predict the response to future RNA interference-based therapy.

Figure 1

Oncomine meta-analysis of CA expression arrays for miR machinery-associated genes. The box plot is the interquartile range and the whiskers are the 10–90th% range. Normalized expression units are log2 transformed. Array Median is set to 0 and array standard deviation is set to 1. A. DICER1 was significantly down-regulated in CA samples (n = 9) when compared to normal colonic mucosa samples (n = 8). DICER1 was down-regulated in CA specimens positive for K-Ras mutation (n = 8) when compared to K-Ras wild type samples (n = 32). B. Ago2 was significantly up-regulated in CA. C. CA at an advanced stage (Duke D, n = 6) showed higher PRKRA level than earlier stages of CA (Duke A, n = 6; Duke B, n = 14, and Duke C, n = 16).

Figure 2

DICER1 immunoreactivity in normal colon mucosa and CA. A. Normal colonic mucosa. DICER1 immunoreactivity is limited to the basal rim of cytoplasm. B. A representative example of CA with loss of DICER1. C. A representative example of CA with increased diffuse cytoplasmic DICER1 expression. Immunohistochemistry, ×200 original magnification.