LKW, a Putative Dual-specificity Kinase which is Down-regulated in Several Invasive Systems

Abstract

Using Affymetrix GeneChip® arrays, we have established the transcriptional profiles of two sublines of the human pancreatic adenocarcinoma cell lines SUIT-2, S2-007 (metastatic) and S2-028 (non-metastatic). By comparison of ESTs corresponding to differentially regulated mRNAs, we have identified the putative dual-specificity kinase LKW as down-regulated in the metastatic cell line S2-007. LKW is composed of 358 amino acids and contains catalytic domains corresponding to those of Ser/Thr- and Tyr-kinases. The gene encoding LKW consists of four exons separated by three introns and is located on chromosome 20p12.2-p13. In parallel LKW has been identified in different experimental settings by other groups and is referred to as NIPK, SKIP3 and TRB3. We noticed that the metastatic propensity of two additional pancreatic cellular systems correlates with the down-regulation of mRNA levels corresponding to LKW. Evaluation of a panel of mammary carcinoma cell lines scored as non-invasive and invasive based on an in vitro invasion assay indicated down-regulation of LKW mRNA levels in the invasive cell lines. mRNA for LKW was shown to be overexpressed in pancreatic carcinomas compared to normal pancreas and tissues derived from patients with chronic pancreatitis as well as in colon, kidney, breast and ovarian carcinomas compared to their matching normal tissues. Analysis of colorectal carcinomas covering Duke's stages A, B, C and D revealed down-regulation of LKW mRNA in specimens corresponding to Duke's stages C and D, representing invasive and metastatic stages compared to the less invasive stages corresponding to Duke's stages A and B. Our results indicate that down-regulation of mRNA encoding LKW correlates with an invasive status of mammary carcinoma cell lines and the metastatic propensity of colorectal carcinoma.