Abstract DCPS is a candidate cutaneous squamous cell carcinoma (SCC) susceptibility gene as determined by allelic imbalance mapping of over 400 matched SCC and normal DNA samples. DCPS is one of three genes located in a region of 11q24 showing strong evidence of preferential allelic loss. Consistently, by immunohistochemistry it shows no protein expression in 23% of SCCs and decreased expression in 30% of SCCs. There are high levels of protein expression in all of the normal skin tissues assessed. DCPS, a decapping scavenger enzyme, impacts aspects of mRNA metabolism, such as pre-mRNA splicing and decay. The hypothesis driving this research is that DCPS acts as a tumor suppressor and that in humans there are alleles conferring greater resistance to tumors, which are selectively lost during tumorigenesis. To test whether DCPS acts as a tumor suppressor, we studied functional effects of increasing and decreasing expression of DcpS in a mouse keratinocyte cell line. Pre-mRNA splicing was examined by quantitative assessment of different splice forms of mini-gene transcripts between low, endogenous, and overexpression cell lines. Preliminary data suggest that first intron splicing occurs more efficiently in DcpS overexpression cell lines and that there is no change in second intron splicing in DcpS overexpression cell lines. In stable DcpS knockdown cell lines, no differences were observed in first or second intron splicing. Differences in mRNA stability were assessed between the three levels of expression by mRNA stability assays. Preliminary data suggest that DcpS knockdown cell lines have more stable mRNA of the two tested transcripts than endogenous and overexpression cell lines. By MTT assays to measure proliferation, DcpS knockdown lines exhibited more growth than endogenous and overexpression lines between 24 and 48 hours, but there were no differences at later time points. Future studies will examine apoptosis, migration, and cell cycle parameters in these cell lines. This research has the potential to identify a new mechanism of cancer susceptibility involving RNA splicing and stability, improve cancer risk screening, and identify therapeutic and preventative targets. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 103. doi:1538-7445.AM2012-103