Abstract 4048: Increased expression of PACS-1 in cervical cancer is associated with loss of microRNA449a

Cervical cancer is one of the leading causes of female death world wide with approximately 50,000 deaths per year. We identified a 300 kb deletion of chromosome 11q13 in cervical cancer and mapped eleven genes to this region. Of these, phosphofurin acidic cluster sorting −1 (PACS-1) gene encodes a multi-functional sorting protein involved in secretory pathway membrane traffic. Expression studies showed the presence of an abnormal PACS-1 transcript in tumorigenic cell lines. Protein expression studies in paired normal and cervical tumors showed over-expression of PACS-1 protein in tumor specimens. RT-PCR indicated that protein over-expression was related to over-expression at the RNA level. These findings together with the absence of detectable mutations in PACS-1 exons in HeLa or SiHa cervical carcinoma cell lines raised the possibility that dysregulation of a microRNA (miRNA) may alter PACS-1 expression in cervical cancer. Consistent with this possibility, a UCSC genome database search showed the presence of binding sites for miRNA449a in the 3′ UTR (untranslated region) of the PACS-1 RNA transcript. Co-transfection of PACS-1 3′UTR luciferase reporter with miRNA449a resulted in reduced expression of luciferase. Expression of miR449a in HeLa and SiHa cells led to reduced expression of PACS-1 and increased expression of p53 and p21 proteins. FACS analysis of HeLa cells transfected with miR449a showed a reduction in S phase indicating the growth suppressive effect of miR449a. These results indicate that miR449a regulates PACS-1 expression and loss of miR449a expression leads to over-expression of PACS-1. This in turn seems to result in the destabilization of p53 in cervical cancer. Our findings suggest PACS-1 plays a role in cervical cancer development and its expression is regulated post-transcriptionally by miRNA449a. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4048.