Abstract LB-023: Plk2 loss occurs commonly in colorectal carcinomas but not in adenomas

Abstract

Abstract Plk2 is a target of p53. Our previous studies demonstrated that in the wild-type p53 context, Plk2 impacts mTOR signaling in the same manner as TSC1, and human tumor cells deficient in Plk2 grew significantly larger than control tumor cells. Other investigators have demonstrated that Plk2 phosphorylates mutant p53 in a positive feedback loop. We investigated Plk2's tumor suppressor functions as they relate to mTOR signaling. Archived pathology specimens from 12 colorectal adenocarcinomas (4 early stage and 8 advanced stage) were stained for phosphorylated mTOR (serine 2448), phosphorylated ribosomal S6 (Serine 235/236), Plk2, p53, Ki67, and glucose transporter 1 (Glut1). We show that Plk2 is expressed in normal colon epithelium, with a punctate staining pattern in the supranuclear region. In colorectal adenocarcinoma, Plk2 demonstrates partial loss of expression, complete loss of expression, or disrupted expression manifested as irregular or abnormal localization. Loss of Plk2 expression is more pronounced in the invasive front in some cases. Strong expression of phosphorylated mTOR is observed in the invasive front, which is presumed to be less hypoxic. Phosphorylated S6 and Glut1 expression partially correlate with phosphorylated mTOR expression but appear more diffuse in some cases. p53 and Ki67 expression is diffuse, rather than specific to the tumor invasive front in the subset of cases examined. In order to determine at what stage in carcinogenesis Plk2 is lost, an additional 8 archived pathology specimens (tubular adenomas, sessile serrated polyps and hyperplastic polyps) from 6 patients were evaluated for Plk2 expression. All specimens were found to be positive for Plk2 expression. We conducted a TCGA search of Plk2 alterations in colorectal adenocarcinomas. Plk2 is mutated in only 8 of 498 (all p53 wild-type) cases. Neither Plk2 methylation (in the gene body not in the regulatory region CpG islands and shores) nor copy number changes correlated with mRNA expression changes and appeared to be independent of p53 status. Loss of Plk2 expression along with accentuated expression of phosphorylated mTOR, phosphorylated S6, and Glut1 at the invasive front at least in some colorectal carcinomas is consistent with previous findings that an interaction between Plk2 and TSC1 / mTOR signaling molecules plays a role in tumor suppression during hypoxic conditions. Plk2 protein expression was found to be lost at the same stage in colorectal carcinogenesis as p53 genetic loss. The p53 dependence of Plk2 loss and tumor suppressor function as they relate to mTOR signaling may have therapeutic implications. Citation Format: Elizabeth M. Matthew, Zhaohai Yang, Suraj Peri, Namrata Vijayvergia, Amriti Lulla, Eric Ross, Wafik S. El-Deiry. Plk2 loss occurs commonly in colorectal carcinomas but not in adenomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-023.