Abstract 4762: Gremlin 2 is repressed in invasive endometrial cancer and inhibits cell growth in vitro

Abstract

Abstract Background: There are limited therapeutic opportunities for the treatment of advanced or metastatic endometrial cancer (EC), and limited diagnostic tools of myometrial invasion for fertility sparing management of early stage EC. Novel approach based on molecular profiling of EC cells are required. Patients and Methods: We used microarray analysis of EC tumour samples in order to identify tumour-specific changes in gene expression. Identified the most frequently and lowest repressed gene was subjected to immunohistochemistry of tissues of EC. MTT assay and migration assay using EC cells were also conducted to evaluate the antitumor activity of the identified gene. Results: The most significantly suppressed gene in EC compared with the control was Gremlin 2 with an 8.5-fold reduction (p<0.001). Immunohistochemistry revealed that Gremlin 2 was expressed in 4 of 4 tissues of normal endometrium, in 4 of 4 tissues of atypical endometrial hyperplasia and 5 of 5 tissues of low grade EC with FIGO stage IA without myometrial invasion. Among 13 patients with low-grade FIGO stage I with myometrial invasion, Gremlin 2 was partially expressed in the myometrial invasion front in 11 (85%) patients. The MTT assay revealed the proliferation of Ishikawa cells incubated with 1.0 ìg/ml and 5.0 ìg/ml of Gremlin 2 and HEC-1A cells incubated with 5.0 ìg/ml of Gremlin 2 were significantly reduced (P = 0.029, P = 0.025, and P = 0.048, respectively). The proliferation of Ishikawa cells was significantly attenuated after incubation with Gremlin 2 for 72 h (P = 0.024). On the other hand, the migration assay did not show influence of Gremlin 2 on Ishikawa or HEC-1A cells. Conclusion: Gremlin 2, formerly known as protein related to Dan and cerberus (PRDC), has been implicated in development of the embryo and the ovarian follicle in animals, however, there is no report of Gremlin 2 in association with neoplasm or cancer. Gremlin 2 downregulation may lead to carcinogenesis and progression of EC. We suggest that re-activation of Gremlin 2-associated pathways could suppress EC progression, and should thus be explored as a potential novel therapeutic approach as well as diagnostic tool of myometrial invasion. Citation Format: Hiroshi Tsubamoto, Kayo Inoue, Kazuko Sakata, Hiroaki Shibahara, Yasuo Miyoshi. Gremlin 2 is repressed in invasive endometrial cancer and inhibits cell growth in vitro. [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 4762.