Abstract 1852: Merlin/NF2 is associated with elevated aromatase expression and estrogen formation in human liver tissues and liver cancer cells: An unifying model for hepatocellular carcinoma development and progression

It is recognized that the product of neurofibromatosis type 2 (NF2) tumor suppressor gene, also referred to as Merlin/neurofibromin, is implicated in the homeostatic regulation of the liver stem cell niche through the control of abundance and signaling of epidermal growth factor receptor (EGFR), with a mechanism independent of the Mst/Lats/Yap Hippo pathway [1]. We have previously reported that locally elevated estrogen formation, driven by abnormally high expression and function of the aromatase enzyme, may be implicated in both development and progression of human hepatocellular carcinoma (HCC) through the activation of a rapid signaling pathway mediated by amphiregulin (AREG) and EGFR [2]. In this framework, we have recently presented a model by which the aromatase-estrogen-amphiregulin-EGFR axis is activated in response to tissue injury and/or inflammatory disease, with its alteration eventually leading to development not only of major human tumors (liver, breast, prostate), but also to other non-neoplastic diseases, including type 2 diabetes, obesity, Alzheimer9s disease, heart disease and stroke [3]. In the present work, we have investigated the expression of merlin/neurofibromin (NF2) in different liver cancer cells and liver tissues in relation to aromatase expression/function, estrogen receptor (ER) status, amphiregulin and EGFR. Our data indicate that NF2 expression is strictly associated to aromatase, AREG and EGFR expression, being elevated in HCC tissues and HepG2 cells, intermediate in cirrhotic tissues and Huh7 liver cancer cells, and lower in nontumoral liver and HA22T cells. In addition, NF2 expression is inversely related to that of wild type hERα66 and proportional to the expression of the membrane-associated hERα36 splice variant, as measured by exon-specific RT-PCR analysis, both in vivo and in vitro. Furthermore, incubation with 1 nM estradiol induced a significant decrease of NF2 expression in both HA22T and Huh7 cells (over 54% and 22%, respectively), while no change could be observed in HepG2 cells, this effect being inversely related to aromatase expression and activity in these HCC cell lines. Based on this combined evidence, we propose here that NF2 may behave as a protein sensing tissue damage and, at least in human liver, increasing, via a Hippo-independent mechanism, aromatase-driven local estrogen formation, eventually leading to regulation of oval stem cells differentiation and tissue repair. An alteration of this putative NF2-aromatase-estrogen axis or a deficiency in NF2 may therefore be implicated in HCC development and/or progression. [1] Drvarov O & Cubero FJ 2011. Hepatology 53(5): 1767-70 [2] Carruba G et al. 2011. Horm Mol Biol Clin Invest 5(3): 153-160. [3] Carruba G. 2011. Gordon Research Conference, Invited Paper. Note: This abstract was not presented at the meeting. Citation Format: Letizia Cocciadiferro, Vitale Miceli, Orazia M. Granata, Giuseppe Carruba. Merlin/NF2 is associated with elevated aromatase expression and estrogen formation in human liver tissues and liver cancer cells: An unifying model for hepatocellular carcinoma development and progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1852. doi:10.1158/1538-7445.AM2015-1852