Abstract 4079: Perturbations in tat-interacting protein 30 (TIP30) levels contribute to pancreatic cancer aggressiveness
Authors: Imade E. Imasuen-Williams, Francis Enane, Murray Korc
Journal: Cancer Research (2018)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer characterized by a high frequency of key driver mutations, (e.g. KRAS, TP53, CDKN2A, and SMAD4), as well many less frequent driver mutations. In addition, there is overexpression of growth factors such as TGF-βs, growth factor receptors such as the EGF receptor (EGFR), a markedly desmoplastic stroma, and a propensity to develop metastases and chemoresistance. Consequently, the 5-year survival rate for PDAC is 8-9% with current therapeutic modalities such as gemcitabine plus nab-paclitaxel or FOLFIRINOX. There is an urgent need, therefore, to devise novel therapies in PDAC. In this regard, we previously reported that high microRNA-10b (miR-10b) levels in the cancer cells from PDAC tissues are associated with decreased patient survival and earlier appearance of metastatic disease following neoadjuvant radiochemotherapy (Preis, et al, Clin Cancer Res, 2011), and that miR-10b targets the 3'UTR of tat-interacting protein 30 (TIP30) and downregulates TIP30 mRNA levels, and that these alterations enhance EGF- and TGF-β-mediated pancreatic cancer cell (PCC) invasion and migration (Ouyang et al, Oncogene, 2013). We therefore analyzed genetic alterations in TIP30 in PDAC data from The Cancer Genome Atlas (TCGA) and found that TIP30 exhibited both copy number gains (23%, n=109) and losses (26%, n=109), with parallel changes in TIP30 mRNA levels. Reduction of TIP30 mRNA levels correlated with increased PDAC survival when compared to PDAC with increased mRNA expression (p=0.004, n=182). However, in the absence of TIP30 expression levels in the normal pancreas in TCGA, the significance of this observation is not clear. We therefore evaluated the effects of TIP30 downregulation in human PCCs (hPCCs) using siRNA targeting TIP30 or a vector expressing miR-10b and empty vector controls. Both manipulations increased EGFR and AKT protein levels. To delineate the potential role of TIP30 in PDAC, we generated compound mutant Pdx1-Cre; LSL-KrasG12D; Tip30+/- (KTip30+/-C) mice carrying mutated KrasG12D and heterozygous Tip30 deletion in the pancreas. Heterozygous Tip30 deletion alone did not alter pancreatic cyto-architecture, but accelerated Kras-associated malignant transformation and progression to murine PDAC. Derived murine PCCs exhibited accelerated proliferation and increased EGFR expression. Our results indicate that TIP30 loss enhances PDAC aggression, in part through effects on EGFR. In conclusion, partial loss of TIP30 in miR-10b overexpressing hPCCs or heterozygous loss of Tip30 in a murine model of PDAC resulted in an enhanced PCC aggressive phenotype and increased EGFR levels. To advance our understanding of the role of TIP30 in PDAC we are now evaluating a cohort of mice with homozygous Tip30 deletion. Supported, in part by National Cancer Institute grant CA-075059 to M.K. and CA075059-17S2 Diversity Supplement to IIW. Citation Format: Imade E. Imasuen-Williams, Francis Enane, Murray Korc. Perturbations in tat-interacting protein 30 (TIP30) levels contribute to pancreatic cancer aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4079.