B04: Nuclear Pore Complex (NPC) alterations and functional implications in hepatocarcinogenesis

The nuclear pore complex (NPC) is embedded in the nuclear envelope and is composed of ~30 NPC components most of which termed Nucleoporins (Nups). As the only gate for nucleocytoplasmic transport virtually all HCC relevant signalling cascades including their effectors have to pass the NPC. Given also transport-independent functions (e.g. chromatin interaction) of particular Nups, several levels can be envisioned at which signal transduction and gene expression in HCC are modulated by NPC components. We could previously show that Nup98 is dysregulated in HCC and exerts a potential tumor suppressive role by regulating the p53 target gene induction post -transcriptionally. Own preliminary data further suggest a role of Nup155 in shaping the p53 response at the level of mRNA translation and altered abundance of ~20-30% of all Nups measured by targeted proteomics in HCC cell lines. Here, we aim to further characterize NPC alterations in the development and progression of HCC by using quantitative mass spectrometry based proteomics as one of the key technologies and to approach the following research goals: 1) Identification of NPC remodelling between tumorous and non-tumorous liver-derived cell lines and tissues, 2) Defining the functional relevance of de-regulated Nups in liver cancer cells in vitro and in vivo, and 3) Dissecting the mechanisms by which candidate Nups function as modulators of oncogenic and/or tumorsuppressive pathways. We expect novel insights into a largely unstudied research area in hepatocarcinogenesis with potential diagnostic and therapeutic implications. Reversion or inhibition of NPC alterations in a therapeutic approach may substantially interfere with several liver cancer-relevant signalling pathways.

Publications

Holzer K, Drucker E, Roessler S, Dauch D, Heinzmann F, Waldburger N, Eiteneuer E, Herpel E, Breuhahn K, Zender L, Schirmacher P, Ori A, Singer S (2016) Proteomic analysis reveals guanine monophosphate synthetase (GMPS) as p53 repression target in liver cancer. Am J Pathol [epub ahead of print]
Winkler J, Roessler S, Sticht C, DiGuilio A, Drucker E, Holzer K, Eiteneuer E, Herpel E, Breuhahn K, Gretz N, Schirmacher P, Ori A, Singer S (2016) Cellular Apoptosis Susceptibility (CAS) is linked to integrin β1 and required for tumor cell migration and invasion in hepatocellular carcinoma (HCC) Oncotarget 7:22883-92.
Winkler J, Ori A, Holzer K, Sticht C, Dauch D, Eiteneuer EM, Pinna F, Geffers R, Ehemann V, Andres-Pons A, Breuhahn K, Longerich T, Lorenzo Bermejo J, Gretz N, Zender L, Schirmacher P, Beck M, Singer S (2014) Prosurvival function of the cellular apoptosis susceptibility/importin-alpha1 transport cycle is repressed by p53 in liver cancer. Hepatology 60:884-95.
Malz M, Bovet M, Samarin J, Rabenhorst U, Sticht C, Bissinger M, Roessler S, Lorenzo Bermejo J, Renner M, Calvisi DF, Singer S, Ganzinger M, Weber A, Gretz N, Zornig M, Schirmacher P, Breuhahn K (2014) Overexpression of far upstream element (FUSE) binding protein (FBP)-interacting repressor (FIR) supports growth of hepatocellular carcinoma. Hepatology 60:1241-50.
Tschaharganeh DF, Chen X, Latzko P, Malz M, Gaida MM, Felix K, Ladu S, Singer S, Pinna F, Gretz N, Sticht C, Tomasi ML, Delogu S, Evert M, Fan B, Ribback S, Jiang L, Brozzetti S, Bergmann F, Dombrowski F, Schirmacher P, Calvisi DF, Breuhahn K (2013) Yes-associated protein upregulates Jagged-1 and activates the Notch pathway in human hepatocellular carcinoma. Gastroenterology 144:1530-1542.
Singer S, Zhao R, Barsotti AM, Ouwehand A, Fazollahi M, Coutavas E, Breuhahn K, Neumann O, Longerich T, Pusterla T, Powers MA, Giles, KM, Leedman P J, Hess J., Grunwald D, Bussemaker HJ, Singer RH, Schirmacher P, Prives C (2012) Nuclear pore component Nup98 is a potential tumor suppressor and regulates posttranscriptional expression of select p53 target genes. Mol Cell 48:799- 810.
Kossatz U, Breuhahn K, Wolf B, Hardtke-Wolenski M, Wilkens L, Steinemann D, Singer S, Brass F, Kubicka S, Schlegelberger B, Schirmacher P, Manns MP, Singer JD, Malek NP (2010) The cy-clin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells. J Clin Invest 120:3820-3833.
Singer S, Malz M, Herpel E, Warth A, Bissinger M, Keith M, Muley T, Meister M, Hoffmann H, Penzel R, Gdynia G, Ehemann V, Schnabel PA, Kuner R, Huber P, Schirmacher P, Breuhahn K (2009) Coordinated expression of stathmin family members by far upstream sequence element-binding protein- 1 increases motility in non-small cell lung cancer. Cancer Res 69:2234-2243.
Xue W, Krasnitz A, Lucito R, Sordella R, Vanaelst L, Cordon-Cardo C, Singer S, Kuehnel F, Wigler M, Powers S, Zender L, Lowe SW (2008) DLC1 is a chromosome 8p tumor suppressor whose loss promotes hepatocellular carcinoma. Genes Dev 22:1439-1444.
Singer S, Ehemann V, Brauckhoff A, Keith M, Vreden S, Schirmacher P, Breuhahn K (2007) Protumorigenic overexpression of stathmin/Op18 by gain-of-function mutation in p53 in human hepatocarcinogenesis. Hepatology 46:759-768.