Florian Stadler

Inhibition of the IFN-β Response in Hepatocellular Carcinoma by Alternative Spliced Isoform of IFN Regulatory Factor-3

The intrinsic oncolytic specificity of vesicular stomatitis virus (VSV) is currently being exploited to develop alternative therapeutic strategies for hepatocellular carcinoma (HCC). We have observed earlier that, in contrast to cultured human HCC cells, primary human hepatocytes (PHHs) are refractory to VSV infection. Impairment of the type I interferon (IFN) pathway in HCC cells has been suggested to be the mechanism by which these cells become susceptible to VSV infection. The goal of this study was to elucidate the nature of the IFN defect in human HCC. We demonstrate here that the defect in IFN-β signaling in HCC cells results from a deregulated IFN regulatory factor-3 (IRF3) pathway. Expression of IRF3-spliced variant (IRF3-nirs3) was constitutively observed in HCC cells and, importantly, also in primary HCC samples. In contrast, IRF3 was readily activated in PHHs after stimulation with dsRNA or infection with VSV. In addition, overexpression of IRF3-nirs3 significantly abrogated the IFN-β response to VSV infection and improved viral growth. Our data provide evidence that aberrant splicing of IRF3 in HCC contributes to the defect in IFN-mediated antiviral defenses. This work may provide a potential molecular basis for selecting HCC patients for oncolytic VSV therapy in future clinical trials.The intrinsic oncolytic specificity of vesicular stomatitis virus (VSV) is currently being exploited to develop alternative therapeutic strategies for hepatocellular carcinoma (HCC). We have observed earlier that, in contrast to cultured human HCC cells, primary human hepatocytes (PHHs) are refractory to VSV infection. Impairment of the type I interferon (IFN) pathway in HCC cells has been suggested to be the mechanism by which these cells become susceptible to VSV infection. The goal of this study was to elucidate the nature of the IFN defect in human HCC. We demonstrate here that the defect in IFN-beta signaling in HCC cells results from a deregulated IFN regulatory factor-3 (IRF3) pathway. Expression of IRF3-spliced variant (IRF3-nirs3) was constitutively observed in HCC cells and, importantly, also in primary HCC samples. In contrast, IRF3 was readily activated in PHHs after stimulation with dsRNA or infection with VSV. In addition, overexpression of IRF3-nirs3 significantly abrogated the IFN-beta response to VSV infection and improved viral growth. Our data provide evidence that aberrant splicing of IRF3 in HCC contributes to the defect in IFN-mediated antiviral defenses. This work may provide a potential molecular basis for selecting HCC patients for oncolytic VSV therapy in future clinical trials.

Synthesis and Structure of RE2Rh2Cd (RE = La, Ce, Pr, Nd, Sm)

New intermetallic cadmium compounds RE2Rh2Cd (RE= La, Ce, Pr, Nd, Sm) were synthesized from the elements in sealed tantalum tubes in a high-frequency furnace. They were characterized through X-ray powder data: Mo2FeB2 type, space group P4/mbm, Z = 2. Single crystal data of the cerium compound (a = 762.8(1), c = 377.8(1) pm, wR2 = 0.0662, 199 F2 values, and 13 variable parameters) revealed small defects on the rhodium position leading to the composition Ce2Rh186(3)Cd for the investigated crystal. According to the course of the cell volumes Ce2Rh2Cd may be classified as a mixedvalent compound. The Ce2Rh2Cd structure is an intergrowth of slightly distorted AlB2 and CsCl related slabs of compositions CeRh2 and CeCd. Within the CeRh2 slab short Ce-Rh contacts (284-300 pm) are indicative of strong Ce-Rh bonding. The Rh-Rh distance within the AlB2 related slab is 289 pm.