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Hepatology. 2018 Nov;68(5):1817-1832. doi: 10.1002/hep.30102. Epub 2018 Oct 12.

The Long Noncoding RNA Cancer Susceptibility 9 and RNA Binding Protein Heterogeneous Nuclear Ribonucleoprotein L Form a Complex and Coregulate Genes Linked to AKT Signaling.

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Division of RNA Biology & Cancer, German Cancer Research Center.
Faculty of Biosciences, Heidelberg University.
Institute of Pathology, University Hospital Heidelberg.
Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology, University of Heidelberg.
Division of Signaling and Functional Genomics, German Cancer Research Center.
Institute of Physiology and Pathophysiology, University of Heidelberg.
Department of Experimental Surgery-Cancer Metastasis, Medical Faculty Mannheim, and Centre for Biomedicine and Medical Technology Mannheim, University of Heidelberg.
Genomics and Proteomics Core Facility, German Cancer Research Center, Heidelberg, Germany.
Division of Cancer Research, Department of Thoracic Surgery, Medical Center, University of Freiburg.
Faculty of Medicine, University of Freiburg.
German Cancer Consortium, Freiburg, Germany.


The identification of viability-associated long noncoding RNAs (lncRNAs) might be a promising rationale for new therapeutic approaches in liver cancer. Here, we applied an RNA interference screening approach in hepatocellular carcinoma (HCC) cell lines to find viability-associated lncRNAs. Among the multiple identified lncRNAs with a significant impact on HCC cell viability, we selected cancer susceptibility 9 (CASC9) due to the strength of its phenotype, expression, and up-regulation in HCC versus normal liver. CASC9 regulated viability across multiple HCC cell lines as shown by clustered regularly interspaced short palindromic repeats interference and single small interfering RNA (siRNA)-mediated and siRNA pool-mediated depletion of CASC9. Further, CASC9 depletion caused an increase in apoptosis and a decrease of proliferation. We identified the RNA binding protein heterogeneous nuclear ribonucleoprotein L (HNRNPL) as a CASC9 interacting protein by RNA affinity purification and validated it by native RNA immunoprecipitation. Knockdown of HNRNPL mimicked the loss-of-viability phenotype observed upon CASC9 depletion. Analysis of the proteome (stable isotope labeling with amino acids in cell culture) of CASC9-depleted and HNRNPL-depleted cells revealed a set of coregulated genes which implied a role of the CASC9:HNRNPL complex in AKT signaling and DNA damage sensing. CASC9 expression levels were elevated in patient-derived tumor samples compared to normal control tissue and had a significant association with overall survival of HCC patients. In a xenograft chicken chorioallantoic membrane model, we measured decreased tumor size after knockdown of CASC9. Conclusion: Taken together, we provide a comprehensive list of viability-associated lncRNAs in HCC; we identified the CASC9:HNRNPL complex as a clinically relevant viability-associated lncRNA/protein complex which affects AKT signaling and DNA damage sensing in HCC.


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