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| Item Type: | Article |
|---|---|
| Title: | A dual role of Caspase-8 in triggering and sensing proliferation-associated DNA damage, a key determinant of liver cancer development |
| Creators Name: | Boege, Y., Malehmir, M., Healy, M.E., Bettermann, K., Lorentzen, A., Vucur, M., Ahuja, A.K., Böhm, F., Mertens, J.C., Shimizu, Y., Frick, L., Remouchamps, C., Mutreja, K., Kähne, T., Sundaravinayagam, D., Wolf, M.J., Rehrauer, H., Koppe, C., Speicher, T., Padrissa-Altés, S., Maire, R., Schattenberg, J.M., Jeong, J.S., Liu, Lei, Zwirner, S., Boger, R., Hüser, N., Davis, R.J., Müllhaupt, B., Moch, H., Schulze-Bergkamen, H., Clavien, P.A., Werner, S., Borsig, L., Luther, S.A., Jost, P.J., Weinlich, R., Unger, K., Behrens, A., Hillert, L., Dillon, C., Di Virgilio, M., Wallach, D., Dejardin, E., Zender, L., Naumann, M., Walczak, H., Green, D.R., Lopes, M., Lavrik, I., Luedde, T., Heikenwalder, M. and Weber, A. |
| Abstract: | Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apoptotic function of caspase-8, but no caspase-3 or caspase-8 cleavage. It may represent a DNA damage-sensing mechanism in hepatocytes that can act via JNK and subsequent phosphorylation of the histone variant H2AX. |
| Keywords: | Liver, Hepatocellular Carcinoma, DNA Damage Response, Replication Stress, Apoptosis, Animals, Mice |
| Source: | Cancer Cell |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press / Elsevier |
| Volume: | 32 |
| Number: | 3 |
| Page Range: | 342-359 |
| Date: | 11 September 2017 |
| Additional Information: | Copyright © 2017 The Authors. |
| Official Publication: | https://doi.org/10.1016/j.ccell.2017.08.010 |
| External Fulltext: | View full text on PubMed Central |
| PubMed: | View item in PubMed |
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