Already, almost a quarter of the world's population suffers from non-alcoholic fatty liver (NAFLD) and this problem is steadily increasing. Non-alcoholic steatohepatitis (NASH), the chronic progressive manifestation of NAFLD, is the second most important cause of hepatocellular carcinoma (HCC). NAFLD thus represents a major socio-economic burden on the health care system and is of increasing importance. There are currently no drugs nor therapies that can treat NASH or stop the progression of the disease to HCC. At the same time, treatment options for HCC are limited and many patients show resistance to sorafenib, the only drug currently approved for first-line therapy. Although there have been major advances uncovering the genetic basis for NAFLD and HCC, the epigenetic mechanisms driving HCC remains largely elusive. Nevertheless, recent studies suggest epigenetic manipulation could be a promising approach to prevent the progression of NAFLD and HCC. Pan-Histone deacetylase (Pan-HDAC) inhibitors (e.g. Verinostat, PXD-101, Resminostat) are under clinical trials for HCC therapy. Pan-HDAC inhibitors have side effects and most importantly, others and we have observed that specific genetic knockouts of HDAC (e.g. HDAC3 and HDAC2) induce liver cancer under normal condition. We require more specific and alternate approach to develop therapy against this deadly disease. Epigenetic mechanisms underlying NAFLD progression remain elusive. Here, we are systematically investigating epigenetic factors that regulate NASH and transition to HCC in recently established our diet-induced NASH/HCC mouse models that recapitulate pathophysiological aspects of human NASH/HCC. Employing mass-spectrometry and next generation sequencing, we have identified putative targets that will be characterized and exploited for developing potential therapeutics for this deadly disease.
Background: Different inflammatory states, e.g. chronic hepatitis B or C viral infection, have been shown to contribute to the development of hepatocellular carcinoma (HCC). In patients with chronic liver disease the serum levels of interleukin 6 (IL-6) are elevated and increase even more when HCC develops. However, there is still not much known about the regulation of IL-6 signaling during hepatocarcinogenesis. Recently, we applied an integrative genomic and transcriptomic approach which revealed that loss of chromosome 8 p is associated with poor prognosis. In addition, we showed that the two chromosome 8 p genes SORBS3 and SH2D4A are functional tumor suppressor genes in vitro and in vivo. The goal of this study is to dissect the molecular mechanisms of SORBS3 and SH2D4A mediated tumor suppression.
Introduction Gallbladder cancer (GBC) is an aggressive malignancy and represents the most common biliary tract cancer (BTC). Molecular drivers and biomarkers for GBC are poorly identified. This study combines proteomic analysis of patient samples, in vitro characterizations, and molecular mechanism investigations of potential oncogene in GBC aggressiveness.
Question A detailed understanding of the molecular alterations in different forms of cholangiocarcinogenesis is crucial for a better understanding of cholangiocarcinoma (CCA) and may pave the way to early diagnosis and better treatment options.
Abstract Nuclear transport is an essential, highly selective process in eukaryotic cells which guarantees the bidirectional communication between the nucleus and the cytoplasm. Emerging evidence suggests that aberrant expression of nuclear transport factors may contribute to cancer formation and progression. We could recently show that the nuclear exporter Cellular apoptosis susceptibility (CAS) is overexpressed in hepatocellular carcinoma (HCC), the functional implications of which remain, however, not completely understood. Here, we integrated proteomics, transcriptomics and functional assays with patient data to further characterize the role of CAS in HCC. We found that CAS depletion in HCC cells led to deregulation of integrins, particularly integrin-beta1, and resulted in reduced cell migration and invasion. Moreover, we determined that high expression levels of CAS in HCC cases were associated with macroangioinvasion and poorer patient outcome. Our data indicate that CAS is linked to integrin signaling and correlates with an aggressive HCC phenotype. Citation Format: Juliane Winkler, Carsten Sticht, Amanda DiGuilio, Eva Maria Eiteneuer, Kerstin Holzer, Stephanie Rössler, Norbert Gretz, Kai Breuhahn, Peter Schirmacher, Alessandro Ori, Stephan Singer. Cellular apoptosis susceptibility (CAS) regulates integrin-beta1 and is required for tumor cell migration and invasion in hepatocellular carcinoma (HCC). [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A46.
Cholangiocarcinoma is a rapidly fatal cancer entity with a median survival of less than one year. In contrast to many other malignancies, no substantial therapeutic breakthrough has been made in the past decades limiting the treatment to cytotoxic chemotherapy with little beneficial effect for most patients. Targeted therapy tailored for the individual has shown substantial success in the recent past as a promising avenue for cancer therapy.
Apoptosis is critical for maintaining tissue homeostasis, and apoptosis evasion is considered as a hallmark of cancer. However, increasing evidence also suggests that proapoptotic molecules can contribute to the development of cancer, including liver cancer. The aim of this study was to further clarify the role of the proapoptotic B‐cell lymphoma 2 homology domain 3 (BH3)‐only protein BH3 interacting‐domain death agonist (BID) for chronic liver injury (CLI) and hepatocarcinogenesis (HCG). Loss of BID significantly delayed tumor development in two mouse models of Fah ‐mediated and HBsTg ‐driven HCG, suggesting a tumor‐promoting effect of BID. Liver injury as well as basal and mitogen‐stimulated hepatocyte proliferation were not modulated by BID. Moreover, there was no in vivo or in vitro evidence that BID was involved in DNA damage response in hepatocytes and hepatoma cells. Our data revealed that CLI was associated with strong activation of oxidative stress (OS) response and that BID impaired full activation of p38 after OS. Conclusion: We provide evidence that the tumor‐promoting function of BID in CLI is not related to enhanced proliferation or an impaired DNA damage response. In contrast, BID suppresses p38 activity and facilitates malignant transformation of hepatocytes. (H epatology 2015;62:816–828)
Intraductal papillary neoplasms (IPN) and biliary epithelial neoplasia (BilIN) are distinct precursor lesions that may progress to biliary tract carcinoma (BTC). A comprehensive characterization of the inflammatory microenvironment of IPN and BilIN precursor lesions was the main aim of our study. Immunohistochemistochemical staining with anti-CD3, -CD4, -CD8, -CD20, -CD68, -CD163, -CD56, and -MUM1 antibodies was used to investigate tumor-infiltrating immune cell populations in tissue samples from patients in whom coexisting precursor lesions and invasive BTC were identified. Using a triplet sample set of nonneoplastic epithelium, precursor lesions, and invasive BTC, we extensively analyzed the spatiotemporal evolution of the immune microenvironment during IPN- and BilIN-related carcinogenesis. We found that stromal CD3+(P=0.002), CD4+(P=0.007) and CD8+(P<0.001) T cells were significantly reduced in IPN compared to nonneoplastic epithelium. Similarly, fewer CD20+B cells (P=0.008), MUM1+plasma cells (P=0.012) and CD163+M2-like macrophages (P=0.008) were observed in IPN compared to nonneoplastic epithelium. Stromal CD68+(P=0.001) and CD163+(P<0.001) macrophages significantly increased during the transition from IPN to invasive BTC. Intraepithelial CD4+and CD8+T cells conversely decreased from nonneoplastic epithelium to IPN and were similarly distributed in invasive BTC. BilIN-associated biliary carcinogenesis was characterized by a significant reduction of intraepithelial CD8+T-lymphocyte infiltration at the transition from non-tumorous biliary epithelium to BilIN(P=0.008) and a further decrease from BilIN to BTC (P=0.004). We conclude that IPN and BilIN undergo distinct immune-cell changes throughout biliary carcinogenesis
Activating KRAS mutations are among the most abundant genetic alterations in intrahepatic cholangiocarcinoma (iCCA) and are associated with early recurrence, poor response, and reduced survival. Poly(ADP-ribose)polymerase-1 (PARP-1) is frequently observed to be upregulated in iCCA. Evidence indicate potential therapeutic relevance for PARP-1 inhibition in iCCA that preferentially affects KRAS-mutated cancers, but exact mechanisms remain unknown.
Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive malignancy of the biliary tract and characterized by its profound genetic heterogeneity. Activating KRAS mutations rank among the most abundant genetic alterations and the presence of this genetic alteration is associated with early recurrence, poor therapeutic response and reduced overall survival in iCCA. In preliminary experiments we found that inhibition of DNA damage response protein Poly (ADP-ribose) polymerase 1 (PARP-1) reduces survival of KRAS-mutated iCCA cell lines; though the exact mechanisms of PARP-1 in cholangiocarcinogenesis are still unknown.
