FAT10 (HLA-F-adjacent transcript 10) is a ubiquitin-like modifier that is commonly overexpressed in various tumors. It was found to play a role in mitotic regulation through its interaction with mitotic arrestdeficient 2 (MAD2). Overexpression of FAT10 promotes tumor growth and malignancy. Here, we identified the MAD2-binding interface of FAT10 to be located on its first ubiquitin-like domain whose NMR structure thus was determined. We further proceeded to demonstrate that disruption of the FAT10-MAD2 interaction through mutation of specific MAD2-binding residues did not interfere with the interaction of FAT10 with its other known interacting partners. Significantly, ablation of the FAT10-MAD2 interaction dramatically limited the promalignant capacity of FAT10, including promoting tumor growth in vivo and inducing aneuploidy, proliferation, migration, invasion, and resistance to apoptosis in vitro. Our results strongly suggest that the interaction of FAT10 with MAD2 is a key mechanism underlying the promalignant property of FAT10 and offer prospects for the development of anticancer strategies.chromosomal instability | ubiquitin | aneuploidy | cancer progression | FAT10 F AT10 (HLA-F-adjacent transcript 10) is a ubiquitin-like modifier protein that functions as a proteasomal degradation signal (1-3). Recent studies, however, have suggested that FAT10's functions extend beyond protein degradation. FAT10 is expressed mainly in tissues of the immune system, including the spleen and thymus (4, 5). In immune cells, FAT10 is strongly induced by proinflammatory stimuli and facilitates T-cell activation by enhancing antigen presentation of mature dendritic cells (6). FAT10 also is induced by proinflammatory cytokines in various tissues outside the immune system including the liver and colon (7,8), although the physiological functions of this response remain unknown. What is clear, however, is that constitutive induction of FAT10 has deleterious consequences in promoting cellular malignancy. Our group recently has reported that ectopic expression of FAT10 induced malignant transformation in nontumorigenic cells and tumor promotion in tumorigenic cells (9), implicating FAT10 in facilitating tumor growth and progression. This finding is consistent with multiple reports that found FAT10 to be up-regulated in several tumor types including tumors of the liver and colon (5,8,10,11).To date, the mechanism underlying FAT10's promalignant characteristic remains unclear. One compelling albeit indirect piece of evidence stems from the finding that FAT10 interacts with the spindle checkpoint protein mitotic arrest-deficient 2 (MAD2) during mitosis and reduces MAD2 localization to the kinetochores, resulting in aneuploidy (7, 12), a phenomenon closely associated with tumorigenesis and a hallmark of many solid tumors (13). Given the strong association between aneuploidy, chromosomal instability, and cancer development (reviewed in ref. 14), we hypothesized that FAT10 induces malignant progression through its interaction with MAD2. The...

To date, studies of the roles of microRNAs (miRNAs) in hepatocellular carcinoma (HCC) have either focused on specific individual miRNAs and a small number of suspected targets or simply reported a list of differentially expressed miRNAs based on expression profiling. Here, we seek a more in-depth understanding of the roles of miRNAs and their targets in HCC by integrating the miRNA and messenger RNA (mRNA) expression profiles of tumorous and adjacent non-tumorous liver tissues of 100 HCC patients. We assessed the levels of 829 mature miRNAs, of which 32 were significantly differentially expressed. Statistical analysis indicates that six of these miRNAs regulate a significant proportion of their in silico predicted target mRNAs. Three of these miRNAs (miR-26a, miR-122, and miR-130a) were down-regulated in HCC, and their up-regulated gene targets are primarily associated with aberrant cell proliferation that involves DNA replication, transcription and nucleotide metabolism. The other three miRNAs (miR-21, miR-93, and miR-221) were up-regulated in HCC, and their down-regulated gene targets are primarily involved in metabolism and immune system processes. We further found evidence for a coordinated miRNA-induced regulation of important cellular processes, a finding to be considered when designing therapeutic applications based on miRNAs.

Hepatocellular Carcinoma (HCC) is one of the most common cancers in the world and it is often associated with poor prognosis. Liver transplantation and resection are two currently available curative therapies. However, most patients cannot be treated with such therapies due to late diagnosis. This underscores the urgent need to identify potential markers that ensure early diagnosis of HCC. As more evidences are suggesting that epigenetic changes contribute hepatocarcinogenesis, DNA methylation was poised as one promising biomarker. Indeed, genome wide profiling reveals that aberrant methylation is frequent event in HCC. Many studies showed that differentially methylated genes and CpG island methylator phenotype (CIMP) status in HCC were associated with clinicopathological data. Some commonly studied hypermethylated genes include p16, SOCS1, GSTP1 and CDH1. In addition, studies have also revealed that methylation markers could be detected in patient blood samples and associated with poor prognosis of the disease. Undeniably, increasing number of methylation markers are being discovered through high throughput genome wide data in recent years. Proper and systematic validation of these candidate markers in prospective cohort is required so that their actual prognostication and surveillance value could be accurately determined. It is hope that in near future, methylation marker could be translate into clinical use, where patients at risk could be diagnosed early and that the progression of disease could be more correctly assessed.