Akt kinase plays a central role in cell growth, metabolism and tumorigenesis. Although TRAF6 E3 ligase orchestrates IGF-1-mediated Akt ubiquitination and activation, it is unclear whether TRAF6 is involved in Akt activation by other growth factor receptors as well. Here we show that Akt ubiquitination is also induced by activation of ErbB receptors; unexpectedly, Skp2 SCF complex, but not TRAF6, is a critical E3 ligase for ErbB receptor-mediated Akt ubiquitination and membrane recruitment. Interestingly, Skp2 deficiency impairs Akt activation, Glut1 expression, glucose uptake and glycolysis, and breast cancer progression in various tumor models. Moreover, Skp2 overexpression correlates with Akt activation, breast cancer metastasis, and serves as a marker for poor prognosis in Her2-positive patients. Finally, we showed that Skp2 silencing sensitizes Her2-overexpressing tumors to Herceptin treatment. Our study suggests that distinct E3 ligases are utilized by diverse growth factors for Akt ubiquitination and activation.

The above article reported an important role of Skp2 in Akt activation, glycolysis, and Herceptin sensitivity. During the course of preparing Figure 6F, we inadvertently redisplayed the image from the HE (4003) image for Metastatic (M), Neu/Skp2 À/À column (fourth image on the bottom row) as the HE ( 4003) image for Metastatic (M), Neu column (third image on the bottom row). The corrected figure, which does not affect the results and interpretation as discussed in the paper, appears below and with the article online. We sincerely regret our error and apologize for the inconvenience that it may have caused.

BackgroundTo report the feasibility, efficacy, and toxicity of stereotactic body radiotherapy (SBRT) for the treatment of portal vein tumor thrombosis (PVTT) and/or inferior vena cava tumor thrombosis (IVCTT) in patients with advanced hepatocellular carcinoma (HCC).Materials and methodsForty-one patients treated with SBRT using volumetric modulated arc therapy (VMAT) for HCC with PVTT/IVCTT between July 2010 and May 2012 were analyzed. Of these, 33 had PVTT and 8 had IVCTT. SBRT was designed to target the tumor thrombosis and deliver a median total dose of 36 Gy (range, 30–48 Gy) in six fractions during two weeks.ResultsThe median follow-up was 10.0 months. At the time of analysis, 15 (36.6%) achieved complete response, 16 (39.0%) achieved partial response, 7 (17.1%) patients were stable, and three (7.3%) patients showed progressive disease. No treatment-related Grade 4/5 toxicity was seen within three months after SBRT. One patient had Grade 3 elevation of bilirubin. The one-year overall survival rate was 50.3%, with a median survival of 13.0 months. The only independent predictive factor associated with better survival was response to radiotherapy.ConclusionsVMAT-based SBRT is a safe and effective treatment option for PVTT/IVCTT in HCC. Prospective randomized controlled trials are warranted to validate the role of SBRT in these patients.

Understanding the mechanism by which cell growth, migration, polyploidy, and tumourigenesis are regulated may provide important therapeutic strategies for cancer therapy. Here we identify the Skp2-macroH2A1 (mH2A1)-CDK8 axis as a critical pathway for these processes, and deregulation of this pathway is associated with human breast cancer progression and patient survival outcome. We showed that mH2A1 is a new substrate of Skp2 SCF complex whose degradation by Skp2 promotes CDK8 gene and protein expression. Strikingly, breast tumour suppression upon Skp2 deficiency can be rescued by mH2A1 knockdown or CDK8 restoration using mouse tumour models. We further show that CDK8 regulates p27 protein expression by facilitating Skp2-mediated p27 ubiquitination and degradation. Our study establishes a critical role of Skp2-mH2A1-CDK8 axis in breast cancer development and targeting this pathway offers a promising strategy for breast cancer therapy.

Epstein-Barr virus (EBV)-encoded molecules have been detected in the tumor tissues of several cancers, including nasopharyngeal carcinoma (NPC), suggesting that EBV plays an important role in tumorigenesis.However, the nature of EBV with respect to genome width in vivo and whether EBV undergoes clonal expansion in the tumor tissues are still poorly understood. In this study, next-generation sequencing (NGS) was used to sequence DNA extracted directly from the tumor tissue of a patient with NPC. Apart from the human sequences, a clinically isolated EBV genome 164.7 kb in size was successfully assembled and named GD2 (GenBank accession number HQ020558). Sequence and phylogenetic analyses showed that GD2 was closely related to GD1, a previously assembled variant derived from a patient with NPC. GD2 contains the most prevalent EBV variants reported in Cantonese patients with NPC, suggesting that it might be the prevalent strain in this population. Furthermore, GD2 could be grouped into a single subtype according to common classification criteria and contains only 6 heterozygous point mutations, suggesting the monoclonal expansion of GD2 in NPC. This study represents the first genome-wide analysis of a clinical isolate of EBV directly extracted from NPC tissue. Our study reveals that NGS allows the characterization of genome-wide variations of EBV in clinical tumors and provides evidence of monoclonal expansion of EBV in vivo. The pipeline could also be applied to the study of other pathogen-related malignancies. With additional NGS studies of NPC, it might be possible to uncover the potential causative EBV variant involved in NPC.Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that infects more than 90% of the worldwide human population. Following the first discovery of EBV particles in cultured lymphoma cells from patients with Burkitt's lymphoma (BL) (12, 13), EBV and its encoded molecules were also detected in cases of nasopharyngeal carcinoma (NPC) (52) and several other malignancies, such as non-Hodgkin lymphoma (NHL) (51) and T-cell and Hodgkin lymphomas (22,43,44). Both the presence of virus sequences in tumor cells and the virus's oncogenic potency (24, 46) strongly associate EBV with NPC. However, the genome-wide nature of the EBV in NPC tissue is still poorly understood.EBV harbors different genetic variations in different geographic populations (4,10,18,21,40,(48)(49)(50). Likewise, the prevalence characteristics of NPC show remarkable geographical and ethnic differences, with a high prevalence rate in southern China, especially in the Guangdong province (5). Several EBV genes, including EBNA2, LMP1, and EBNA1, have been implicated in the development of NPC (10,17,28,34). Certain EBV subtypes such as China 1 and V-val, as classified by the sequence variations of these genes, were found more frequently in patients with NPC than in controls and thus have been associated with NPC (26, 50). However, an NPCspecific EBV subtype has not yet been identified, suggesting that EBV subtypes cannot be classi...