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Genomic sequencing analysis of tumors provides potential molecular therapeutic targets for precision medicine. However, identifying a key driver gene or mutation that can be used for hepatocellular carcinoma (HCC) treatment remains difficult. Here, we performed whole-exome sequencing on genomic DNA obtained from six pairs of HCC and adjacent tissues and identified two novel somatic mutations of UBE2S (p. Gly57Ala and p. Lys63Asn). Predictions of the functional effects of the mutations showed that two amino-acid substitutions were potentially deleterious. Further, we observed that wild-type UBE2S, especially in the nucleus, was significantly higher in HCC tissues than that in adjacent tissues and closely related to the clinicopathological features of patients with HCC. Functional assays revealed that overexpression of UBE2S promoted the proliferation, invasion, metastasis, and G1/S phase transition of HCC cells in vitro, and promoted the tumor growth significantly in vivo. Mechanistically, UBE2S interacted with TRIM28 in the nucleus, both together enhanced the ubiquitination of p27 to facilitate its degradation and cell cycle progression. Most importantly, the small-molecule cephalomannine was found by a luciferase-based sensitive high-throughput screen (HTS) to inhibit UBE2S expression and significantly attenuate HCC progression in vitro and in vivo, which may represent a promising strategy for HCC therapy.

BackgroundSomatic mutations are involved in hepatocellular carcinoma (HCC) progression, but the genetic mechanism associated to hepatocarcinogenesis remains poorly understood. We report that Eyes absent homolog 2 (EYA2) suppresses the HCC progression, while EYA2(A510E) mutation identified by exome sequencing attenuates the tumor-inhibiting effect of EYA2.MethodsWhole-exome sequencing was performed on six pairs of human HCC primary tumors and matched adjacent tissues. Focusing on EYA2, expression level of EYA2 in human HCC samples was evaluated by quantitative real-time PCR, western blot and immunohistochemistry. Loss- and gain-of-function studies, hepatocyte-specific deletion of EYA2 (Eya2−/−) in mice and RNA sequencing analysis were used to explore the functional effect and mechanism of EYA2 on HCC cell growth and metastasis. EYA2 methylation status was evaluated using Sequenom MassARRAY and publicly available data analysis.ResultsA new somatic mutation p.Ala510Glu of EYA2 was identified in HCC tissues. The expression of EYA2 was down-regulated in HCC and associated with tumor size (P = 0.001), Barcelona Clinic Liver Cancer stage (P = 0.016) and tumor differentiation (P = 0.048). High level of EYA2 was correlated with a favorable prognosis in HCC patients (P = 0.003). Results from loss-of-function and gain-of-function experiments suggested that knockdown of EYA2 enhanced, while overexpression of EYA2 attenuated, the proliferation, clone formation, invasion, and migration of HCC cells in vitro. Delivery of EYA2 gene had a therapeutic effect on inhibition of orthotopic liver tumor in nude mice. However, EYA2(A510E) mutation led to protein degradation by unfolded protein response, thus weakening the inhibitory function of EYA2. Hepatocyte-specific deletion of EYA2 in mice dramatically promoted diethylnitrosamine-induced HCC development. EYA2 was also down-regulated in HCC by aberrant CpG methylation. Mechanically, EYA2 combined with DACH1 to transcriptionally regulate SOCS3 expression, thus suppressing the progression of HCC via SOCS3-mediated blockade of the JAK/STAT signaling pathway.ConclusionsIn our study, we identified and validated EYA2 as a tumor suppressor gene in HCC, providing a new insight into HCC pathogenesis.

Background. An increasing number of systematic reviews/meta-analyses (SRs/MAs) of clinical trials have begun to investigate the effects of traditional Chinese medicine (TCM) nursing in patients with stroke. To systematically appraise and synthesize these results, we conducted an overview of SRs/MAs. Methods. Eight databases from their inception to April 2020 were searched to include all SRs/MAs on TCM nursing for stroke. Methodological quality assessment was performed using Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR-2) and evidence quality assessment was performed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). Results. Eleven SRs/MAs regarding TCM nursing for stroke were included. The assessments with AMSTAR-2 indicated that the methodological quality of all included SRs/MAs was critically low. According to the evaluation results of GRADE, 10 (40%) outcomes were rated as critically low-quality evidence, 7 (28%) low-quality evidence, and 8 (32%) moderate-quality evidence. Descriptive analysis results showed that TCM nursing was effective for stroke. Conclusions. All included SRs/MAs suggested positive findings of TCM nursing for stroke, but the credibility of the results is limited. Studies with methodologically rigorous and adequately powered are still needed in this field.

It has been reported that zerumbone (ZER) has marked effects on the regulation of cell proliferation and migration in multiple types of cancer, and has anti-cancer effects on various types of malignant cell. However, the effects and underlying molecular mechanisms of treatment with ZER on melanoma cells remain unclear. In the present study, the effect of treatment with ZER on the proliferation, migration and mitochondrial function of the human melanoma cell line CHL-1 was investigated. The results of the present study indicated that treatment with ZER significantly inhibited CHL-1 cell proliferation (P