The nucleotide sequence of the infectious spleen and kidney necrosis virus (ISKNV) genome was determined and found to comprise 111,362 bp with a G+C content of 54.78%. It contained 124 potential open reading frames (ORFs) with coding capacities ranging from 40 to 1208 amino acids. The analysis of the amino acid sequences deduced from the individual ORFs revealed that 35 of the 124 potential gene products of ISKNV show significant homology to functionally characterized proteins of other species. Some of the putative gene products of ISKNV showed significant homologies to proteins in the GenBank/EMBL/DDBJ databases including enzymes and structural proteins involved in virus replication, transcription, protein modification, and virus-host interaction. In addition, one major repeated sequence showing significant homology to the Red Sea bream iridovirus (RSIV) genome was identified. Based on the information obtained from biological properties (including histopathology, tissue tropisms, natural host range, and geographic distribution), physiochemical and physical properties, and genome analysis, we suggest that ISKNV, RSIV, sea bass iridovirus, grouper iridovirus, and African lampeye iridovirus may belong to a new genus of the Iridoviridae family and are tentatively referred to as cell hypertrophy iridoviruses.

We have isolated a tiger frog virus (TFV) from diseased tiger frogs, Rana tigrina rugulosa. The genome was a linear double-stranded DNA of 105,057 basepairs in length with a base composition of 55.01% G+C. About 105 open reading frames were identified with coding capacities for polypeptides ranging from 40 to 1294 amino acids. Computer-assisted analyses of the deduced amino acid sequences revealed that 39 of 105 putative gene products showed significant homology to functionally characterized proteins of other species in the GenBank/EMBL/DDBJ databases. These proteins included enzymes and structural proteins involved in virus replication, transcription, modification, and virus--host interaction. The deduced amino acid sequences of TFV gene products showed more than 90% identity to FV3, but a low degree of similarity among TFV, ISKNV, and LCDV-1. The results from this study indicated that TFV may belong to the genus Ranavirus of the family Iridoviridae.

Anaplastic thyroid carcinoma (ATC) responds for the majority of death of thyroid carcinoma and often causes chemotherapy resistance. We investigated the influence of circEIF6 (Hsa_circ_0060060) on the cisplatin-sensitivity in papillary thyroid carcinoma (PTC) and ATC cells, and explored its regulation to downstream molecules miR-144-3p and Transforming Growth Factor α (TGF-α). Differentially expressed circRNAs in PTC were analyzed using the GSE93522 data downloaded. Expressions of circEIF6, miR-144-3p, TGF-α, autophagy-related proteins and apoptosis-related proteins were determined using qRT-PCR or western blot. RNA pull-down assay and dual luciferase report assay were applied to reveal the target relationships. Autophagy marker LC3 and cell proliferation marker ki67 were evaluated by immunofluorescence and immunohistochemistry. Cell viability was evaluated with MTT assay and cell apoptosis was assessed by flow cytometric analysis. CircEIF6, could promote autophagy induced by cisplatin, thus inhibiting cell apoptosis and enhancing the resistance of PTC and ATC cells to cisplatin. Has-miR-144-3p was the target of circEIF6 and was regulated by circEIF6. Besides, circEIF6 promoted autophagy by regulating miR-144-3p/TGF-α axis, enhancing the cisplatin-resistance in PTC and ATC cells. CircEIF6 promoted tumor growth by regulating miR-144-3p/TGF-α and circEIF6 knock-down enhanced cisplatin sensitivity in vivo. CircEIF6 could provide a target for therapy of cisplatin-resistance in thyroid carcinoma.

Dysregulation of the Wnt/β-catenin signaling pathway is critically involved in gastric cancer (GC) progression. However, current Wnt pathway inhibitors being studied in preclinical or clinical settings for other cancers such as colorectal and pancreatic cancers are either too cytotoxic or insufficiently efficacious for GC. Thus, we screened new potent targets from β-catenin destruction complex associated with GC progression from clinical samples, and found that scaffolding protein RACK1 deficiency plays a significant role in GC progression, but not APC, AXIN, and GSK3β. Then, we identified its upstream regulator UBE2T which promotes GC progression via hyperactivating the Wnt/β-catenin signaling pathway through the ubiquitination and degradation of RACK1 at the lysine K172, K225, and K257 residues independent of an E3 ligase. Indeed, UBE2T protein level is negatively associated with prognosis in GC patients, suggesting that UBE2T is a promising target for GC therapy. Furthermore, we identified a novel UBE2T inhibitor, M435-1279, and suggested that M435-1279 acts inhibit the Wnt/β-catenin signaling pathway hyperactivation through blocking UBE2T-mediated degradation of RACK1, resulting in suppression of GC progression with lower cytotoxicity in the meantime. Overall, we found that increased UBE2T levels promote GC progression via the ubiquitination of RACK1 and identified a novel potent inhibitor providing a balance between growth inhibition and cytotoxicity as well, which offer a new opportunity for the specific GC patients with aberrant Wnt/β-catenin signaling.

Trastuzumab is the backbone of HER2-directed gastric cancer therapy, but poor patient response due to insufficient cell sensitivity and drug resistance remains a clinical challenge. Here, we report that HER2 is involved in cell mitotic promotion for tumorigenesis by hyperactivating a crucial HER2-SHCBP1-PLK1 axis that drives trastuzumab sensitivity and is targeted therapeutically. SHCBP1 is an Shc1-binding protein but is detached from scaffold protein Shc1 following HER2 activation. Released SHCBP1 responds to HER2 cascade by translocating into the nucleus following Ser273 phosphorylation, and then contributing to cell mitosis regulation through binding with PLK1 to promote the phosphorylation of the mitotic interactor MISP. Meanwhile, Shc1 is recruited to HER2 for MAPK or PI3K pathways activation. Also, clinical evidence shows that increased SHCBP1 prognosticates a poor response of patients to trastuzumab therapy. Theaflavine-3, 3’-digallate (TFBG) is identified as an inhibitor of the SHCBP1-PLK1 interaction, which is a potential trastuzumab sensitizing agent and, in combination with trastuzumab, is highly efficacious in suppressing HER2-positive gastric cancer growth. These findings suggest an aberrant mitotic HER2-SHCBP1-PLK1 axis underlies trastuzumab sensitivity and offer a new strategy to combat gastric cancer.