miR-124 plays a neurons-protective role via apoptosis-inhibiting pathway in ischemic stroke.

TRAF6 plays a crucial role in the regulation of the innate and adaptive immune responses. Although studies have shown that TRAF6 has oncogenic activity, the role of TRAF6 in melanoma is unclear. Here, we report that TRAF6 is overexpressed in primary as well as metastatic melanoma tumors and melanoma cell lines. Knockdown of TRAF6 with shRNA significantly suppressed malignant phenotypes including cell proliferation, anchorage-independent cell growth and metastasis in vitro and in vivo. Notably, we demonstrated that Basigin (BSG)/CD147, a critical molecule for cancer cell invasion and metastasis, is a novel interacting partner of TRAF6. Furthermore, depletion of TRAF6 by shRNA reduced the recruitment of BSG to the plasma membrane and K63-linked ubiquitination, in turn, which impaired BSG-dependent MMP9 induction. Taken together, our findings indicate that TRAF6 is involved in regulating melanoma invasion and metastasis, suggesting that TRAF6 may be a potential target for therapy or chemo-prevention in melanoma.

TRAF6 (TNF Receptor-Associated Factor 6) is an E3 ubiquitin ligase that contains a Ring domain, induces K63-linked polyubiquitination, and plays a critical role in signaling transduction. Our previous results demonstrated that TRAF6 is overexpressed in melanoma and that TRAF6 knockdown dramatically attenuates tumor cell growth and metastasis. In this study, we found that EGCG can directly bind to TRAF6, and a computational model of the interaction between EGCG and TRAF6 revealed that EGCG probably interacts with TRAF6 at the residues of Gln54, Gly55, Asp57 ILe72, Cys73 and Lys96. Among these amino acids, mutation of Gln54, Asp57, ILe72 in TRAF6 could destroy EGCG bound to TRAF6, furthermore, our results demonstrated that EGCG significantly attenuates interaction between TRAF6 and UBC13(E2) and suppresses TRAF6 E3 ubiquitin ligase activity in vivo and in vitro. Additionally, the phosphorylation of IκBα, p-TAK1 expression are decreased and the nuclear translocation of p65 and p50 is blocked by treatment with EGCG, leading to inactivation of the NF-κB pathway. Moreover, EGCG significantly inhibits cell growth as well as the migration and invasion of melanoma cells. Taken together, these findings show that EGCG is a novel E3 ubiquitin ligase inhibitor that could be used to target TRAF6 for chemotherapy or the prevention of melanoma.

Huaier (Trametes robiniophila murr) Cancer therapyTotal RNA-and small RNA-sequencing RNA editing events Transcriptional controlRecent advances in cancer therapy integrate most advanced devices and inventions among broad areas of science [1][2][3] . Although a rapid progress in the methodology 4-8 , many tasks remain unsolved for successful control of cancer, and for diseases originated from multiple factors and environmental stresses throughout a life-long time 9 . Recent advancement in technology enabled to cultivate those useful natural herb species in quantity 10-14 , and quality-controlled distribution in the conventional granule forms. In 1970's, Huaier (Tremetes robiniophila Murr) has been recognized widely as anticancer drug in China 12-14 (Chinese administration license No. Z-20000109).Huaier has been introduced with its significant anti-cancer effects without any side effects and/or toxicity [13][14][15][16][17][18][19][20][21][22][23] . The effective ingredient of Huaier was proteoglycan, which consists of 41.53% polysaccharides, 12.93% amino acids and 8.72% water 13,14 . The proteoglycan is the most effective anticancer element among all of the isolated ingredients of Huaier extract, which was confirmed on breast cancer MCF-7 15 , liver cancer H22 16, 17 , MHCC97-H 18 , lung cancer 19 , ovarian cancer 20 , colorectal cancer 21 , and human fibrosarcoma HT1080 cells 22 . More importantly, Huaier has no toxicity or side provided a simple and successful evidence that the rescue of Hippo signalling pathway was a molecular basis of anti-cancer effects of Huaier 4, 5 . However, it was not enough, either, to explain all functions associated to anti-cancer effects, such as 1) immunological alterations both to enhance and also inhibit the excessive reaction, 2) normal tissue reproduction after the specific cell death and elimination of cell debris in cancer lesion, and 3) reduction of (oxidative) stress materials in liver, and 4) recovery from the opportunistic infections during cancer therapy, and etc. Therefore, we initiated clinical research to identify Huaier effects on every biophysiological system and influences each other. The samples used in this approach should be free from the effects of chemotherapeutic agents, especially molecular-targeting anti-cancer drugs, which disrupted largely molecular mechanisms. The present study was thus constructed with a collaboration of cancer patients, not a large in number, but wished to have Huaier treatment.The medical characteristics of the 31 volunteer patients were summarized in Table 1. The mean age is 67 years old, since this research excluded the congenital cancer or tumour. The present study summarizes the results from 92 sample sequencing from 31 patients, including 2 normal controls (patient No. 21 and 26), and 4 with benign tumours (No. 13,14,18,and 20). Normal control No. 21 was the same as No. 25, the opportunistic infection case after 8 months of the end of first research period as No. 21. In order to compare the results with the other volunteer patients...

Deregulation of the tyrosine kinase signalling is often associated with tumour progression and drug resistance, but its underlying mechanisms are only partly understood. In this study, we investigated the effects of the receptor tyrosine kinase AXL on the stability of the MDMX-MDM2 heterocomplex and the activity of p53 in melanoma cells. Our data demonstrated that AXL overexpression or activation through growth arrest-specific 6 (Gas6) ligand stimulation increases MDMX and MDM2 protein levels and decreases p53 activity. Upon activation, AXL stabilizes MDMX through a post-translational modification that involves phosphorylation of MDMX on the phosphosite Ser314, leading to increased affinity between MDMX and MDM2 and favouring MDMX nuclear translocation. Ser314 phosphorylation can also protect MDMX from MDM2-mediated degradation, leading to stabilization of the MDMX-MDM2 complex. We identified CDK4/6 and p38 MAPK as the two kinases mediating AXL-induced modulation of the MDMX-MDM2 complex, and demonstrated that suppression of AXL, either through siRNA silencing or pharmacological inhibition, increases expression levels of p53 target genes P21, MDM2, and PUMA, improves p53 pathway response to chemotherapy, and sensitizes cells to both Cisplatin and Vemurafenib. Our findings offer an insight into a novel signalling axis linking AXL to p53 and provide a potentially druggable pathway to restore p53 function in melanoma.