Background There is growing evidence that tripartite motif-containing protein 44 (TRIM44) plays crucial role in tumor development. However, the underlying mechanism of this deubiquitinating enzyme remains unclear. Methods Large clinical samples were used to detect TRIM44 expression and its associations with clinicopathological features and prognosis. Gain- and loss-of-function experiments in cell lines and mouse xenograft models were performed to elucidate the function and underlying mechanisms of TRIM44 induced tumor progression. Co-immunoprecipitation (Co-IP) assays and mass spectrometric analyses were applied to verify the interacting proteins of TRIM44. Results We found that TRIM44 was commonly amplified in melanoma tissues compared with paratumoral tissues. TRIM44 expression also positively correlated with more aggressive clinicopathological features, such as Breslow depth ( p = 0.025), distant metastasis ( p = 0.012), and TNM stage ( p = 0.002). Importantly, we found that TRIM44 was an independent indicator of prognosis for melanoma patients. Functionally, overexpression of TRIM44 facilitated cell invasion, migration, apoptosis resistance and proliferation in vitro, and promoted lung metastasis and tumorigenic ability in vivo. Importantly, high level of TRIM44 induced melanoma cell epithelial-mesenchymal transition (EMT), which is one of the most important mechanisms for the promotion of tumor metastasis. Mechanistically, high levels of TRIM44 increased the levels of p-AKT (T308) and p-mTOR (S2448), and a specific AKT inhibitor inhibited TRIM44-induced tumor progression. Co-IP assays and mass spectrometric analyses indicated that TRIM44 overexpression induces cell EMT through activating AKT/mTOR pathway via directly binding and stabilizing TOLL-like receptor 4 (TLR4), and TLR4 interference impeded TRIM44 induced tumor progression. Moreover, we demonstrated that TRIM44 is the target of miR-26b-5p, which is significantly downregulated in melanoma tissues and may be responsible for the overexpression of TRIM44. Conclusions TRIM44, regulated by miR-26b-5p, promotes melanoma progression by stabilizing TLR4, which then activates the AKT/mTOR pathway. TRIM44 shows promise as a prognostic predictor and a therapeutic target for melanoma patients. Electronic supplementary material The online version of this article (10.1186/s13046-019-1138-7) contains supplementary material, which is available to authorized users.

BackgroundAngiogenesis is an important component of wound healing and tissue repair. Kindlin-2 is an integrin-associated protein, encoded by the KINDLIN-2 gene, which has been shown to affect cell adhesion and migration of cells, including endothelial cells. The aim of this study was to use a mouse model of wound healing to evaluate the effects of expression of KINDLIN-2 on angiogenesis in wound healing in vivo.Material/MethodsThirty-six male C57BL/6 mice were studied in an established model that used a wound created on the back. Mice were divided randomly into three groups: the normal group (n=12) received injections of normal (0.9%) saline; the KINDLIN-2(−) group (n=12) received injections of adeno-associated virus with small interfering (si)RNA targeting the KINDLIN-2 gene (AAV-KINDLIN-2-siRNA); and the control (group (n=12) received injections of adeno-associated virus containing a scrambled RNA sequence (AAV-control-RNA). Wound healing was analyzed by biochemical examination of the exudates and histology. Evans blue dye was injected into the caudal vein of each mouse, two weeks after wound healing to assess neovascular permeability.ResultsWound healing was significantly delayed in the KINDLIN-2 gene knockdown mice (AAV-KINDLIN-2-siRNA) compared with that of the normal group and the control group, and neovascular permeability was increased. In the AAV-KINDLIN-2-siRNA group, blood vessels were shorter and thinner compared with the normal group and the control group.ConclusionsIn a mouse model of wound healing, KINDLIN-2 gene knockdown inhibited wound healing, and increased neovascular permeability in vivo.