Abstract
BackgroundThere 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.MethodsLarge 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.ResultsWe 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.ConclusionsTRIM44, 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.
Highlights
There is an increasing incidence of cutaneous melanoma, which accounts for 232,100 (1.7%) of all newly diagnosed primary malignant tumors annually
tripartite motif-containing protein 44 (TRIM44) is overexpressed in melanoma and TRIM44 overexpression correlates with a poor prognosis By retrieving the database, we found that TRIM44 is significantly upregulated in multiple cancers, including melanoma (Fig. 1a)
QRT-PCR and Western blot results indicated that TRIM44 expression was significantly upregulated in melanoma tissues relative to matched peritumorous tissues (Fig. 1b and c)
Summary
There is an increasing incidence of cutaneous melanoma, which accounts for 232,100 (1.7%) of all newly diagnosed primary malignant tumors annually. Most have E3 ubiquitin ligase activities as they contain a RING-finger domain They are involved in a variety of cellular processes, such as protein degradation, cell cycle progression, transcriptional regulation, DNA repair, and signal transduction [4, 5]. Studies indicate that, unlike most TRIM family members, TRIM44 contains a zinc finger ubiquitin protease domain (UBP) and functions as a deubiquitinating enzyme [8,9,10]. Chen et al finds that TRIM44 stabilizes hypoxia inducible factor-1α and stimulates multiple myeloma cell growth under hypoxia [10]. Despite this evidence, only a handful of publications link TRIM44 function with cancers and the mechanisms underlying this association are even less clear. The underlying mechanism of this deubiquitinating enzyme remains unclear
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