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    • The tripartite motif containing TRIM proteins contain

    2019-04-23

    The tripartite motif-containing (TRIM) proteins contain a RING domain, which is most commonly used to polyubiquitinate target proteins for proteasome-dependent degradation [9]. Accumulated evidence pointed to the involvement of TRIM proteins in the development, progression or metastasis of cancers [10] in addition to the innate immune response [11]. Several TRIM proteins such as TRIM16 [12], TRIM24 [13], TRIM33 [14], TRIM26 [15] and TRIM35 [16] have been reported to exert tumor-suppressive activity in HCC by inhibiting cancer cell proliferation, epithelial to mesenchymal cell transition, metastasis or the Warburg effect. TRIM7 (also known as glycogenin-interacting protein 1 [GNIP1]) belongs to class IV of the TRIM family proteins. Members of this group contain a RING domain, two B box domains, and a PRYSPRY domain (also termed the B30.2 domain). TRIM7 interacts directly with glycogenin, a glucosyltransferase required for the biosynthesis of glycogen [17]. TRIM7 has ubiquitin ligase activity for a c-Jun coactivator, RING domain AP-1 coactivator 1 (RACO-1) and cooperates with Ras to drive lung tumorigenesis [18]. However, there has been no investigation on the expression and functions of TRIM7 in HCC.
    Materials and methods
    Results
    Discussion In this study, we showed that TRIM7 expression was upregulated in HCC tissues and associated with tumor size, pTNM stage, serum AFP concentration, serum HBV DNA copy number and OS of HCC patients. In vitro experiments and In vitro experiments (Fig. S5) present reliable evidence supporting the notion that TRIM7 acts as an oncogene in HCC pathogenesis by promoting cell proliferation and gamma secretase inhibitors progression. Chakraborty A et al. have reported that TRIM7 drive lung tumorigenesis by inducing the ubiquitination of RACO-1 and cooperating with Ras [18]. Our data together with the Chakraborty A et al. study document the critical roles of TRIM7 in human malignancies. The AKT [22] and MAPK pathways, including extracellular signal regulated kinase (ERK) [23], c-Jun NH2-terminal kinase (JNK) [24] and p38 [25], are critical regulators of cell proliferation. Although studied less extensively, the contribution of p38 to the induction of the G1/S checkpoint in response to extracellular stimuli has been described [26,27]. The present study showed that TRIM7 knockdown clearly decreased phosphorylated p38 (p-p38) in both in vitro cultured MHCC-97H cells and in vivo xenograft samples (Fig. S5C). P53 is a well-known tumor suppressor. The activation of p53 leads to the accumulation of p21 and a G1/S checkpoint [26,27]. Here, we found that the protein levels of p53 and p21 were increased by TRIM7 knockdown both in vitro and in vivo (Fig. S5C). We speculated that the TRIM7 knockdown-induced G1/S checkpoint could occur through the regulation of p38 and p53/p21 signaling. Protein phosphatases are negative regulators of MAPK signaling. DUSPs, a subset of protein tyrosine phosphatases, are known to play important roles in the regulation of MAPK signaling [20]. Here, we explored whether TRIM7 mediated the phosphorylation of p38 through regulating DUSPs. First, we showed that TRIM7 overexpression specifically reduced DUSP6 expression at the protein level and did not affect DUSP6 mRNA expression. Next, the experiment with MG132, a proteasome inhibitor, suggested that DUSP6 protein was degraded in a proteasome-dependent manner. Considering that TRIM7 has ubiquitin ligase activity [18], we speculated that TRIM7 is involved in the regulation of DUSP6 ubiquitination, which was supported by the findings that TRIM7 interacted with DUSP6 in HCC cells and that DUSP6 ubiquitination was increased in cells overexpressing TRIM7. Thus, we demonstrated that TRIM7 enhanced the polyubiquitination and degradation of DUSP6, which may contribute to the increased phosphorylation of p38. Moreover, when HepG cells were transduced with DUSP6-overexpressing virus, the ectopic expression of TRIM7 did not exert a promotional effect on HCC cell proliferation or the activation of p38. These results showed that TRIM7 regulated the p38 pathway by inducing the ubiquitination of DUSP6 in HCC cells.