增强的有氧糖酵解有助于胰腺癌转移,但是糖酵解异常激活的潜在机制尚未完全阐明。E3连接酶三方基序16(TRIM16)涉及许多癌症的进展。然而,TRIM16在胰腺癌中的作用和分子机制尚不清楚.在这项研究中,我们报道TRIM16在胰腺癌组织中显著上调,TRIM16的高表达与胰腺癌患者预后不良有关。多因素分析显示,TRIM16是胰腺癌患者预后不良的独立预测因子。此外,体外和体内证据表明TRIM16通过增强糖酵解促进胰腺癌细胞转移。此外,我们揭示了TRIM16通过调节sineoculishomeobox1(SIX1)来控制糖酵解和胰腺癌细胞的转移,促进糖酵解的重要转录因子。TRIM16通过抑制SIX1的泛素化和降解来上调SIX1,由NF-κB诱导激酶(NIK)介导,SIX1的上游调节器。因此,NIK抑制剂可以抑制SIX1的表达,TRIM16过表达胰腺癌细胞的糖酵解和转移。机理研究表明,TRIM16与NIK的E3连接酶竞争,肿瘤坏死因子受体相关因子3(TRAF3),在NIK的ISIIAQA序列基序中,然后稳定NIK蛋白。我们的研究将TRIM16-NIK-SIX1轴确定为有氧糖酵解和胰腺癌转移的关键调节途径。表明该轴可能是治愈胰腺癌的优异治疗靶点。
Enhanced aerobic glycolysis contributes to the metastasis of pancreatic cancer metastasis, but the mechanism underlying the abnormal activation of glycolysis has not been fully elucidated. The E3 ligase tripartite motif 16 (TRIM16) is involved in the progression of many cancers. However, the role of and molecular mechanism by which TRIM16 acts in pancreatic cancer are unclear. In this study, we report that TRIM16 was significantly upregulated in pancreatic cancer tissues, and high expression of TRIM16 was associated with poor prognosis in patients with pancreatic cancer. Multivariate analyses showed that TRIM16 was an independent predictor of poor outcomes among patients with pancreatic cancer. In addition, in vitro and in vivo evidence showed that TRIM16 promoted pancreatic cancer cell metastasis by enhancing glycolysis. Furthermore, we revealed that TRIM16 controlled glycolysis and pancreatic cancer cell\'s metastasis by regulating sine oculis homeobox 1 (SIX1), an important transcription factor that promotes glycolysis. TRIM16 upregulated SIX1 by inhibiting its ubiquitination and degradation, which was mediated by NF-κB-inducing kinase (
NIK), an upstream regulator of SIX1. Hence,
NIK inhibitor can suppress SIX1 expression, glycolysis and metastasis in TRIM16-overexpressing pancreatic cancer cells. Mechanistic investigations demonstrated that TRIM16 competed with
NIK\'s E3 ligase, TNF receptor-associated factor 3 (TRAF3), at the ISIIAQA sequence motif of
NIK, and then stabilized
NIK protein. Our study identified the TRIM16-
NIK-SIX1 axis as a critical regulatory pathway in aerobic glycolysis and pancreatic cancer metastasis, indicating that this axis can be an excellent therapeutic target for curing pancreatic cancer.