Tripartite motif 31 promotes resistance to anoikis of hepatocarcinoma cells through regulation of p53-AMPK axis
Tripartite motif 31 promotes resistance to anoikis of hepatocarcinoma cells through regulation of p53-AMPK axis
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三联基序 31 通过调节 p53-AMPK 轴促进肝癌细胞对失巢凋亡的抵抗。
DOI：
10.1016/j.yexcr.2018.04.013
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发表时间：
2018-07-01
影响因子：
3.7
通讯作者：
Han, Lihui
中科院分区：
文献类型：
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作者：
Guo, Pengbo;Qiu, Yumin;Han, Lihui
抗失巢凋亡是癌细胞获得成功转移的重要特征，而肝细胞癌细胞这一过程中涉及的分子机制尚不完全清楚。在这里，我们证明了含有三方基序的(TRIM)31，TRIM家族的一个新成员，在锚定剥夺的肝癌细胞中与其附着的对应物相比显著上调。当我们用其特异的干扰RNA阻断TRIM31的表达时，肝癌细胞对失巢凋亡的抗性被显著逆转。我们进一步证实，AMPK通路的过度激活是TRIM31介导肝癌细胞对失巢诱导耐受的原因；TRIM31可以直接靶向AMPK通路上游抑制因子P53，并以环状结构域依赖的方式介导K48连接的P53的普遍降解。因此，我们证明了TRIM31通过靶向P53的降解和随后过度激活AMPK途径促进了对失巢凋亡的抵抗。因此，我们的研究首次明确了TRIM31在肝细胞癌耐受过程中的作用，并可能为靶向TRIM31的转移性肿瘤的治疗开辟新的途径。
Anoikis-resistance is an essential feature of cancer cells to obtain successful metastasis, whereas the molecular mechanism involved in this process of hepatocellular carcinoma (HCC) cells is not fully understood. Here we demonstrated that tripartite motif-containing (TRIM) 31, a new member of the TRIM family, was significantly upregulated in the anchorage-deprived HCC cells compared with their attached counterpart. When we blocked TRIM31 expression by its specific interference RNAs, the anoikis-resistance of HCC cells was significantly reversed. We further verified that overactivation of AMPK pathway was responsible for TRIM31-mediated resistance to anoikis of HCC cells; and TRIM31 could directly target p53, the upstream suppressor of AMPK pathway, and mediate K48-linked ubiquitous degradation of p53 in a RING-domain-dependent way. Therefore we demonstrated that TRIM31 promoted anoikis-resistance by targeting p53 for degradation and subsequently overactivating AMPK pathway. Thus our study defined for the first time the role of TRIM31 in the anoikisresistant process of HCC cells, and it may pave a new avenue for manipulation of metastatic cancer by targeting TRIM31.