STK33 promotes hepatocellular carcinoma through binding to c-Myc.
STK33 promotes hepatocellular carcinoma through binding to c-Myc.
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STK33通过与c-Myc结合促进肝细胞癌
DOI：
10.1136/gutjnl-2014-307545
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发表时间：
2016-01
期刊：
影响因子：
24.5
通讯作者：
Shen F
中科院分区：
文献类型：
--
作者：
Yang T;Song B;Zhang J;Yang GS;Zhang H;Yu WF;Wu MC;Lu JH;Shen F
目的研究发现STK33在肿瘤细胞增殖中起重要作用。我们研究了STK33在肝细胞癌（HCC）中的作用及其潜在机制。设计分析251例HCC患者STK33表达与临床分期及生存率的关系。采用他莫昔芬（TAM）诱导的肝细胞特异性STK33转基因和敲除小鼠模型，研究STK33在肝肿瘤发生中的作用。在体外和体内研究STK33在HCC细胞系细胞增殖中的作用。结果肝癌患者中STK33表达频繁上调。发现STK33表达增加与晚期HCC分期和较短患者无病生存期之间存在显著关联。在体外和体内，STK33的过表达均增加了HCC细胞的增殖，而抑制STK33则抑制了这种作用。使用tam诱导的肝细胞特异性STK33转基因小鼠模型，我们发现STK33的过表达导致肝细胞增殖增加，导致肿瘤细胞破裂。使用tam诱导的肝细胞特异性STK33敲除小鼠模型，我们发现，当进行二乙基亚硝胺（DEN）肝癌生物测定，STK33KOflox/flox时，Alb-ERT2-Cre小鼠的肿瘤形成发生率明显低于对照小鼠。潜在的机制可能是STK33直接结合c-Myc并增加其转录活性。特别是STK33的c端阻断STK33/c-Myc的关联，下调HCC细胞增殖，减少den诱导的肝肿瘤细胞数量和肿瘤大小。结论STK33在肝细胞增殖和肝肿瘤发生中起重要作用。STK33的c端可能是治疗STK33过表达HCC患者的潜在治疗靶点。
Objective STK33 has been reported to play an important role in cancer cell proliferation. We investigated the role of STK33 in hepatocellular carcinoma (HCC) and its underlying mechanisms. Design 251 patients with HCC were analysed for association between STK33 expression and clinical stage and survival rate. Tamoxifen (TAM)-inducible, hepatocyte-specific STK33 transgenic and knockout mice models were used to study the role of STK33 in liver tumorigenesis. HCC cell lines were used to study the role of STK33 in cell proliferation in vitro and in vivo. Results STK33 expression was found to be frequently upregulated in patients with HCC. Significant associations were found between increased expression of STK33 and advanced HCC staging and shorter disease-free survival of patients. Overexpression of STK33 increased HCC cell proliferation both in vitro and in vivo, whereas suppression of STK33 inhibited this effect. Using a TAM-inducible, hepatocyte-specific STK33 transgenic mouse model, we found that overexpression of STK33 resulted in increased hepatocyte proliferation, leading to tumour cell burst. Using a TAM-inducible, hepatocyte-specific STK33 knockout mouse model, we found that, when subjected to the diethylnitrosamine (DEN) liver cancer bioassay, STK33KOflox/flox, Alb-ERT2-Cre mice exhibited a markedly lower incidence of tumour formation compared with control mice. The underlying mechanism may be that STK33 binds directly to c-Myc and increases its transcriptional activity. In particular, the C-terminus of STK33 blocks STK33/c-Myc association, downregulates HCC cell proliferation, and reduces DEN-induced liver tumour cell number and tumour size. Conclusions STK33 plays an essential role in hepatocellular proliferation and liver tumorigenesis. The C-terminus of STK33 could be a potential therapeutic target in the treatment of patients with STK33-overexpressed HCC.