USP39 promotes the growth of human hepatocellular carcinoma in vitro and in vivo
USP39 promotes the growth of human hepatocellular carcinoma in vitro and in vivo
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USP39在体外和体内促进人肝细胞癌的生长
DOI：
10.3892/or.2015.4065
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发表时间：
2015-08-01
期刊：
影响因子：
4.2
通讯作者：
Ding, Yitao
中科院分区：
文献类型：
--
作者：
Yuan, Xianwen;Sun, Xitai;Ding, Yitao
泛素特异性蛋白酶39（USP 39）在mRNA剪接中起重要作用。在本研究中，我们研究了USP 39在调节肝细胞癌（HCC）生长中的作用。我们在100多个HCC临床样本中检测到USP 39表达。USP 39在肝癌组织中的表达显著高于癌旁正常组织，且与肝癌的病理分级密切相关。在体外，USP 39敲低抑制HepG 2细胞中的细胞增殖和集落形成，而上调USP 39促进肿瘤细胞生长。流式细胞仪检测显示，USP 39基因敲低可使HepG 2细胞发生G2/M期阻滞，并诱导细胞凋亡。通过shRNA敲低USP 39抑制裸鼠中异种移植瘤生长。此外，USP 39基因敲减后，p-Cdc 2表达上调，p-Cdc 25 c和p-myt 1表达下调，而总Cdc 2、Cdc 25 c和myt 1的表达无明显变化。我们还发现，p-Cdc 2在USP 39过表达细胞中减少，并且在来自裸鼠的HepG 2/KD细胞的异种移植肿瘤中上调。同时，FoxM 1及其靶基因PLK 1和cyclin B1在USP 39基因敲减细胞中的表达水平降低。这些结果表明，USP 39可能有助于HCC肿瘤细胞中的FoxM 1剪接。我们的数据表明，USP 39敲低通过G2/M期阻滞抑制体外和体内HCC的生长，这部分是通过抑制FoxM 1剪接实现的。
Ubiquitin specific protease 39 (USP39) plays an important role in mRNA splicing. In the present study, we investigated the role of USP39 in regulating the growth of hepatocellular carcinoma (HCC). We detected USP39 expression in more than 100 HCC clinical samples. The USP39 expression was significantly higher in the tumor tissues compared to the adjacent normal tissues, and was strongly associated with the pathological grade of HCC. USP39 knockdown inhibited cell proliferation and colony formation in vitro in the HepG2 cells, while upregulation of USP39 promoted tumor cell growth. FCM assay showed that USP39 knockdown led to G2/M arrest and induced apoptosis in the HepG2 cells. USP39 knockdown by shRNA inhibited xenograft tumor growth in nude mice. Moreover, USP39 knockdown led to the upregulation of p-Cdc2 and down-regulation of p-Cdc25c and p-myt1, while the expression of total Cdc2, Cdc25c and myt1 was not changed in the USP39-knockdown cells. We also found that p-Cdc2 was decreased in the USP39-overexpressing cells and was upregulated in the xenografted tumors derived from the HepG2/KD cells from nude mice. Meanwhile, the expression levels of FoxM1 and its target genes PLK1 and cyclin B1 were decreased in the USP39-knockdown cells. These results suggest that USP39 may contribute to FoxM1 splicing in HCC tumor cells. Our data indicate that USP39 knockdown inhibited the growth of HCC both in vitro and in vivo through G2/M arrest, which was partly achieved via the inhibition of FoxM1 splicing.