State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, No.2 Tiansheng Road, Beibei District, Chongqing, 400716, China.
Cancer Center, Reproductive Medicine Center, Medical Research Institute, Southwest University, Chongqing, 400716, China.
J Exp Clin Cancer Res. 2020 Sep 21;39(1):194. doi: 10.1186/s13046-020-01696-7.
Nuclear casein kinase and cyclin-dependent kinase substrate (NUCKS), a novel gene first reported in 2001, is a member of the high mobility group (HMG) family. Although very little is known regarding the biological roles of NUCKS, emerging clinical evidence suggests that the NUCKS protein can be used as a biomarker and therapeutic target in various human ailments, including several types of cancer.
We first assessed the potential correlation between NUCKS expression and gastric cancer prognosis. Then functional experiments were conducted to evaluate the effects of NUCKS in cell proliferation, cell cycle, apoptosis and autophagy. Finally, the roles of NUCKS on gastric cancer were examined in vivo.
We found that NUCKS was overexpressed in gastric cancer patients with poor prognosis. Through manipulating NUCKS expression, it was observed to be positively associated with cell proliferation in vitro and in vivo. NUCKS knockdown could induce cell cycle arrest and apoptosis. Then further investigation indicated that NUCKS knockdown could also significantly induce a marked increase in autophagy though the mTOR-Beclin1 pathway, which could be was rescued by NUCKS restoration. Moreover, silencing Beclin1 in NUCKS knockdown cells or adding rapamycin in NUCKS-overexpressed cells also confirmed these results.
Our findings revealed that NUCKS functions as an oncogene and an inhibitor of autophagy in gastric cancer. Thus, the downregulation or inhibition of NUCKS may be a potential therapeutic strategy for gastric cancer.
核酪蛋白激酶和细胞周期依赖性激酶底物（NUCKS）是 2001 年首次报道的一种新基因，是高迁移率族（HMG）家族的成员。尽管人们对 NUCKS 的生物学功能知之甚少，但新出现的临床证据表明，NUCKS 蛋白可用作各种人类疾病（包括多种类型的癌症）的生物标志物和治疗靶标。
我们首先评估了 NUCKS 表达与胃癌预后之间的潜在相关性。然后进行功能实验以评估 NUCKS 在细胞增殖、细胞周期、细胞凋亡和自噬中的作用。最后，在体内检查了 NUCKS 对胃癌的作用。
我们发现 NUCKS 在预后不良的胃癌患者中过表达。通过操纵 NUCKS 表达，观察到其与体外和体内的细胞增殖呈正相关。NUCKS 敲低可诱导细胞周期停滞和细胞凋亡。然后进一步的研究表明，NUCKS 敲低还可以通过 mTOR-Beclin1 途径显著诱导自噬的明显增加，而 NUCKS 恢复可以挽救这种增加。此外，在 NUCKS 敲低细胞中沉默 Beclin1 或在 NUCKS 过表达细胞中添加雷帕霉素也证实了这些结果。
我们的研究结果表明，NUCKS 在胃癌中作为癌基因和自噬抑制剂发挥作用。因此，下调或抑制 NUCKS 可能是治疗胃癌的一种潜在治疗策略。
