SLC38A4 functions as a tumour suppressor in hepatocellular carcinoma through modulating Wnt/β-catenin/MYC/HMGCS2 axis
SLC38A4 functions as a tumour suppressor in hepatocellular carcinoma through modulating Wnt/β-catenin/MYC/HMGCS2 axis
复制标题
SLC38A4 通过调节 Wnt/β-连环蛋白/MYC/HMGCS2 轴作为肝细胞癌的肿瘤抑制因子。
DOI：
10.1038/s41416-021-01490-y
复制
发表时间：
2021-07-17
影响因子：
8.8
通讯作者：
Yuan, Ji-hang
中科院分区：
文献类型：
--
作者：
Li, Jie;Li, Ming-han;Yuan, Ji-hang
胚胎肝发育和肝细胞癌（HCC）有许多共同的分子改变。确定共同的分子事件将为HCC的预后提供新的生物标志物和治疗靶点。方法采用qRT-PCR、western blot、TCGA和GEO数据分析SLC38A4和HMGCS2的表达水平及临床相关性。通过功能分析研究SLC38A4的生物学作用。采用qRT-PCR、western blot、免疫荧光、荧光素酶报告基因法、TCGA和GEO数据集对SLC38A4的下游信号通路进行研究。结果SLC38A4沉默被确定为癌胎分子事件。DNA高甲基化导致Slc38a4/ Slc38a4在胎儿肝脏和HCC中的下调。SLC38A4低表达与HCC患者预后不良相关。功能实验表明，SLC38A4缺失在体外促进HCC细胞增殖、干细胞化和迁移，抑制HCC细胞凋亡，并进一步抑制HCC体内肿瘤发生。HMGCS2被确定为SLC38A4的关键下游靶点。SLC38A4通过上调AXIN1和抑制Wnt/ β -catenin/MYC轴增加HMGCS2的表达。功能修复实验显示HMGCS2过表达逆转了SLC38A4缺失在HCC中的致癌作用。结论SLC38A4下调被认为是一种新的癌胎事件，SLC38A4被认为是HCC中一种新的肿瘤抑制因子。
Background Many molecular alterations are shared by embryonic liver development and hepatocellular carcinoma (HCC). Identifying the common molecular events would provide a novel prognostic biomarker and therapeutic target for HCC. Methods Expression levels and clinical relevancies of SLC38A4 and HMGCS2 were investigated by qRT-PCR, western blot, TCGA and GEO datasets. The biological roles of SLC38A4 were investigated by functional assays. The downstream signalling pathway of SLC38A4 was investigated by qRT-PCR, western blot, immunofluorescence, luciferase reporter assay, TCGA and GEO datasets. Results SLC38A4 silencing was identified as an oncofetal molecular event. DNA hypermethylation contributed to the downregulations of Slc38a4/SLC38A4 in the foetal liver and HCC. Low expression of SLC38A4 was associated with poor prognosis of HCC patients. Functional assays demonstrated that SLC38A4 depletion promoted HCC cellular proliferation, stemness and migration, and inhibited HCC cellular apoptosis in vitro, and further repressed HCC tumorigenesis in vivo. HMGCS2 was identified as a critical downstream target of SLC38A4. SLC38A4 increased HMGCS2 expression via upregulating AXIN1 and repressing Wnt/beta-catenin/MYC axis. Functional rescue assays showed that HMGCS2 overexpression reversed the oncogenic roles of SLC38A4 depletion in HCC. Conclusions SLC38A4 downregulation was identified as a novel oncofetal event, and SLC38A4 was identified as a novel tumour suppressor in HCC.