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/β-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.

中文翻译：

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SLC38A4 通过调节 Wnt/β-catenin/MYC/HMGCS2 轴在肝细胞癌中发挥抑癌作用

背景

胚胎肝发育和肝细胞癌 (HCC) 共有许多分子改变。识别常见的分子事件将为 HCC 提供新的预后生物标志物和治疗靶点。

方法

通过 qRT-PCR、蛋白质印迹、TCGA 和 GEO 数据集研究 SLC38A4 和 HMGCS2 的表达水平和临床相关性。通过功能测定研究了 SLC38A4 的生物学作用。通过 qRT-PCR、蛋白质印迹、免疫荧光、荧光素酶报告基因测定、TCGA 和 GEO 数据集研究 SLC38A4 的下游信号通路。

结果

SLC38A4 沉默被确定为癌胎儿分子事件。DNA 高甲基化导致胎儿肝脏和 HCC 中 Slc38a4/SLC38A4 的下调。SLC38A4的低表达与HCC患者的不良预后相关。功能测定表明，SLC38A4 耗竭促进 HCC 细胞增殖、干细胞和迁移，并在体外抑制 HCC 细胞凋亡，并在体内进一步抑制 HCC 肿瘤发生。HMGCS2 被确定为 SLC38A4 的关键下游目标。SLC38A4 通过上调 AXIN1 和抑制 Wnt/β-catenin/MYC 轴来增加 HMGCS2 的表达。功能拯救分析表明，HMGCS2 过表达逆转了 SLC38A4 耗竭在 HCC 中的致癌作用。

结论

SLC38A4 下调被确定为一种新的癌胎儿事件，并且 SLC38A4 被确定为 HCC 中的一种新的肿瘤抑制因子。