Background

Gene and protein expression of the glucose transporter GLUT6 are elevated in multiple cancers, including endometrial cancer. However, the extrinsic and intrinsic mechanisms that regulate GLUT6 expression in this malignancy are unknown. Herein we investigate the potential mechanisms regulating GLUT6 expression in endometrial cancer.

Methods

Data mining of the GLUT6 gene (SLC2A6) in The Cancer Genome Atlas (TCGA) PanCan datasets was performed in cBioPortal. A transcriptome PCR array was used to identify regulators of GLUT6 expression. The role of RELA in regulating GLUT6 gene and protein expression was investigated by overexpressing constitutively active and dominant-negative RELA in endometrial cells. Endometrial cells were treated with the pro-inflammatory cytokine TNFα and the expression of RELA, IκBα, TNFα, and GLUT6 were examined by Western blotting and RT-qPCR.

Results

GLUT6 is altered in 1% of all cancer samples (157 of 10, 967 samples) within TCGA datasets including 4.7% of uterine (endometrial) cancers. GLUT6 expression was positively co-expressed with multiple members of the NF-κB signalling pathway including NFKB2, RELB, NFKBIE, and TNF in endometrial cancer samples. A transcriptome PCR array identified RELA as the top potential transcriptional regulator of GLUT6 expression. Overexpression of constitutively active RELA increased GLUT6 gene expression in normal endometrial epithelial cells (hUE-Ts), while overexpression of dominant-negative RELA decreased GLUT6 expression in cancerous RL95–2 endometrial cells. TNFα treatment activated canonical NF-κB signalling and increased the expression of GLUT6, but not that of other glucose transporters (GLUTs 1, 3, 4, 8, 10, or 12) in endometrial cells.

Conclusions

TNFα is a cytokine that is commonly increased in obesity-related endometrial cancer and the findings herein support a potential mechanism whereby TNFα may contribute to endometrial cancer initiation or progression by increasing GLUT6 expression. Furthermore, we identified RELA, an important downstream mediator of the TNFα signalling cascade, as a regulator of GLUT6 expression in endometrial cells. Future studies are warranted to determine how GLUT6 expression affects endometrial tumourigenesis or cancer progression.

中文翻译：

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NF-κB 信号通路调节子宫内膜癌中 GLUT6 的表达。

背景

葡萄糖转运蛋白 GLUT6 的基因和蛋白质表达在多种癌症中升高，包括子宫内膜癌。然而，在这种恶性肿瘤中调节 GLUT6 表达的外在和内在机制尚不清楚。在此，我们研究了调节子宫内膜癌中 GLUT6 表达的潜在机制。

方法

在 cBioPortal中对癌症基因组图谱 (TCGA) PanCan 数据集中的 GLUT6 基因 ( SLC2A6 ) 进行数据挖掘。转录组 PCR 阵列用于鉴定 GLUT6 表达的调节因子。通过在子宫内膜细胞中过度表达组成型活性和显性阴性 RELA，研究了 RELA 在调节 GLUT6 基因和蛋白质表达中的作用。用促炎细胞因子 TNFα 处理子宫内膜细胞，并通过蛋白质印迹和 RT-qPCR 检查 RELA、IκBα、TNFα 和 GLUT6 的表达。

结果

包括 4.7% 的子宫（子宫内膜）癌在内的 TCGA 数据集中所有癌症样本的 1%（107 个样本中的 157 个，967 个样本）中 GLUT6 发生了改变。GLUT6 表达与 NF-κB 信号通路的多个成员（包括NFKB2、RELB、NFKBIE和TNF）在子宫内膜癌样本中呈阳性共表达。转录组 PCR 阵列鉴定了RELA作为 GLUT6 表达的最大潜在转录调节因子。组成型活性 RELA 的过表达增加了正常子宫内膜上皮细胞 (hUE-Ts) 中的 GLUT6 基因表达，而显性阴性 RELA 的过表达降低了癌性 RL95-2 子宫内膜细胞中的 GLUT6 表达。TNFα 治疗激活了经典的 NF-κB 信号传导并增加了 GLUT6 的表达，但不增加子宫内膜细胞中其他葡萄糖转运蛋白（GLUT 1、3、4、8、10 或 12）的表达。

结论

TNFα 是一种通常在肥胖相关子宫内膜癌中增加的细胞因子，本文的发现支持一种潜在机制，即 TNFα 可能通过增加 GLUT6 表达促进子宫内膜癌的发生或进展。此外，我们将 TNFα 信号级联的重要下游介质 RELA 鉴定为子宫内膜细胞中 GLUT6 表达的调节剂。未来的研究需要确定 GLUT6 表达如何影响子宫内膜肿瘤发生或癌症进展。