Background

Leucin-rich repeat containing protein A (LRRC8A), a component of the volume-regulated anion channel (VRAC), is activated by cell swelling and mediates regulatory volume decrease. We previously reported the expression of and important roles for several ion transporters in various gastrointestinal cancers, which have potential as novel targets for cancer treatment; however, the significance of LRRC8A in gastric cancer (GC) remains unclear.

Materials and methods

Knockdown experiments were performed by transfecting human GC cell lines with LRRC8A siRNA. Gene expression was then assessed using microarray analysis. Samples from 132 patients with GC were subjected to immunohistochemistry (IHC) for LRRC8A, and its relationships with clinicopathological factors and prognosis were examined.

Results

The knockdown of LRRC8A suppressed the proliferation and movement of cells and enhanced apoptosis. The results of the microarray analysis showed the up- or down-regulated expression of genes related to the p53 signaling pathway (JNK, p53, p21, Bcl-2, and FAS) in LRRC8A-knockdown cells. IHC revealed a correlation between the expression of LRRC8A and the pT status (p = 0.015), and multivariate analysis identified the strong expression of LRRC8A as an independent prognostic factor for 5-year survival in GC patients (p = 0.0231).

Conclusions

The present results indicate that LRRC8A functions as a mediator of and/or biomarker for GC.

中文翻译：

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LRRC8A通过p53信号通路影响胃癌细胞的生长

背景

富含亮氨酸重复序列的蛋白 A (LRRC8A) 是体积调节阴离子通道 (VRAC) 的一种成分，可被细胞肿胀激活并介导调节体积减少。我们之前报道了几种离子转运蛋白在各种胃肠道癌症中的表达和重要作用，它们有可能成为癌症治疗的新靶点；然而，LRRC8A 在胃癌 (GC) 中的意义仍不清楚。

材料和方法

通过用 LRRC8A siRNA 转染人 GC 细胞系来进行敲低实验。然后使用微阵列分析评估基因表达。对 132 名 GC 患者的样本进行 LRRC8A 的免疫组织化学 (IHC) 检测，并检查其与临床病理因素和预后的关系。

结果

LRRC8A的敲低抑制了细胞的增殖和运动并增强了细胞凋亡。微阵列分析结果显示，在 LRRC8A 敲低细胞中，与 p53 信号通路（JNK、p53、p21、Bcl-2 和 FAS）相关的基因表达上调或下调。IHC 显示 LRRC8A 的表达与 pT 状态之间存在相关性（p  = 0.015），多变量分析确定 LRRC8A 的强表达是 GC 患者 5 年生存率的独立预后因素（p  = 0.0231）。

结论

目前的结果表明 LRRC8A 作为 GC 的介质和/或生物标志物起作用。