SLC25A18 has prognostic value in colorectal cancer and represses Warburg effect and cell proliferation via Wnt signaling
SLC25A18 has prognostic value in colorectal cancer and represses Warburg effect and cell proliferation via Wnt signaling
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SLC25A18 在结直肠癌中具有预后价值，并通过 Wnt 信号传导抑制 Warburg 效应和细胞增殖
DOI：
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发表时间：
2020
影响因子：
5.3
通讯作者：
Tianshu Liu
中科院分区：
文献类型：
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作者：
Li Liang;Yanjie Chen;Yiyi Yu;Weiyu Pan;Yuehong Cui;Xiaojing Xu;Ke Peng;Mengling Liu;Khalid Rashid;Yingyong Hou;Tianshu Liu
结直肠癌（Colorectal cancer，CRC）是世界范围内常见的恶性肿瘤。溶质载体家族25成员18（SLC 25 A18）转运谷氨酸穿过线粒体内膜，并涉及一些非肿瘤疾病，但对其在恶性肿瘤中的作用知之甚少。本研究旨在探讨SLC 25 A18在结直肠癌中的作用及其机制。我们对癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）进行了生物信息学分析，以确定SLC 25 A18表达与临床病理特征的相关性。通过功能实验研究了SLC 25 A18在体内外上调或下调后对有氧糖酵解和细胞增殖的影响。对106例原发性或转移性结直肠癌患者的组织芯片进行SLC 25 A18免疫组化染色，以评估其预测和预后价值。SLC 25 A18在结直肠癌中表达较低，且与患者的分期、年龄和血清癌胚抗原水平呈负相关。SLC 25 A18的高表达表明手术后无病生存时间较长。SLC 25 A18的外源性过表达降低了葡萄糖消耗、乳酸产生、细胞内ATP浓度和细胞增殖，并废除了CTNNB 1、PKM 2、LDHA和MYC的表达。Wnt/β-连环蛋白的抑制恢复了SLC 25 A18抑制的细胞活性。SLC 25 A18在临床上预测了手术或药物治疗后较长的生存时间。这些结果表明，增加的SLC 25 A18表达通过Wnt/β-catenin级联抑制瓦尔堡效应和细胞增殖，并提示治疗后预后更好。
Colorectal cancer (CRC) is a common malignant tumor worldwide. The solute carrier family 25 member 18 (SLC25A18) transports glutamate across the inner mitochondrial membrane and involves some non-tumor dis- eases, yet little is known about its role in malignancy. Here, we studied the function and mechanism of SLC25A18 in CRC. We conducted a bioinformatic analysis of the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to identify the correlation of SLC25A18 expression with clinic-pathological characteristics. Function experiments were implemented to estimate the variation of aerobic glycolysis and cell proliferation due to in vitro and in vivo up- or down-regulation of SLC25A18. Immunohistochemical staining of SLC25A18 was performed on a tissue microarray of 106 patients with primary or metastatic CRC to evaluate its predictive and prognostic value. SLC25A18 expression was low in the CRC samples and was negatively correlated with stage, age and serum carci- noembryonic antigen levels. High expression of SLC25A18 indicated longer disease-free survival time after surgery. Exogenous overexpression of SLC25A18 decreased glucose consumption, lactate production, intracellular ATP con- centration and cell proliferation and abrogated expression of CTNNB1, PKM2, LDHA and MYC. Inhibition of Wnt/β- catenin restored SLC25A18-repressed cellular activities. SLC25A18 clinically predicted a longer survival time after surgery or medicine treatment. These results showed that increased SLC25A18 expression inhibits Warburg effect and cell proliferation via Wnt/β-catenin cascade, and suggest a better prognosis after treatment.