Liang Li, Chen Yanjie, Yu Yiyi, Pan Weiyu, Cui Yuehong, Xu Xiaojing, Peng Ke, Liu Mengling, Rashid Khalid, Hou Yingyong, Liu Tianshu
Department of Medical Oncology, Zhongshan Hospital of Fudan University NO. 180, Fenglin Road, Xuhui District, Shanghai 200032, China.
Department of Gastroenterology and Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University NO. 180, Fenglin Road, Xuhui District, Shanghai 200032, China.
Am J Cancer Res. 2020 May 1;10(5):1548-1567. eCollection 2020.
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 diseases, 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 and 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 carcinoembryonic 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 concentration 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.
结直肠癌（CRC）是全球常见的恶性肿瘤。溶质载体家族25成员18（SLC25A18）负责将谷氨酸转运穿过线粒体内膜，且与一些非肿瘤性疾病有关，但对其在恶性肿瘤中的作用知之甚少。在此，我们研究了SLC25A18在结直肠癌中的功能和机制。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SLC25A18表达与临床病理特征之间的相关性。开展功能实验以评估SLC25A18上调或下调导致的有氧糖酵解和细胞增殖变化。对106例原发性或转移性结直肠癌患者的组织芯片进行SLC25A18免疫组织化学染色，以评估其预测和预后价值。SLC25A18在结直肠癌样本中的表达较低，且与分期、年龄和血清癌胚抗原水平呈负相关。SLC25A18高表达表明术后无病生存期更长。SLC25A18的外源性过表达降低了葡萄糖消耗、乳酸生成、细胞内ATP浓度和细胞增殖，并消除了CTNNB1、PKM2、LDHA和MYC的表达。抑制Wnt/β-连环蛋白可恢复SLC25A18抑制的细胞活性。SLC25A18在临床上可预测手术或药物治疗后的生存期更长。这些结果表明，SLC25A18表达增加通过Wnt/β-连环蛋白级联反应抑制瓦伯格效应和细胞增殖，并提示治疗后预后较好。
