Overexpression of GDP dissociation inhibitor 1 gene associates with the invasiveness and poor outcomes of colorectal cancer

GDP dissociation inhibitor (<i>GDI)</i> regulates the GDP/GTP exchange reaction of most Rab proteins by inhibiting GDP dissociation. This study evaluated the potential prognostic and predictive value of <i>GDI1</i> in colorectal cancer (CRC). To address the prognostic power of <i>GDI1</i>, we performed individual and pooled survival analyses on six independent CRC microarray gene expression datasets. <i>GDI1</i>-enriched signatures were also analyzed. Kaplan–Meier and Cox proportional analyses were employed for survival analysis. An immunohistochemistry (IHC) analysis was performed to validate the clinical relevance and prognostic significance of the GDI1 protein level in CRC tissue samples. The results revealed that <i>GDI1</i> mRNA level was significantly linked with the aggressiveness of CRC, which is compatible with gene set enrichment analysis. A meta-analysis and pooled analysis demonstrated that a higher mRNA <i>GDI1</i> expression was dramatically correlated with a worse survival in a dose-dependent manner in CRC patients. Further IHC analysis validated that the protein expression of GDI1 in both cytoplasm and membrane also significantly impacted the outcome of CRC patients. In CRC patients with stage III, chemotherapy significantly reduced the relative risk of death in low-<i>GDI1</i> subgroup (hazard ratio (HR) = 0.22; 95% confidence interval (95% CI) 0.09–0.56, <i>p</i> = 0.0003), but not in high-<i>GDI1</i> subgroup (HR = 0.63; 95% CI 0.35–1.14, <i>p</i> = 0.1137). Therefore, both high mRNA and protein levels of GDI1 were significantly related to poor outcomes in CRC patients. <i>GD11</i> may serve as a prognostic biomarker for CRC.

GDP解离抑制蛋白（GDP dissociation inhibitor，GDI）可通过抑制GDP解离，调控绝大多数Rab蛋白的GDP/GTP交换反应。本研究评估了结直肠癌（colorectal cancer，CRC）中GDI1潜在的预后及预测价值。为探究GDI1的预后效能，我们对6项独立的CRC基因表达微阵列数据集开展了单因素及合并生存分析，并对GDI1富集的基因特征进行了分析。生存分析采用卡普兰-迈耶法与考克斯比例风险分析。本研究同时实施了免疫组化（immunohistochemistry，IHC）分析，以验证GDI1蛋白水平在CRC组织样本中的临床相关性与预后意义。研究结果显示，GDI1的mRNA表达水平与CRC的侵袭性显著相关，该结论与基因集富集分析结果一致。荟萃分析与合并分析表明，在CRC患者中，GDI1 mRNA的高表达与不良生存结局呈显著的剂量依赖性关联。进一步的IHC分析证实，GDI1蛋白在细胞质与细胞膜中的表达均对CRC患者的预后产生显著影响。在Ⅲ期CRC患者中，化疗可显著降低低GDI1亚组患者的死亡相对风险（风险比（hazard ratio，HR）=0.22；95%置信区间（95% CI）0.09~0.56，p=0.0003），但对高GDI1亚组患者无明显获益（HR=0.63；95% CI 0.35~1.14，p=0.1137）。综上，GDI1的mRNA与蛋白高表达均与CRC患者的不良预后显著相关，GDI1可作为CRC的预后生物标志物。