Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.
Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan, Taiwan.
Oncogene. 2020 Sep;39(37):5933-5949. doi: 10.1038/s41388-020-01390-0. Epub 2020 Aug 4.
Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide and prognosis after potentially curative gastrectomy remains poor. Administration of GC-targeting molecules in combination with adjuvant chemo- or radiotherapy following surgical resection has been proposed as a potentially effective treatment option. Here, we have identified DOCK6, a guanine nucleotide exchange factor (GEF) for Rac1 and CDC42, as an independent biomarker for GC prognosis. Clinical findings indicate the positive correlation of higher DOCK6 expression with tumor size, depth of invasion, lymph node metastasis, vascular invasion, and pathological stage. Furthermore, elevated DOCK6 expression was significantly associated with shorter cumulative survival in both univariate and multivariate analyses. Gene ontology analysis of three independent clinical GC cohorts revealed significant involvement of DOCK6-correlated genes in the WNT/β-catenin signaling pathway. Ectopic expression of DOCK6 promoted GC cancer stem cell (CSC) characteristics and chemo- or radioresistance concomitantly through Rac1 activation. Conversely, depletion of DOCK6 suppressed CSC phenotypes and progression of GC, further demonstrating the pivotal role of DOCK6 in GC progression. Our results demonstrate a novel mechanistic link between DOCK6, Rac1, and β-catenin in GCCSC for the first time, supporting the utility of DOCK6 as an independent marker of GC.
胃癌（GC）是全球癌症相关死亡的第三大主要原因，手术后潜在可治愈的患者预后仍然较差。在手术切除后联合辅助化疗或放疗使用 GC 靶向分子已被提议作为一种潜在有效的治疗选择。在这里，我们鉴定了 DOCK6，一种 Rac1 和 CDC42 的鸟嘌呤核苷酸交换因子（GEF），作为 GC 预后的独立生物标志物。临床研究结果表明，DOCK6 表达较高与肿瘤大小、浸润深度、淋巴结转移、血管侵犯和病理分期呈正相关。此外，在单因素和多因素分析中，升高的 DOCK6 表达与累积生存率明显缩短显著相关。对三个独立的临床 GC 队列的基因本体分析表明，DOCK6 相关基因显著参与 WNT/β-catenin 信号通路。DOCK6 的异位表达通过 Rac1 的激活同时促进 GC 癌症干细胞（CSC）特征和化疗或放疗耐药性。相反，DOCK6 的耗竭抑制了 GC 的 CSC 表型和进展，进一步证明了 DOCK6 在 GC 进展中的关键作用。我们的研究结果首次证明了 DOCK6、Rac1 和 GCCSC 中 β-catenin 之间的新的机制联系，支持 DOCK6 作为 GC 的独立标志物的效用。
