DOCK6 promotes chemo- and radioresistance of gastric cancer by modulating WNT/β-catenin signaling and cancer stem cell traits.

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.