The Mechanism and Significance of Dysregulated Dock6 in Wnt/Β-Catenin Associated Chemo- and Radio-Resistance and Progression of Cancers

Gastric cancer (GC) was recorded as the third leading cause of cancer-related deaths worldwide, and overall and recurrent survival after potentially curative gastrectomy for advanced gastric cancer remains poor. Thus, developing the GC targeting molecules in combination with adjuvant radiotherapy, or adjuvant chemotherapy following surgical resection is an important trend for GC treatment. Dedicator of cytokinesis (DOCK) represents a protein family belonging to atypical Rho guanine nucleotide exchange factors (GEF) for Rac and/or Cdc42 GTPases. DOCK6, a member of the Dock-C subfamily, exchanges GDP for GTP for Rac1 and Cdc42, both in vitro and in vivo. At present, little is known about the potential activity of DOCK6 in cancer progression and CSC development. Here, we identified DOCK6 as an independent biomarker for GC prognosis. The clinical findings indicated that higher DOCK6 expression is positively correlated with tumor size, depth of invasion, lymph node metastasis, vascular invasion and pathological stage. Elevated DOCK6 expression was associated with significantly shorter cumulative survival in both univariate and multivariate analyses. To establish the downstream effectors of DOCK6, we analyzed thousands of genes in relation to DOCK6 expression from three GC datasets published in the literature. Genes displaying a positive correlation with DOCK6 were subsequently analyzed using Metacore and shown to be significantly involved in the WNT/β-catenin signaling pathway. This finding suggested that DOCK6 may act as a tumor promoter through WNT/β-catenin activation. To confirm the role of DOCK6, its effect on tumor progression and recurrence following chemotherapy and radiotherapy will be examined in nude mice. In the current proposal, we will examine the potential role of DOCK6 and its regulatory mechanism during cancer progression and recurrence following chemotherapy and radiotherapy. Five aims are proposed on the basis of the preliminary results or clinical analysis. Aim 1: To study the effects of WNT signal on DOCK6 expression, and DOCK6 induces WNT/β-catenin activation. Aim 2: To determine the DOCK6-regulated/associated genes and its downstream signaling. Aim 3: To study whether DOCK6 is associated with cancer stemness and chemo- and radio-resistance. Aim 4: To study whether DOCK6 is associated with radiation driven EMT. Aim 5: To determine the expression levels of DOCK6 associated/regulated genes in clinical specimens. Specific Aim 6: To identify and characterize small compounds targeting to DOCK6 induced WNT/β-catenin activation and chemo- and radio-resistance.The significance of the proposal: 1) it will offer an opportunity to identify the new function of DOCK6 in cancer progression and recurrence and 2) it will provide a strategy to explore the oncogenic mechanism of DOCK6 in gastric cancer. Finally, the novel molecular mechanisms and potential of therapeutic application targeting to WNT/β-catenin and DOCK6 in gastric cancer progression and recurrence will be established.

Project ID:PC10708-1106
External Project ID:MOST107-2320-B182-025