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

Abstract

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

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Fig. 1: DOCK6 overexpression in human GC is correlated with patient prognosis.
Fig. 2: DOCK6 depletion suppresses proliferation and Matrigel invasion of GC cells.
Fig. 3: Overexpression of DOCK6 promotes GC progression, chemo- and radioresistance, and GC stemness.
Fig. 4: Silencing of DOCK6 suppresses cancer progression and chemo- and radioresistance via inhibiting GC stemness.
Fig. 5: DOCK6 activates Rac1 and concomitant WNT/β-catenin signaling to promote GC proliferation, Matrigel invasion, and chemo- and radioresistance.
Fig. 6: DOCK6 exerts its GEF activity to activate Rac1 and promoting aggressive properties of GC.

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Acknowledgements

This work was supported by grants from Chang Gung Memorial Hospital, Taoyuan, Taiwan (CMRPD1H0631-0632, CMRPD1G0421-0423, CMRPD1J0051, NMRPD1G0942, and NMRPD1G0951 to K-HL; CMRPG6F0621-0623 and NMRPG6G0051 to C-SW) and the Ministry of Science and Technology of the Republic of China (MOST 106-2320-B-182-031-MY3 and 106-2320-B-182-032-MY3 to K-HL, 106-2314-B-182A-130 to C-SW, and MOST 105-2321-B-182 -002-MY3 and 107-2320-B-182-025 to H-CC).

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Study concept and design acquisition of data: H-CC, C-YT, H-YY, L-HW, W-JC, C-SW, and K-HL. Analysis and interpretation of data: H-CC, C-YT, H-YY, C-HL, W-JW, K-FL, L-YL, J-HH, Y-FC, M-MT, C-TY, and CHW. Drafting of the manuscript: H-CC, C-YT, and H-YY. Critical revision of the manuscript for important intellectual content: C-HL, W-JW, Y-FC, CHW, C-CH, and L-HW. Review and editing: C-TY, C-CH, L-HW, W-JC, C-SW, and K-HL. Obtained funding: H-CC, C-CH, W-JC, C-SW, and K-HL. Technical and material support: J-HH, C-TY, CHW, C-CH, and L-HW.

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Correspondence to Lu-Hai Wang, Wei-Jan Chen or Kwang-Huei Lin.

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Chi, HC., Tsai, CY., Wang, CS. et al. DOCK6 promotes chemo- and radioresistance of gastric cancer by modulating WNT/β-catenin signaling and cancer stem cell traits. Oncogene 39, 5933–5949 (2020). https://doi.org/10.1038/s41388-020-01390-0

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