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

Oncogene volume 39, pages 5933–5949 (2020)Cite this article

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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).

Author information

Author notes

  1. These authors contributed equally: Hsiang-Cheng Chi, Chung-Ying Tsai, Chia-Siu Wang, Huang-Yu Yang, Lu-Hai Wang, Wei-Jan Chen, Kwang-Huei Lin

Authors and Affiliations

  1. Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan

    Hsiang-Cheng Chi

  2. Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan, Taiwan

    Hsiang-Cheng Chi, Cheng Heng Wu & Kwang-Huei Lin

  3. Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan

    Hsiang-Cheng Chi & Lu-Hai Wang

  4. Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Chung-Ying Tsai

  5. Department of General Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan

    Chia-Siu Wang, Ming-Ming Tsai & Ching-Chuan Hsieh

  6. Kidney Research Institute, Nephrology Department, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan

    Huang-Yu Yang

  7. Graduate Institute of Biomedical Sciences, College of Medicine, Chang-Gung University, Taoyuan, Taiwan

    Huang-Yu Yang & Yen-Fang Chang

  8. Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Huang-Yu Yang

  9. Institute of Biochemistry and Molecular Biology, College of Life Science, National Yang-Ming University, Taipei, Taiwan

    Chien-Hui Lo & Won-Jing Wang

  10. Taiwan International Graduate Program (TIGP) in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan

    Chien-Hui Lo & Won-Jing Wang

  11. Department of Pathology, Chang Gung Memorial Hospital, Chiayi, Taiwan

    Kam-Fai Lee

  12. Department of Microbiology and Internal Medicine, National Taiwan University, Taipei, Taiwan

    Li-Yin Lai

  13. Department of Radiation Oncology, Institute for Radiological Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan

    Ji-Hong Hong

  14. Department of Nursing, Chang Gung University of Science and Technology, Taoyuan, Taiwan

    Ming-Ming Tsai

  15. Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan

    Ming-Ming Tsai & Kwang-Huei Lin

  16. Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan

    Chau-Ting Yeh & Kwang-Huei Lin

  17. Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan

    Lu-Hai Wang

  18. Division of Cardiology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

    Wei-Jan Chen

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Contributions

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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