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Theranostics 2017; 7(5):1114-1132. doi:10.7150/thno.18175 This issue Cite

Research Paper

The YAP1/SIX2 axis is required for DDX3-mediated tumor aggressiveness and cetuximab resistance in KRAS-wild-type colorectal cancer

De-Wei Wu1, Po-Lin Lin1, Lee Wang2, Chi-Chou Huang3, Huei Lee1✉

1. Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
2. Department of Public Health, Chung Shan Medical University, Taichung, Taiwan
3. Department of Surgery, Chung Shan Medical University, Taichung, Taiwan

✉ Corresponding author: Huei Lee, Ph. D., Professor, Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Room 5, 12th floor, F building, No. 3, Park Street, Nangang District 115, Taipei, Taiwan. Tel: 886-27361661 ext. 7 More

Citation:
Wu DW, Lin PL, Wang L, Huang CC, Lee H. The YAP1/SIX2 axis is required for DDX3-mediated tumor aggressiveness and cetuximab resistance in KRAS-wild-type colorectal cancer. Theranostics 2017; 7(5):1114-1132. doi:10.7150/thno.18175. https://www.thno.org/v07p1114.htm
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Abstract

Graphic abstract

The mechanism underlying tumor aggressiveness and cetuximab (CTX) resistance in KRAS-wild-type (KRAS -WT) colorectal cancer remains obscure. We here provide evidence that DDX3 promoted soft agar growth and invasiveness of KRAS-WT cells, as already confirmed in KRAS-mutated cells. Mechanistically, increased KRAS expression induced ROS production, which elevated HIF-1α and YAP1 expression. Increased HIF-1α persistently promoted DDX3 expression via a KRAS/ROS/HIF-1α feedback loop. DDX3-mediated aggressiveness and CTX resistance were regulated by the YAP1/SIX2 axis in KRAS-WT cells and further confirmed in animal models. Kaplan-Meier and Cox regression analysis indicated that DDX3, KRAS, and YAP1 expression had prognostic value for OS and RFS in KRAS-WT and KRAS-mutated tumors, but SIX2 and YAP1/SIX2 were prognostic value only in KRAS-WT patients. The observation from patients seemed to support the mechanistic action of cell and animal models. We therefore suggest that combining YAP1 inhibitors with CTX may therefore suppress DDX3-mediated tumor aggressiveness and enhance CTX sensitivity in KRAS-WT colorectal cancer.

Keywords: DDX3, YAP1, SIX2, KRAS, and colorectal cancer.

Citation styles

APA
Wu, D.W., Lin, P.L., Wang, L., Huang, C.C., Lee, H. (2017). The YAP1/SIX2 axis is required for DDX3-mediated tumor aggressiveness and cetuximab resistance in KRAS-wild-type colorectal cancer. Theranostics, 7(5), 1114-1132. https://doi.org/10.7150/thno.18175.

ACS
Wu, D.W.; Lin, P.L.; Wang, L.; Huang, C.C.; Lee, H. The YAP1/SIX2 axis is required for DDX3-mediated tumor aggressiveness and cetuximab resistance in KRAS-wild-type colorectal cancer. Theranostics 2017, 7 (5), 1114-1132. DOI: 10.7150/thno.18175.

NLM
Wu DW, Lin PL, Wang L, Huang CC, Lee H. The YAP1/SIX2 axis is required for DDX3-mediated tumor aggressiveness and cetuximab resistance in KRAS-wild-type colorectal cancer. Theranostics 2017; 7(5):1114-1132. doi:10.7150/thno.18175. https://www.thno.org/v07p1114.htm

CSE
Wu DW, Lin PL, Wang L, Huang CC, Lee H. 2017. The YAP1/SIX2 axis is required for DDX3-mediated tumor aggressiveness and cetuximab resistance in KRAS-wild-type colorectal cancer. Theranostics. 7(5):1114-1132.

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