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

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.

A double-edged function of DDX3, as an oncogene or tumor suppressor, in cancer progression (Review)

“…ROS generation by DDX3-mediated KRAS expression promotes YAP1 transcription through increasing HIF-1α bound to YAP1 promoter. Finally the YAP1/SIX2 axis results in the DDX3-induced cell invasiveness (39).…”

“…In contrast, several groups obtain different conclusions of the role of DDX3 in colorectal cancer (37)(38)(39)(40). In KRAS-mutated colon cancer cells, DDX3 promotes cell invasion and the nodule formation of xenograft lung tumor due to β-catenin/TCF activation through the CK1ε/Dvl2 axis (37).…”

“…Accordingly, the colorectal tumor growth and metastasis mediated by KRAS gene mutations seem to require β-catenin/TCF activation by DDX3. While in KRAS-wild-type colorectal cancer, DDX3 promotes cell aggressiveness through the KRAS/HIF-1α/YAP1/SIX2 cascade (39). Inhibition of DDX3 by a small inhibitor RK-33 reduces cell proliferation and causes a G1 arrest in colorectal cancer cells (40).…”

“…Inhibition of DDX3 by a small inhibitor RK-33 reduces cell proliferation and causes a G1 arrest in colorectal cancer cells (40). In addition, a high DDX3 expression leads to poor clinical overall survival (OS) for colorectal cancer patients (37)(38)(39)(40).…”

Prognostic and clinicopathological significance of YAP in Colorectal carcinoma: A systematic review and meta-analysis

“…We excluded 941 articles after screening the titles and abstracts. Then we included 12 studies after reviewing 43 Full-text articles in detail [9][10][11][12][13][14][15][16][17][18][19][20]. A owchart of the retrieval process is shown in Fig.1.…”