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IRAK4 mediates colitis-induced tumorigenesis and chemoresistance in colorectal cancer
Qiong Li, … , Ryan C. Fields, Kian-Huat Lim
Qiong Li, … , Ryan C. Fields, Kian-Huat Lim
Published September 17, 2019
Citation Information: JCI Insight. 2019;4(19):e130867. https://doi.org/10.1172/jci.insight.130867.
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Research Article Oncology Therapeutics

IRAK4 mediates colitis-induced tumorigenesis and chemoresistance in colorectal cancer

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Abstract

Aberrant activation of the NF-κB transcription factors underlies chemoresistance in various cancer types, including colorectal cancer (CRC). Targeting the activating mechanisms, particularly with inhibitors to the upstream IκB kinase (IKK) complex, is a promising strategy to augment the effect of chemotherapy. However, clinical success has been limited, largely because of low specificity and toxicities of tested compounds. In solid cancers, the IKKs are driven predominantly by the Toll-like receptor (TLR)/IL-1 receptor family members, which signal through the IL-1 receptor–associated kinases (IRAKs), with isoform 4 (IRAK4) being the most critical. The pathogenic role and therapeutic value of IRAK4 in CRC have not been investigated. We found that IRAK4 inhibition significantly abrogates colitis-induced neoplasm in APCMin/+ mice, and bone marrow transplant experiments showed an essential role of IRAK4 in immune cells during neoplastic progression. Chemotherapy significantly enhances IRAK4 and NF-κB activity in CRC cells through upregulating TLR9 expression, which can in turn be suppressed by IRAK4 and IKK inhibitors, suggesting a feed-forward pathway that protects CRC cells from chemotherapy. Lastly, increased tumor phospho-IRAK4 staining or IRAK4 mRNA expression is associated with significantly worse survival in CRC patients. Our results support targeting IRAK4 to improve the effects of chemotherapy and outcomes in CRC.

Authors

Qiong Li, Yali Chen, Daoxiang Zhang, Julie Grossman, Lin Li, Namrata Khurana, Hongmei Jiang, Patrick M. Grierson, John Herndon, David G. DeNardo, Grant A. Challen, Jingxia Liu, Marianna B. Ruzinova, Ryan C. Fields, Kian-Huat Lim

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Figure 8

Prognostic impact of IRAK activation or expression in colon cancer.

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Prognostic impact of IRAK activation or expression in colon cancer.
(A) ...
(A) Representative IHC images showing different intensities of p-IRAK4 staining as determined by H score from 2 commercial colon cancer TMAs (US Biomax BC051110b, HCol-Ade180Sur-08) (scale bars: 100 μm). (B–D) The overall survival (OS) by Kaplan-Meier analysis of patients with different stages of colon cancer as stratified by the H score of p-IRAK4 staining of 2 commercial colon cancer TMAs (US Biomax BC051110b, HCol-Ade180Sur-08). (E) Overall survival by Kaplan-Meier analysis of stage IIb–III colon cancer patients as stratified by the IRAK4 mRNA expression (Z score cutoff at 0.5) from TCGA (provisional) database. (F) Correlation (Wilcoxon signed-rank test) of p-IRAK4 IHC staining intensity between matched primary and liver metastatic CRC samples from a cohort of 32 patients who underwent surgery at Washington University from years 2000 to 2010. (G) Representative IHC images showing different intensities of p-IRAK4 IHC staining in liver metastasis samples, and Kaplan-Meier overall survival, as stratified by p-IRAK4 H score from a cohort of 204 patients who underwent liver resection surgery at Washington University from years 2000 to 2010.

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