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Usage Information

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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Usage data is cumulative from December 2022 through December 2023.

Usage JCI PMC
Text version 474 224
PDF 84 65
Figure 294 2
Supplemental data 25 4
Citation downloads 19 0
Totals 896 295
Total Views 1,191

Usage information is collected from two different sources: this site (JCI) and Pubmed Central (PMC). JCI information (compiled daily) shows human readership based on methods we employ to screen out robotic usage. PMC information (aggregated monthly) is also similarly screened of robotic usage.

Various methods are used to distinguish robotic usage. For example, Google automatically scans articles to add to its search index and identifies itself as robotic; other services might not clearly identify themselves as robotic, or they are new or unknown as robotic. Because this activity can be misinterpreted as human readership, data may be re-processed periodically to reflect an improved understanding of robotic activity. Because of these factors, readers should consider usage information illustrative but subject to change.

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