Interleukin-1 receptor-associated kinases (IRAK1, IRAK2, IRAK3 [IRAK-M], and IRAK4) are serine-threonine kinases involved in toll-like receptor and interleukin-1 signaling pathways, through which they regulate innate immunity and inflammation. Evidence exists that IRAKs play key roles in the pathophysiologies of cancers, and metabolic and inflammatory diseases, and that IRAK inhibition has potential therapeutic benefits. Molecules capable of selectively interfering with IRAK function and expression have been reported, paving the way for the clinical evaluation of IRAK inhibition. Herein, we focus on IRAK1, review its structure and physiological roles, and summarize emerging data for IRAK1 inhibitors in preclinical and clinical studies.

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Inhibition of interleukin-1 receptor-associated kinase 1 (IRAK1) as a therapeutic strategy.

Stem and progenitor cell alterations in myelodysplastic syndromes.

Frequent relapse and drug resistance in patients with hepatocellular carcinoma (HCC) can be attributed to the existence of tumor-initiating cells (TIC) within the tumor bulk. Therefore, targeting liver TICs may improve the prognosis of these patients. From transcriptome sequencing of 16 pairs of clinical HCC samples, we report that interleukin-1 receptor-associated kinase 1 (IRAK1) in the TLR/IRAK pathway is significantly upregulated in HCC. IRAK1 overexpression in HCC was further confirmed at the mRNA and protein levels and correlated with advanced tumor stages and poor patient survival. Interestingly, IRAK4, an upstream regulator of IRAK1, was also consistently upregulated. IRAK1 regulated liver TIC properties, including self-renewal, tumorigenicity, and liver TIC marker expression. IRAK1 inhibition sensitized HCC cells to doxorubicin and sorafenib treatment in vitro via suppression of the apoptotic cascade. Pharmacological inhibition of IRAK1 with a specific IRAK1/4 kinase inhibitor consistently suppressed liver TIC populations. We identified aldo-keto reductase family 1 member 10 (AKR1B10) as a novel downstream target of IRAK1, which was found to be overexpressed in HCC and significantly correlated with IRAK1 expression. Knockdown of AKR1B10 negated IRAK1-induced TIC functions via modulation of the AP-1 complex. Inhibition of IRAK1/4 inhibitor in combination with sorafenib synergistically suppressed tumor growth in an HCC xenograft model. In conclusion, targeting the IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway may be a potential therapeutic strategy against HCC.Significance: IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway regulates cancer stemness and drug resistance and may be a novel therapeutic target in HCC. Cancer Res; 78(9); 2332-42. ©2018 AACR.

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IRAK1 augments cancer stemness and drug resistance via the AP-1/AKR1B10 signaling cascade in hepatocellular carcinoma

Background IRAK1 has been repoted to play an essential role in the development of multiple cancers. However, the clinical significance of IRAK1 in hepatocellular carcinoma (HCC) and the underlying molecular mechanism remain unclear. Therefore, we aimed to investigate the role of IRAK1 in the pathogenesis of HCC in this study. Materials and methods HCC tissues and para-carcinoma tissues were collected for immunohistochemistry (IHC) analysis to evaluate IRAK1 expression. Data of IRAK1 expression were downloaded from the cancer genome atlas (TCGA) for analyzing the clinical significance of IRAK1. Receiver operating characteristic (ROC) curve and survival analyses were carried out to assess the diagnostic and prognostic significance of IRAK1 in IHC and TCGA data. Additionally, we investigated the alteration of IRAK1 gene in HCC from cBioPortal to generate a network of the interaction between IRAK1 and the neighboring genes. The influence of IRAK1 gene alteration on the prognosis of HCC patients was evaluated by survival analysis. Results Analysis of both IHC and TCGA data revealed a significant upregulation of IRAK1 in HCC tissues. The IHC analysis revealed there was an increasing trend in IRAK1 expression among normal liver tissues, liver cirrhosis tissues, para-carcinoma tissues and HCC tissues. The ROC curves for IHC and TCGA data demonstrated that IRAK1 exhibited a significant diagnostic value for HCC. Moreover, IRAK1 expression was observed to be associated with tumor size, metastasis and T-stage. The survival analysis indicated that the upregulation of IRAK1 predicted a worse overall survival of HCC. Additionally, data from cBioPortal confirmed that 29% of HCC tissues possessed an alteration of the IRAK1 gene. Conclusion IRAK1 may act as an oncogene in the development of HCC with its overexpression in HCC. Moreover, IRAK1 might serve as a promising diagnostic and therapeutic target for HCC.

Diagnostic and prognostic roles of IRAK1 in hepatocellular carcinoma tissues: an analysis of immunohistochemistry and RNA-sequencing data from the cancer genome atlas.

Introduction Interleukin-1 receptor-associated kinase 1 (IRAK1) was shown to contribute to a variety of cancer-related processes. However, the function of IRAK1 in hepatocellular carcinoma (HCC) pathogenesis has not been investigated in detail.
 Methods
 IRAK1 expression in HCC was examined by immunohistochemistry, qRT-PCR, and Western blot assays. In addition, Huh7 and Hep3B cells were transfected with IRAK1 siRNAs and/or a NOD-like receptor family pyrindomain containing 3 (NLRP3) plasmid. Western blot, EdU staining, and Transwell assays were performed to determine changes of apoptosis, proliferation, migration, and invasion in HCC cells. Moreover, changes in the expression of proteins involved in the MAPKs/NLRP3/IL-1β pathway were confirmed by Western blotting.
 Results
 IRAK1 was found to be highly upregulated in HCC tissues and cells. Knockdown of IRAK1 signaling prevented the proliferation, invasion, migration, epithelial–mesenchymal transition (EMT) of HCC cells. Mechanistically, we found that activation of the MAPKs/NLRP3/IL-1β pathway could be markedly suppressed by IRAK1 knockdown in HCC cells. Furthermore, our data showed that NLRP3 could partially reverse the reduced aggressive biological behaviors of HCC cells which were caused by RAK1 knockdown.
 Conclusion
 Knockdown of IRAK1 prevented HCC progression by inhibiting the ability of NLRP3 to block the MAPKs/IL-1β pathway, suggesting that approach as a strategy for treating HCC.

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Downregulation of IRAK1 Prevents the Malignant Behavior of Hepatocellular Carcinoma Cells by Blocking Activation of the MAPKs/NLRP3/IL-1β Pathway

Interleukin-1 receptor associated kinase 1 (IRAK1), as a down-stream of toll-like receptor (TLR) signaling, plays important roles in series of malignancies. However, the role of IRAK1 in hepatocellular carcinoma (HCC) remains little known. In our study, reverse transcription-PCR (RT-PCR), Western Blot, and immunohistochemical staining were used to assess the mRNA and protein levels of IRAK1 in clinical samples and cell lines. Cell counting assay and flow cytometry were employed to analyze the effect of IRAK1 on cell cycle and apoptosis. Transwell assay was used to study the role of IRAK1 in cell migration. Moreover, subcutaneous xenograft tumor models predict the efficacy of targeting IRAK1 against HCC in vivo. IRAK1 was over-expressed in HCC tissues and cell lines. Suppression of IRAK1 by small interference RNA (siRNA) or a pharmaceutical IRAK1/4 inhibitor impeded cell growth, induced apoptosis and lessened HCC xenograft tumor growth. Particularly, IRAK1/4 inhibitor treatment caused G1/S cell cycle arrest and apoptosis, confirming IRAK1 as a new therapeutic target for HCC. IRAK1 promotes cell proliferation and protects against apoptosis in HCC, and can be a novel target for HCC treatment.

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Targeting interleukin-1 receptor-associated kinase 1 for human hepatocellular carcinoma

The invention relates to application of water-soluble vitamin E in preparation of a medicine for treating liver cancer. The present invention discloses for the first time that a water-soluble vitaminE compound can inhibit the proliferation of liver cancer cells and inhibit formation of liver cancer. Therefore, the water-soluble vitamin E compound can be applied to the preparation of a healthcareproduct or a pharmaceutical composition for preventing and treating liver cancer.

Chen Yao

Papers

Targeting interleukin-1 receptor-associated kinase 1 for human hepatocellular carcinoma

Application of water-soluble vitamin E in preparation of medicine for treating liver cancer