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( Nicole Pui Yu Ho ),( Bowie Lik Ling Cheng ),( Irene Oi Lin Ng ),( Terence Kin Wah Lee ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1
Aims: Frequent relapse and drug resistance may be attributed to the existence of tumor-initiating cells (T-ICs) in hepatocellular carcinoma (HCC). We investigated the functional role and clinical significance of Interleukin-receptor associated kinase 1 (IRAK1) in regulation of liver tumor-initiating cells (T-ICs) and sorafenib resistance, aiming to develop a novel therapeutic strategy against HCC. Methods: We evaluated the clinic-pathological relevance of IRAK1 in HCC clinical samples by qPCR and immunohistochemical analyses. Lentiviral-based overexpression and knockdown approaches were performed to characterize functional roles of IRAK1 in regulation of liver T-ICs and sorafenib resistance. Molecular pathways mediating the phenotypic alterations was identified through RNA sequencing analysis and functional rescue experiments. The combinatorial effect of IRAK1/4 inhibitor and sorafenib was tested in vivo. Results: From transcriptome sequencing, we identified IRAK1 in TLR/IRAK pathway to be significantly upregulated in HCC. IRAK1 overexpression in HCC was further confirmed at mRNA and protein levels, and correlated with larger tumor size. Interestingly, IRAK4, an upstream regulator of IRAK1, was also found to be consistently upregulated. Through lentiviral based knockdown and overexpression approaches, we demonstrated that IRAK1 regulates traits of liver T-ICs. Similar phenotypic effects were observed when HCC cells were treated with IRAK1/4 inhibitor. Through RNA sequencing analysis by comparing expression profiles between sh-IRAK1 and control cells, we identified Aldo-Keto Reductase Family 1, Member 10 (AKR1B10) as a downstream target of IRAK1. AKR1B10 was found to be overexpressed in HCC, and correlated with IRAK1 expression. Functional analysis demonstrated that knockdown of AKR1B10 offset the IRAK1 induced T-IC functions through regulating AP-1 complex. Using HCC xenograft model, we found that IRAK1/4 inhibitor in combination with sorafenib demonstrated a maximal tumor suppressive effect. Conclusions: IRAK1/AP-1/AKR1B10 signaling cascade regulates liver T-ICs and sorafenib sensitivity. Targeting IRAK1 alone or in combination with sorafenib might be a novel strategy against HCC.