IRAK1 Augments Cancer Stemness and Drug Resistance via the AP-1/AKR1B10 Signaling Cascade in Hepatocellular Carcinoma

Cancer Research
Bowie Y ChengTerence Kin-Wah Lee

Abstract

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. Kn...Continue Reading

References

Jun 13, 1998·The Journal of Biological Chemistry·D CaoS S Chung
Jun 16, 2007·Gastroenterology·Stephanie MaXin-Yuan Guan
Jun 29, 2007·International Journal of Cancer. Journal International Du Cancer·Ruilan YanDeliang Cao
Jul 25, 2008·The New England Journal of Medicine·Josep M LlovetUNKNOWN SHARP Investigators Study Group
Jun 24, 2009·Digestive Diseases·Marcus Alexander WörnsPeter Robert Galle
Oct 9, 2012·Cancer Research·Ratika SrivastavaEduardo Davila
Dec 12, 2012·Nature Biotechnology·Cole TrapnellLior Pachter
Jan 22, 2013·CA: a Cancer Journal for Clinicians·Rebecca SiegelAhmedin Jemal
Jul 13, 2013·Cancer Cell·Garrett W RhyasenDaniel T Starczynowski
Jan 11, 2014·European Journal of Surgical Oncology : the Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology·H B YaoQ S Shao
Feb 14, 2014·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Terence Kin-Wah LeeIrene Oi Lin Ng
Jul 6, 2014·Liver International : Official Journal of the International Association for the Study of the Liver·Fatma E MohamedRajiv Jalan
Feb 3, 2015·The Journal of Clinical Investigation·Zhaoyang LiEduardo Davila
Apr 24, 2015·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Jessica LoTerence Kin Wah Lee
Jun 13, 2015·Oncotarget·Charles DussiauVahid Asnafi
Sep 14, 2016·Journal of Experimental & Clinical Cancer Research : CR·Ning LiHongyang Wang

❮ Previous
Next ❯

Citations

Apr 10, 2019·Cancers·Johanna K DiStefano, Bethany Davis
Apr 2, 2020·British Journal of Cancer·Yu-Man TsuiIrene Oi-Lin Ng
Sep 17, 2020·The Journal of Clinical Endocrinology and Metabolism·Jasna MetovicMauro Papotti
Oct 30, 2020·Frontiers in Cell and Developmental Biology·Juan Li, Ying Zhu
Jun 3, 2021·Metabolites·Satoshi EndoToru Nishinaka
Jun 8, 2021·Frontiers in Immunology·Yimei QueDengju Li
Sep 11, 2021·Nature Reviews. Gastroenterology & Hepatology·Terence Kin-Wah LeeStephanie Ma
Oct 8, 2021·Cancer Biotherapy & Radiopharmaceuticals·Wang-Yang YeYi-Wu Dang
Nov 8, 2021·Current Opinion in Hematology·Joshua Bennett, Daniel T Starczynowski

❮ Previous
Next ❯

Related Concepts

Related Feeds

Carcinoma, Hepatocellular

Hepatocellular Carcinoma is a malignant cancer in liver epithelial cells. Discover the latest research on Hepatocellular Carcinoma here.

Cancer -Omics

A variety of different high-throughput technologies can be used to identify the complete catalog of changes that characterize the molecular profile of cohorts of tumor samples. Discover the latest insights gained from cancer 'omics' in this feed.