RAC1 is essential for WNT-driven expansion and transformation of LGR5+ intestinal stem cells.
Major finding: RAC1 is essential for WNT-driven expansion and transformation of LGR5+ intestinal stem cells.
Mechanism: RAC1-mediated ROS production and NF-κB activity drive stem cell proliferation and tumor growth.
Impact: Inhibition of RAC1 or its downstream pathways may suppress early colorectal cancer growth.
Inactivation of the tumor suppressor adenomatous polyposis coli (APC) is an early event in colorectal tumorigenesis and results in constitutive WNT/β-catenin signaling. Although MYC has been shown to be an essential mediator of WNT signaling in colorectal cancer, targeted MYC inhibitors have not yet been developed, emphasizing the need to identify additional downstream WNT effectors. Recent studies have shown that guanine nucleotide exchange factors (GEF) for the GTPase RAC1 are upregulated upon Apc loss, suggesting that RAC1 activation may promote WNT-driven colorectal cancer growth. Myant and colleagues found that levels of RAC1–GTP were increased in Apc-deficient murine intestines and were correlated with elevated expression of RAC GEFs and MYC in primary human colorectal cancer samples. Genetic deletion of Rac1 decreased intestinal progenitor cell hyperproliferation and suppressed the expansion of leucine-rich repeat containing G protein-coupled receptor 5-positive (LGR5+) intestinal stem cells (ISC) in Apc-null crypts. Furthermore, Rac1 deletion in the context of Apcloss significantly impaired intestinal and colonic adenoma formation and prevented KRAS-mutant tumor growth, consistent with a requirement for RAC1 in WNT-induced transformation and colorectal cancer tumor initiation. The protumorigenic effect of RAC1 was independent of changes in β-catenin nuclear localization and was mediated by enhanced RAC1/NADPH oxidase-stimulated production of reactive oxygen species (ROS) in LGR5+ ISCs and activation of NF-κB signaling upon Apc loss. Induction of ROS or constitutive NF-κB activation partially rescued the proliferation defect in Apc/Rac1-deficient intestinal crypts, whereas inhibition of intracellular ROS accumulation reduced ISC gene expression, diminished intestinal epithelial cell proliferation, and prolonged tumor-free survival in Apc-null mice. These findings identify RAC1 as a critical regulator of the tumor-initiating potential of ISCs downstream of WNT and MYC activation and suggest that RAC1 may be an effective therapeutic target in patients with early-stage colorectal cancer.
Myant KB, Cammareri P, McGhee EJ, Ridgway RA, Huels DJ, Cordero JB, et al. ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. Cell Stem Cell 2013;12:761–73.
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