Abstract
The four R-spondins (RSPO1–4) and their three related receptors LGR4, 5 and 6 (LGR4–6) have emerged as a major ligand-receptor system with critical roles in development and stem cell survival through modulation of Wnt signaling. Recurrent, gain-of-expression gene fusions of RSPO2 (to EIF3E) and RSPO3 (to PTPRK) occur in a subset of human colorectal cancer. However, the exact roles and mechanisms of the RSPO-LGR system in oncogenesis remain largely unknown. We found that RSPO3 is aberrantly expressed at high levels in approximately half of Keap1-mutated lung adenocarcinomas (ADs). This high RSPO3 expression is driven by a combination of demethylation of its own promoter region and deficiency in Keap1 instead of gene fusion as in colon cancer. Patients with RSPO3-high tumors (~9%, 36/412) displayed much poorer survival than the rest of the cohort (median survival of 28 vs 163 months, log-rank test P<0.0001). Knockdown (KD) of RSPO3, LGR4 or their signaling mediator IQGAP1 in lung cancer cell lines with Keap1 deficiency and high RSPO3-LGR4 expression led to reduction in cell proliferation and migration in vitro, and KD of LGR4 or IQGAP1 resulted in decrease in tumor growth and metastasis in vivo. These findings suggest that aberrant RSPO3-LGR4 signaling potentially acts as a driving mechanism in the aggressiveness of Keap1-deficient lung ADs.
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Acknowledgements
We thank TCGA for generating the genomics data, collecting the clinical information and making them available for analysis. We also thank cBioportal for providing data analysis and visualization tools and downloading capability. We thank Dr B Fang at the University of Texas MD Anderson Cancer for the cell lines A549, H460 and H2009 cells. This work was supported in part by the Cancer Prevention and Research Institute of Texas (CPRIT, RP100678), the US National Institute of Health-NIH (R01GM102485), the Texas Emerging Technology Fund and the Janice D. Gordon endowment for bowel cancer research (to QJL), by NIH (R00LM009837, TL1TR000371) and CPRIT (R1006; to JTC) and by the Texas Emerging Technology Fund (to ZA).
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Gong, X., Yi, J., Carmon, K. et al. Aberrant RSPO3-LGR4 signaling in Keap1-deficient lung adenocarcinomas promotes tumor aggressiveness. Oncogene 34, 4692–4701 (2015). https://doi.org/10.1038/onc.2014.417
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DOI: https://doi.org/10.1038/onc.2014.417
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