Study summary · research use only
CircROR1 binds HNRNPL to regulate FOXO4 pre-mRNA splicing, promoting cutaneous melanoma metastasis and serving as a therapeutic target via RNAi-loaded PEG-LNPs
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
In this study (cutaneous melanoma cell lines and xenograft models; species not specified), the authors examined the circular RNA circROR1. CircROR1 levels were reported to correlate positively with HNRNPL levels and tumor metastasis, and negatively with FOXO4 protein levels. CircROR1 upregulation was associated with increased markers of epithelial-mesenchymal transition, cell migration, and invasion, and with reduced PD-L1 expression alongside resistance to PD-L1-antibody therapy in melanoma cells. CircROR1 was reported to recruit HNRNPL, altering its nuclear translocation and preventing intron retention in FOXO4 mRNA, with increased FOXO4α expression counteracting circROR1's effects on metastatic behaviors. A nanoparticle formulation, FA-PEG(si-circ), delivering siRNA against circROR1 was associated with reduced lung colonization by melanoma cells in vivo. The authors describe circROR1 as a candidate target for further nanotherapy research.
Abstract
BACKGROUND: Circular RNAs (circRNAs) contribute to gene expression regulation by interacting with splicing factors, a process that is often disrupted in cancers such as cutaneous melanoma (CM). METHODS: A circRNA microarray analysis was performed to identify differentially expressed circRNAs. qRT‒PCR was conducted to confirm the expression of circROR1. CCK-8, colony formation, wound healing, and transwell assays were used to analyze proliferation, metastasis and apoptosis in CM cells. Xenograft models and IHC experiments were established to confirm the effects of circROR1 on tumor growth and metastasis in vivo. RNA sequencing and pull-down–MS experiments were performed to identify the mechanisms downstream of circROR1. Nuclear and cytoplasmic fractionation, along with FISH experiments, were conducted to determine the cellular localization of circROR1. To target circROR1 for CM treatment, we used a microfluidic strategy to develop FA-PEG(si-circ) nanoparticles for efficient siRNA delivery. RESULTS: In CM samples, circROR1 levels were positively correlated with HNRNPL levels and tumor metastasis but negatively correlated with FOXO4 protein levels. CircROR1 was prevalent in CM, and its upregulation increased the levels of factors involved in epithelial–mesenchymal transition, cell migration, and invasion. CircROR1 overexpression conferred resistance to PD-L1-antibody therapy in CM cells by downregulating PD-L1 expression. CircROR1 recruited HNRNPL, influencing its nuclear translocation, and further prevented intron retention in FOXO4 mRNA. In HNRNPL-overexpressing CM cells, circROR1 upregulation inhibited FOXO4α expression and promoted FOXO4ζ expression. Increased FOXO4α expression counteracted circROR1’s effects and suppressed metastatic behaviors. FA-PEG(si-circ) enhanced siRNA stability and efficiency, reducing CM cell lung colonization in vivo. CONCLUSION: This study identified circROR1 as an oncogenic circular RNA that plays a crucial role in tumor progression and metastasis. CircROR1-targeted nanotherapy is a promising option for the treatment of metastatic cancer.
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