LRRN4 Upregulates the IL23A – JAK2 – STAT3 Signaling Axis and Drives Colorectal Cancer Metastasis

In colorectal cancer (CRC), metastasis drives fatalities, necessitating the discovery of therapeutic targets modulating its progression. Though the secreted protein-coding gene leucine-rich repeat neuronal 4 (LRRN4) was shown to be highly overexpressed in CRC and linked to decreased survival in the analysis of TCGA-CRC datasets, little is known about its function as well as mechanism in CRC metastasis. Thus, our work aimed to investigate LRRN4 functions and its role in CRC metastasis. We first confirmed that CRC metastasis was related to raised LRRN4 expression in CRC tissues. LRRN4 depletion using siRNA/shRNA inhibited CRC metastasis in vitro and in vivo, decreasing vimentin and increasing E-cadherin levels, whereas its overexpression yielded opposite effects. Mechanistically, LRRN4 promoted CRC metastasis by upregulating IL23A expression and triggering JAK2-STAT3 signaling, as evidenced by LRRN4 depletion-reduced IL23A expression and downstream JAK2-STAT3 activity; the STAT3 inhibitor and recombinant human IL23 protein rescued the promotion and inhibition of cell migration induced by LRRN4 overexpression and knockdown, respectively. Kaplan-Meier analysis and the K-independent samples nonparametric test revealed that the upregulated marker proportion was positively related to the likelihood of metastases, and people having raised IL23A and LRRN4 levels had the lowest survival. Finally, elevated LRRN4 expression in CRC tissues was correlated with promoter hypomethylation. Thus, LRRN4 is upregulated by promoter DNA hypomethylation, and the LRRN4-IL23A-JAK2-STAT3 axis is a critical driver of CRC metastasis, representing a promising therapeutic target and prognostic biomarker.