Lymph node metastasis-related circHELQ promotes progression and acts as a nanotherapeutic target in colorectal cancer.

Abstract

Introduction: Studies have highlighted the important roles of circRNAs in various cancers. However, their specific functions in the lymph node metastasis (LNM) of colorectal cancer (CRC) remain largely unclear.

Methods: The Arraystar human circRNA microarray was used to identify circular RNAs (circRNAs) associated with LNM in colorectal cancer (CRC). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to measure circHELQ expression in CRC cell lines and tissue specimens. A series of in vitro and in vivo functional assays were subsequently conducted to investigate the role of circHELQ in LNM and CRC progression. Additionally, fluorescence in situ hybridization, dual-luciferase reporter assays, RNA pull-down, and Western blot experiments were carried out to elucidate the underlying regulatory mechanisms of circHELQ in CRC.

Results: Our results demonstrated that circHELQ expression was significantly upregulated in CRC and that its expression level was closely correlated with LNM. Gain- and loss-of-function experiments revealed that circHELQ promotes CRC progression and metastasis-including proliferation, migration, invasion, lymphatic vessel formation, and LNM-both in vitro and in vivo. Mechanistically, circHELQ acts as a competing endogenous RNA (ceRNA) that sponges miR-4793-3p, thereby alleviating its suppression of VEGFC. This circHELQ/miR-4793-3p/VEGFC axis drives LNM in CRC by upregulating VEGFC expression. Furthermore, we developed a cancer cell membrane-based siRNA delivery system (cMDS) targeting circHELQ, and these nanoparticles effectively suppressed CRC proliferation and LNM.

Conclusions: CircHELQ drives CRC progression and LNM and is a candidate prognostic biomarker. Furthermore, its molecular function renders it a viable target for nanoparticle-based therapeutic strategies against CRC.