CircPRKCA facilitates esophageal squamous cell carcinoma metastasis via m5C-dependent CSF2 mRNA stabilization.

Abstract

Background: Esophageal squamous cell carcinoma (ESCC) is a serious invasive malignancy with an ambiguous etiology. Evidence indicates that circular RNA (circRNA) is significantly involved in the regulatory processes associated with cancer development. Nevertheless, the specific molecular mechanisms through which circRNA facilitates the progression of ESCC are still largely undefined.

Methods: Here, we identified that the expression of hsa_circ_0007580 (designated circPRKCA) was markedly elevated in ESCC. Fluorescence in situ hybridization (FISH) was conducted to verify the expression, intracellular localization, and potential prognostic value of circPRKCA based on the tissue microarray. Gain- and loss-of-function assays were employed to investigate the effects of circPRKCA both in vitro and in vivo. RNA pull-down and mass spectrometry (MS) were performed to identify the proteins bound to circPRKCA. mRNA sequencing was conducted to screen the downstream target genes of circPRKCA. Furthermore, immunoprecipitation and methylated RNA immunoprecipitation (MeRIP) analysis were used to explore the regulatory mechanisms.

Results: We found that circPRKCA exhibited significant upregulation in ESCC tissues and correlated with unfavorable prognostic outcomes. Biological function experiments further confirmed that circPRKCA enhances the capabilities of migration, invasion, and angiogenesis in ESCC. Mechanistically, circPRKCA engages in interaction with Y-box binding protein 1 (YBX1) within the cytoplasmic milieu, consequently preventing the ubiquitination-mediated degradation of YBX1. Increased concentrations of YBX1 increase the stability of granulocyte-macrophage colony-stimulating factor (CSF2) mRNA in a 5-methylcytosine (m5C)-dependent manner. This process facilitates metastasis in ESCC.

Conclusion: In this research, we identified a correlation between circPRKCA and unfavorable prognoses in patients with ESCC. It is instrumental in the metastatic progression of ESCC via the YBX1/CSF2 signaling pathway. Consequently, targeting circPRKCA may represent a promising therapeutic strategy for ESCC.