Abstract
Background: Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers. The two major lethal causes of ESCC are diagnosis at an advanced stage and lymph node metastasis (LNM). Circular RNAs (circRNAs) play critical regulatory roles in cancer progression, though, largely through unclear mechanisms. However, the character of circRNAs in the malignant progression of ESCC remains unclear. Methods: The circRNA microarray was used to explore the circRNAs that were differentially expressed between ESCC and paired adjacent normal tissues. The function of circIMMP2L was validated by gain or loss of function assays. Pull-down, RNA immunoprecipitation assays were used to demonstrate the biological mechanism of circIMMP2L. Tissue microarray (TMA), specimen, and paired plasma were investigated to evaluate the clinical significance of circIMMP2L. Results: CircIMMP2L, commonly upregulated in tumor and plasma from advanced-stage ESCC patients and LNM patients, predicts poorer patient survival. CircIMMP2L was also found to be a significant indicator for LNM, even in the T1 stage of ESCC. CircIMMP2L depletion suppressed the malignant progression of ESCC both in vitro and in vivo. Mechanistically, cytoplasmic circIMMP2L interacted with CtBP1 and facilitated the nuclear retention of CtBP1 in a CtBP2-independent manner. Moreover, circIMMP2L promoted the interaction of CtBP1 with HDAC1 in the nucleus, which is essential for epigenetic remodeling and transcriptional suppression of E-cadherin and p21. Conclusions: These findings demonstrated that circIMMP2L promotes the malignant progression of ESCC mediated by CtBP1 nuclear retention and is a robust biomarker for the diagnosis, prognosis, and LNM in ESCC. Further, the findings extend our knowledge about the mechanism of circRNA regulation of gene transcription through epigenetics.