Dataset Information

CircIMMP2L promotes esophageal squamous cell carcinoma malignant progression via CtBP1 nuclear retention dependent epigenetic modification.

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.

SUBMITTER: Liang Y

PROVIDER: S-EPMC8473481 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The aim of the present study was to examine the function of transgelin (TAGLN) and its underlying mechanism in the ferroptosis of esophageal squamous cell carcinoma (ESCC) cells. To meet this aim, the association between TAGLN expression and the prognosis of patients with ESCC was determined using tissue samples and clinical data. Gene Expression Omnibus databank and Gene Set Enrichment Analysis data were used to examine which genes were co‑expressed with TAGLN, as well as the influence of TAGLN on ESCC. Subsequently, Transwell chamber, wound healing, Cell Counting Kit‑8 viability and colony formation assays were performed to observe the effects of TAGLN on the migration, invasion, viability and proliferation of Eca‑109 and KYSE‑150 cells. The interaction between TAGLN and p53 in the regulation of ferroptosis was detected using reverse transcription‑quantitative PCR, co‑immunoprecipitation and fluorescence co‑localization assays, and a xenograft tumor model was established to examine the effect of TAGLN on tumor growth. The level of TAGLN expression in patients with ESCC was found to be low, compared with normal esophageal tissue, and a positive association was identified between the prognosis of ESCC and TAGLN expression. The expression of the ferroptosis marker protein, glutathione peroxidase 4, was found to be high, whereas that of acyl‑CoA synthetase long‑chain family member 4 was lower in patients with ESCC compared with expression levels in healthy patients. The overexpression of TAGLN resulted in a significant decrease in the invasive and proliferative capabilities of Eca‑109 and KYSE‑150 cells in vitro compared with the control group; in vivo, TAGLN overexpression was found to significantly decrease tumor size, volume and weight after one month of growth. In addition, the proliferation, migration and invasion of Eca‑109 cells in vivo was stimulated by the knockdown of TAGLN. The results of the transcriptome analysis further demonstrated that TAGLN was able to induce ferroptosis‑associated cell functions and pathways. Finally, TAGLN overexpression was found to promote ferroptosis in ESCC through its interaction with p53. Taken together, the findings of the present study suggested that the malignant development of ESCC may be inhibited by TAGLN through the manifestation of ferroptosis.