CircESRP1 inhibits clear cell renal cell carcinoma progression through the CTCF-mediated positive feedback loop

Abstract

Circular RNA (circRNA), a closed continuous loop formed by back-splicing, has been confirmed to be implicated in a variety of human diseases including cancers. However, the underlying molecular mechanism of circRNA regulating the progression of renal cell carcinoma (RCC) remains largely unclear. In the present study, we identified a novel circular RNA, circESRP1, that derived from the ESRP1 gene locus at 8q22.1 exons. Lower expression of circESRP1 was found in clear cell RCC (ccRCC) tissues and cell lines. Besides, circESRP1 expression level showed inversely correlated with the advanced tumor size, TNM stage and distant metastasis of ccRCC. The expression level of circESRP1 exhibited a positive correlation with CTCF protein but negatively correlated with miR-3942 in 79 ccRCC tissues. In vivo experiments, we found that overexpression of circESRP1 effectively repressed xenograft tumor growth and inhibited c-Myc-mediated EMT progression. CircESRP1 acted as a sponge to competitively bind with miR-3942 as confirmed through RNA pull-down, RIP and dual-luciferase reporter assays. Moreover, CTCF, a downstream target of miR-3942, was validated to specifically promote the circESRP1 transcript expression and regulated by circESRP1/miR-3942 pathway to form a positive feedback loop. We also revealed that the circESRP1/miR-3942/CTCF feedback loop regulated the ccRCC cell functions via c-Myc mediated EMT process. This study provides a novel regulatory model of circRNA via forming a positive-feedback loop that perpetuates the circESRP1/miR-3942/CTCF axis, suggesting that this signaling may serve as a novel target for the treatment of ccRCC.

Circ_0003146 upregulates SCARB1 expression by acting as a miR-1272 sponge to promote malignant behaviors of clear cell renal cell carcinoma

“…Gong et al . [23] stated that circESRP1 blocked the cellular EMT process and tumor xenograft growth of ccRCC. Wang et al .…”

“…Gong et al [23] stated that circESRP1 blocked the cellular EMT process and tumor xenograft growth of ccRCC. Wang et al [24] unraveled that circ_0001451 reduced colony formation ability and ccRCC cell proliferation in vitro.…”

CircRNAs as Novel Biomarkers and Therapeutic Targets in Renal Cell Carcinoma

“…According to Li et al (2020b), the circPRRC2A is upregulated in RCC tissues, and its levels are positively correlated with the larger tumor size of RCC. Clinically, high levels of circESRP1 are negatively associated with the advanced tumor size, TNM stage and distant metastasis of ccRCC (Gong et al, 2021). Feng et al (2020) observed that circ_001287 is highly expressed in RCC tissues and cells, and its levels are strongly correlated with the pathological grade, lymph node, tumor size, tumor node metastasis (TNM) stage, and distant metastasis of RCC patients.…”

“…In addition, circRNAs also have tumor suppressive effect in RCC. For instance, circESRP1 is poor expressed in cancer cells and kidney cancer tissues and acts as a suppressor of tumor through miR-3942/ CTCF axis (Gong et al, 2021). CTCF also specifically promote the circESRP1 transcript expression and form a positive feedback loop.…”

Circular RNA circPOLR2A promotes clear cell renal cell carcinoma progression by facilitating the UBE3C-induced ubiquitination of PEBP1 and, thereby, activating the ERK signaling pathway

“…With the development of bioinformatics technology, accumulating studies have shown that dysregulation of circRNAs is involved in the pathogenesis of cancers, including cRCC [12][13][14]. For example, circCHST15, circESRP1 and circEXOC7 were reported to be novel biomarkers that regulate the progression of cRCC [15][16][17]. The reported functions of circRNAs have mainly focused on acting as miRNA sponges [18,19], acting through proteins [20,21], and translatable circR-NAs [22].…”