Key Takeaways & Executive Findings
- •• circ_0006156 is significantly upregulated in ESCC tissues and cell lines, correlating with poor overall survival. • circ_0006156 acts as a sponge for miR-202-5p, relieving its suppression on TGFBR1 and activating the TGFβ/Smad pathway. • Knockdown of circ_0006156 inhibits ESCC cell proliferation, migration, and invasion in vitro and tumor growth in vivo. • circ_0006156 represents a potential novel biomarker and therapeutic target for ESCC.
Abstract
Esophageal squamous cell carcinoma (ESCC) represents a common malignancy of the digestive system. Circular RNAs (circRNAs) are a distinct class of single-stranded non-coding RNAs that are essential in the progression of various tumors given that they can act as microRNA (miRNA) sponges in a manner similar to that of mRNAs. In this study, circ_0006156 is screened to be highly expressed in ESCC tissues through high-throughput sequencing and quantitative real-time polymerase chain reaction. Subsequent in vitro and in vivo experiments are conducted to validate its biological functions. Furthermore, the regulatory relationships among circ_0006156, miR-202-5p, and TGFBR1 are investigated using RNA antisense purification, miRNA sequencing, RNA immunoprecipitation, fluorescence in situ hybridization, dual-luciferase reporter assay, and bioinformatics analyses. The results show significant overexpression of circ_0006156 in ESCC tissues, with relatively shorter overall survival observed in patients with high circ_0006156 expression. circ_0006156 is further identified to directly bind to miR-202-5p. miR-202-5p inhibits the proliferation, migration, and invasion of ESCC cells in vitro and partially rescues the effects induced by circ_0006156. Consistent results are reported by subcutaneous xenograft tumor experiments in nude mice. In addition, circ_0006156 is confirmed to act as an endogenous sponge for miR-202-5p, which results in a relieved suppression of its target gene TGFβR1. In summary, circ_0006156 can regulate TGFβR1 expression by sponging miR-202-5p, which may further activate the TGFβ/Smad pathway and promote ESCC progression. Collectively, circ_0006156 functions as a novel oncogenic RNA in ESCC and may serve as a potential tumor marker.
1. Introduction
Esophageal carcinoma (EC) is a common malignant tumor worldwide, consisting of two primary subtypes of adenocarcinoma and squamous cell carcinoma histologically. In particular esophageal squamous cell carcinoma (ESCC) exhibits a high incidence in China. Circular RNAs (circRNAs) are a type of single-stranded noncoding RNA that are generated from the backsplicing of host genes via various mechanisms. circRNAs are highly conservative and stable owing to their distinctive circular structure. Moreover, circRNAs exhibit differential expression patterns in different tissues and diseases, enabling them to perform important biological functions across various diseases, thereby being recognized as promising biomarkers and targets for diagnosing and treating human diseases.
Critically, circRNAs serve as molecular sponges for microRNAs (miRNAs), which can mediate the role of miRNA in regulating gene expression at both transcriptional and post-translational levels. Despite advancements in circRNA research, there is currently insufficient evidence regarding their roles in the occurrence and development of ESCC. Further investigation and clarifications are needed to elucidate their functions in the tumorigenesis of ESCC and the underlying molecular mechanisms. The TGFβ/Smad signaling can regulate a wide array of cellular responses and plays a significant role in the development of animals. According to prior research, TGFβ receptors may be activated via ligand binding, phosphorylation-mediated activation of Smad proteins, regulation of target gene transcription, as well as modulation of Smad protein activity and degradation. Dysregulation of the TGFβ signaling pathway may trigger tumor development. In the late stages of tumors, the TGFβ signaling pathway may induce tumorigenesis by promoting epithelial-mesenchymal transition (EMT), angiogenesis, immune evasion, and metastasis. For example, NSG1 may promote the progression of ESCC by enhancing intracellular EMT through the TGFβ/Smad signaling pathway. CRELD2 may facilitate the membrane localization of APMAP, activating TGF-β/SMAD and NF-κB signaling pathways, ultimately driving EMT and malignant progression in ESCC cells.
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Zhanpeng Tang, Jian Li, Rongyang Li, Luyuan Ma, Renchang Zhao, Zhenguo Sun, Hui Tian (2026). circ_0006156 promotes esophageal squamous cell carcinoma progression via activation of the TGFβ/Smad pathway. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2026049
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Frequently Asked Questions
What is the role of circ_0006156 in esophageal squamous cell carcinoma?
circ_0006156 is upregulated in ESCC and promotes tumor progression by sponging miR-202-5p, which leads to increased TGFBR1 expression and activation of the TGFβ/Smad pathway.
How does circ_0006156 regulate the TGFβ/Smad pathway?
circ_0006156 acts as a molecular sponge for miR-202-5p, thereby relieving miR-202-5p-mediated suppression of TGFBR1, a key receptor in the TGFβ/Smad pathway, leading to pathway activation.
What is the clinical significance of circ_0006156 expression in ESCC patients?
High expression of circ_0006156 in ESCC tissues is associated with shorter overall survival, suggesting its potential as a prognostic biomarker.
What experimental methods were used to validate the findings?
The study employed high-throughput sequencing, RT-qPCR, RNA antisense purification, miRNA sequencing, RNA immunoprecipitation, fluorescence in situ hybridization, dual-luciferase reporter assays, and in vivo xenograft models.
Could circ_0006156 serve as a therapeutic target for ESCC?
Yes, silencing circ_0006156 inhibited tumor growth and metastasis in vivo, indicating that it may be a potential therapeutic target for ESCC.
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