Key Takeaways & Executive Findings
- •• Cofilin1 is highly expressed in bladder cancer and metastatic lymph nodes, correlating with tumor grade and poor patient survival. • Cofilin1 promotes bladder cancer cell proliferation and migration by binding to cortactin, reducing F-actin, and inducing invadopodia formation. • TCF7L2 transcriptionally activates Cofilin1 and suppresses miR-206 maturation, forming a TCF7L2/miR-206/Cofilin1 axis that drives metastasis. • The TCF7L2/miR-206/Cofilin1 pathway offers novel therapeutic targets for T1G3 bladder cancer, potentially improving treatment strategies and prognosis.
Abstract
Bladder cancer (BCa) is one of the most common malignant tumors of the urinary system, but its pathogenesis is still unclear. T1G3 BCa is particularly invasive and relapses readily after treatment, with progression to invasive cancer or distant metastasis. Therefore, identification of the molecular mechanism by which it invades and metastasizes to guide treatment and predict patient prognosis is needed. Cofilin1 plays an important role in regulating gene expression and the invasiveness of tumors. In this study, we show that Cofilin1 is highly expressed in BCa and lymph nodes with metastasis, which is positively related to the grade of BCa, and is significantly related to clinicopathological parameters and cancer-specific survival. Phenotypic analysis reveals that Cofilin1 knockout inhibits the proliferation and migration of BCa cells, whereas Cofilin1 overexpression promotes the opposite phenotype. Cofilin1 binds to cortactin, thereby reducing the expression of F-actin and promoting the formation of invadopodia in BCa cells. Further experiments reveal that TCF7L2 can bind to the promoter of Cofilin1 and transactivate it, promoting a malignant phenotype. TCF7L2 may also reverse the inhibitory effect of miR-206 on the binding of Cofilin1 and cortactin and promote the metastasis of BCa by inhibiting the transcription maturation of miR-206. This study confirms that Cofilin1 is an oncogene in T1G3 BCa, and the TCF7L2/miR-206/Cofilin1 signaling pathway plays an important role in the formation of invadopodia in BCa.
1. Introduction
Bladder cancer (BCa) is one of the most common urological malignancies and is highly invasive with a poor prognosis [1]. In 2020, there were 573,000 new cases of BCa and 213,000 deaths from the disease worldwide [2]. Approximately 30% of patients with BCa have invasive disease at initial presentation. Moreover, even with radical surgery, the 5-year overall survival rate for these patients is only 50% [3]. Given the highly invasive nature of BCa and the lack of effective treatments, it is important to elucidate the mechanisms by which BCa invades and metastasizes at the molecular level and identify early molecular markers of BCa with high potential for invasion to guide the choice of treatment for T1G3 BCa and improve the survival rate.
Transcription factor 7-like protein 2 (TCF7L2) is a key regulator of the Wnt signaling pathway and has been shown to be important in the development and progression of a variety of malignant tumors [4,5]. MiR-206 is a microRNA that is aberrantly expressed in a variety of tumors and is involved in the regulation of their invasion and metastasis [6]. Cofilin1 belongs to the actin depolymerization factor family and is an actin-binding protein that regulates cytoskeletal remodeling and is closely related to cell migration and invasion [7]. Previous studies have demonstrated that Cofilin1 is significantly upregulated in melanoma and ovarian cancer tissues [8,9] and that the expression of activated forms of Cofilin1 is markedly elevated in some cancers, including those of the breast, lung, and prostate [10–12], whereas the expression of phosphorylated inactivated Cofilin1 is markedly reduced. Activated Cofilin1 induces the formation of invadopodia in tumor cells and enhances their potential for proliferation and invasion. Conversely, silencing of the Cofilin1 gene results in a significant decrease in activated free Cofilin1, which leads to a significant reduction in the generation of invadopodia and disordered maturation in tumor cells, thereby inducing a marked decrease in proliferation and invasiveness. Although Cofilin1 has been shown to be closely related to the development of BCa [13,14], relevant studies have focused on confirming their correlation without exploring the regulatory function or the potential molecular mechanism by which Cofilin1 promotes the invasion and metastasis of BCa.
Therefore, the present study aimed to explore the mechanism by which the TCF7L2/miR-206/Cofilin1 signaling axis induces the formation of invadopodia and the metastasis of BCa. Our initial internal and external experiments detected the expressions of TCF7L2, miR-206, and Cofilin1 in BCa tissues and cells. Next, we explored the expressions of TCF7L2 and miR-206 by transfection.
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Yuzhen Jie, Yinggui Yang, Chengyan Guo, Qinghui Wu, Zhewen Ou, Weifu Wang, Ning Xu, Wei Peng, Yingguang Wu, Jiangfan Peng, Shengchao Ma, Shufang Zhang, Fei Wang (2026). The TCF7L2/miR-206/Cofilin1 axis promotes the metastasis of bladder cancer cells by regulating the formation of invadopodia. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025114
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Frequently Asked Questions
What is the role of Cofilin1 in bladder cancer metastasis?
Cofilin1 is highly expressed in bladder cancer and promotes metastasis by binding to cortactin, reducing F-actin levels, and inducing invadopodia formation, which enhances cell invasion and migration.
How does TCF7L2 regulate Cofilin1 expression?
TCF7L2 binds to the promoter of Cofilin1 and transactivates its expression, thereby promoting a malignant phenotype in bladder cancer cells.
What is the relationship between miR-206 and the TCF7L2/miR-206/Cofilin1 axis?
miR-206 inhibits the binding of Cofilin1 to cortactin, but TCF7L2 can reverse this inhibitory effect by suppressing the transcription maturation of miR-206, thus promoting bladder cancer metastasis.
What are the clinical implications of this study?
The study identifies the TCF7L2/miR-206/Cofilin1 axis as a key pathway in T1G3 bladder cancer invasion and metastasis, offering potential biomarkers for prognosis and novel therapeutic targets for treatment.
How was the study conducted?
The study used internal and external experiments to detect expression levels of TCF7L2, miR-206, and Cofilin1 in bladder cancer tissues and cells, followed by phenotypic analysis and mechanistic investigations including knockout/overexpression studies and binding assays.
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