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<p>Oral submucous fibrosis (OSF) is a precancerous condition primarily caused by arecoline in betel nuts. The transforming growth factor (TGF)-β/mothers against decapentaplegic homolog 3 (Smad3) signaling pathway plays a pivotal role in its pathogenesis. This study explores the interaction between tropomyosin-1 (TPM1) and STIP1 homology and U-Box-containing protein 1 (STUB1) in regulating this pathway and its impact on OSF progression. We found that arecoline dose and time-dependently upregulates the expression of TPM1 mRNA and protein in human oral fibroblasts (HOrF). Treating HOrF with 20&#xa0;μg/mL arecoline for 48&#xa0;h could effectively drive fibroblast proliferation, fibrosis, migration and invasion. TPM1 knockdown reversed these effects. Mechanistically, arecoline upregulates TPM1 by activating the TGF-β/Smad3 signaling pathway. Notably, TPM1 overexpression rescued TGF-β/Smad3 activity even in the presence of the TGF-β inhibitor SB431542, revealing a positive feedback loop. Additionally, Western blotting and co-immunoprecipitation (Co-IP) analyses showed that arecoline downregulates STUB1, thereby inhibiting the ubiquitination of TGF-β/Smad3 in HOrF. Meanwhile, TPM1 competitively binds to STUB1, blocking its interaction with TGF-β/Smad3 and thereby stabilizing the pathway, which exacerbates fibrosis. Statistical analysis (one-way ANOVA with Tukey's HSD post-hoc test or independent-samples t-test) confirmed the significance of all major findings (<i>p</i> &lt; 0.05). In conclusion, activation of the TGF-β/Smad3 pathway upregulates TPM1, which in turn blocks STUB1-mediated ubiquitination of the same cascade, establishing a positive-feedback loop that exacerbates arecoline-induced OSF. These findings improve our understanding of OSF's molecular pathogenesis and offer a potential target for its prevention and treatment.</p>

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Tropomyosin-1 positively regulates TGF-β/Smad3 signaling through STUB1 in arecoline-induced oral submucosal fibrosis

  • 期刊论文

  • 发表日期：

    2025年11月7日

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  • Rong Zhu,
  • Lin Yin,
  • Rong Zhou,
  • Xin Zhang

摘要

Oral submucous fibrosis (OSF) is a precancerous condition primarily caused by arecoline in betel nuts. The transforming growth factor (TGF)-β/mothers against decapentaplegic homolog 3 (Smad3) signaling pathway plays a pivotal role in its pathogenesis. This study explores the interaction between tropomyosin-1 (TPM1) and STIP1 homology and U-Box-containing protein 1 (STUB1) in regulating this pathway and its impact on OSF progression. We found that arecoline dose and time-dependently upregulates the expression of TPM1 mRNA and protein in human oral fibroblasts (HOrF). Treating HOrF with 20 μg/mL arecoline for 48 h could effectively drive fibroblast proliferation, fibrosis, migration and invasion. TPM1 knockdown reversed these effects. Mechanistically, arecoline upregulates TPM1 by activating the TGF-β/Smad3 signaling pathway. Notably, TPM1 overexpression rescued TGF-β/Smad3 activity even in the presence of the TGF-β inhibitor SB431542, revealing a positive feedback loop. Additionally, Western blotting and co-immunoprecipitation (Co-IP) analyses showed that arecoline downregulates STUB1, thereby inhibiting the ubiquitination of TGF-β/Smad3 in HOrF. Meanwhile, TPM1 competitively binds to STUB1, blocking its interaction with TGF-β/Smad3 and thereby stabilizing the pathway, which exacerbates fibrosis. Statistical analysis (one-way ANOVA with Tukey's HSD post-hoc test or independent-samples t-test) confirmed the significance of all major findings (p < 0.05). In conclusion, activation of the TGF-β/Smad3 pathway upregulates TPM1, which in turn blocks STUB1-mediated ubiquitination of the same cascade, establishing a positive-feedback loop that exacerbates arecoline-induced OSF. These findings improve our understanding of OSF's molecular pathogenesis and offer a potential target for its prevention and treatment.