TPP1, as one of the telomere-protective protein complex, functions to maintain telomere stability. In this study, we found that TPP1 was significantly upregulated in esophageal cancer (EC). We found that the proliferation and migration ability were significantly inhibited, while the results of flow cytometry assay indicated that the growth was hindered in the G₁ phase after TPP1 knockdown. However, the proliferative viability and migratory ability were reversed after TPP1 overexpression in EC cells. Then, we found a significant increase in β-galactosidase positivity following TPP1 knockdown and the opposite following TPP1 overexpression in EC cells. Furthermore, TPP1 knockdown increased DNA damage and upregulated expression of the γ-H2AX^S139 in the cell nucleus. Correspondingly, DNA damage was reversed after TPP1 overexpression in EC cells. Similarly, we found that the expression of ATM/ATR pathway proteins were upregulated after TPP1 knockdown, while the expression of the above proteins was downregulated after TPP1 overexpression in EC cells. TPP1 knockdown significantly inhibited the growth of transplanted tumors and upregulated the expression of ATM/ATR pathway proteins in transplanted tissues, whereas TPP1 overexpression significantly promoted their proliferation and downregulated the expression of the above proteins in vivo. Strikingly, we found that TPP1 could reduce the chemosensitivity of EC cells to cisplatin, which may have a potential link to clinical chemoresistance. In conclusion, TPP1 regulates the DNA damage response through the ATM/ATR-p53 signaling pathway and chemoresistance and may be a new target for improving the efficacy of chemotherapy in the treatment of EC.

中文翻译：

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TPP1 抑制食管癌的 DNA 损伤反应和化疗敏感性

TPP1作为端粒保护蛋白复合物之一，具有维持端粒稳定性的作用。在这项研究中，我们发现 TPP1 在食管癌 (EC) 中显着上调。我们发现TPP1敲除后增殖和迁移能力受到显着抑制，而流式细胞仪检测结果表明G ₁期生长受到阻碍。然而，EC细胞中TPP1过表达后，增殖活力和迁移能力发生逆转。然后，我们发现EC细胞中TPP1敲低后β-半乳糖苷酶阳性率显着增加，而TPP1过表达后则相反。此外，TPP1 敲除增加了 DNA 损伤并上调了细胞核中γ-H2AX ^{S139的表达。}相应地，在 EC 细胞中 TPP1 过表达后，DNA 损伤得到逆转。同样，我们发现EC细胞中TPP1敲低后ATM/ATR通路蛋白的表达上调，而TPP1过表达后上述蛋白的表达下调。TPP1敲低显着抑制移植肿瘤的生长并上调移植组织中ATM/ATR通路蛋白的表达，而TPP1过表达显着促进其增殖并下调体内上述蛋白的表达。引人注目的是，我们发现 TPP1 可以降低 EC 细胞对顺铂的化疗敏感性，这可能与临床化疗耐药性存在潜在联系。总之，TPP1通过ATM/ATR-p53信号通路和化疗耐药性调节DNA损伤反应，可能成为提高EC治疗化疗疗效的新靶点。