间质纤维化与食管鳞状细胞癌（ESCC）患者的治疗耐药性和生存率低密切相关。血浆凝溶胶蛋白 (pGSN)（一种血清丰富的蛋白质）的低表达已被发现与炎症和纤维化相关。在这里，我们评估了不同阶段癌症患者的 pGSN 表达和治疗反应，并描绘了所涉及的分子机制，以深入了解 ESCC 的治疗策略。通过酶联免疫吸附测定分析测定了 ESCC 患者的循环 pGSN 水平，并通过免疫组织化学染色分析肿瘤的组织微阵列。进行基于细胞的研究来研究癌症行为和分子机制，并使用小鼠模型来检查 pGSN 诱导的体内肿瘤抑制作用。在 ESCC 进展过程中，循环 pGSN 表达明显降低，低 pGSN 表达与不良治疗反应相关并且生存能力较差。甲基化特异性 PCR 分析证实，pGSN 表达下降部分归因于 GSN 启动子（编码 pGSN 的基因）的过度甲基化。重要的是，基于细胞的免疫沉淀和蛋白质稳定性测定表明，pGSN 与致癌生腱蛋白-C (TNC) 竞争整合素 αvβ3 的结合和降解，揭示 pGSN 表达减少导致癌细胞和成纤维细胞中致癌信号转导的促进。此外，pGSN的过度表达导致TNC表达减弱和癌症相关成纤维细胞（CAF）失活，从而导致小鼠肿瘤生长抑制。我们的结果表明，GSN甲基化导致pGSN分泌减少，导致整合素失调，致癌TNC激活和 CAF 形成。这些发现强调了 pGSN 在 ESCC 治疗耐药和纤维化肿瘤微环境中的作用。© 2024。作者。

Stromal fibrosis is highly associated with therapeutic resistance and poor survival in esophageal squamous cell carcinoma (ESCC) patients. Low expression of plasma gelsolin (pGSN), a serum abundant protein, has been found to correlate with inflammation and fibrosis. Here, we evaluated pGSN expression in patients with different stages of cancer and therapeutic responses, and delineated the molecular mechanisms involved to gain insight into therapeutic strategies for ESCC.Circulating pGSN level in ESCC patients was determined by enzyme-linked immunosorbent assay analysis, and the tissue microarray of tumors was analyzed by immunohistochemistry staining. Cell-based studies were performed to investigate cancer behaviors and molecular mechanisms, and mouse models were used to examine the pGSN-induced tumor suppressive effects in vivo.Circulating pGSN expression is distinctively decreased during ESCC progression, and low pGSN expression correlates with poor therapeutic responses and poor survival. Methylation-specific PCR analysis confirmed that decreased pGSN expression is partly attributed to the hypermethylation of the GSN promoter, the gene encoding pGSN. Importantly, cell-based immunoprecipitation and protein stability assays demonstrated that pGSN competes with oncogenic tenascin-C (TNC) for the binding and degradation of integrin αvβ3, revealing that decreased pGSN expression leads to the promotion of oncogenic signaling transduction in cancer cells and fibroblasts. Furthermore, overexpression of pGSN caused the attenuation of TNC expression and inactivation of cancer-associated fibroblast (CAF), thereby leading to tumor growth inhibition in mice.Our results demonstrated that GSN methylation causes decreased secretion of pGSN, leading to integrin dysregulation, oncogenic TNC activation, and CAF formation. These findings highlight the role of pGSN in therapeutic resistance and the fibrotic tumor microenvironment of ESCC.© 2024. The Author(s).