血浆gelsolin 减少促进了食管鳞癌的纤维化肿瘤微环境并促进了放化疗抵抗。

Decreased plasma gelsolin fosters a fibrotic tumor microenvironment and promotes chemoradiotherapy resistance in esophageal squamous cell carcinoma.

机构信息

Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Department of Internal Medicine, E-Da Hospital, College of Medicine, I-Shou University, Kaohsiung, Taiwan.

出版信息

J Biomed Sci. 2024 Sep 11;31(1):90. doi: 10.1186/s12929-024-01078-7.

DOI:10.1186/s12929-024-01078-7

PMID:39261905

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11389350/

Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

摘要

背景

基质纤维化与食管鳞癌（ESCC）患者的治疗耐药性和生存预后差密切相关。大量存在于血清中的血浆凝胶蛋白（pGSN）低表达与炎症和纤维化相关。在此，我们评估了不同分期癌症患者及治疗反应中的 pGSN 表达情况，并阐明了相关的分子机制，以期深入了解 ESCC 的治疗策略。

方法

通过酶联免疫吸附分析检测 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。进行细胞基础研究以研究癌症行为和分子机制，并使用小鼠模型在体内研究 pGSN 诱导的肿瘤抑制作用。

结果

ESCC 进展过程中循环 pGSN 表达明显降低，低 pGSN 表达与治疗反应不良和生存预后差相关。甲基化特异性 PCR 分析证实，pGSN 表达降低部分归因于 GSN 基因启动子的高甲基化。重要的是，细胞基础免疫沉淀和蛋白稳定性测定表明，pGSN 与致癌性 tenascin-C（TNC）竞争整合素 αvβ3 的结合和降解，表明 pGSN 表达降低导致癌细胞和成纤维细胞中致癌信号转导的促进。此外，过表达 pGSN 导致 TNC 表达减少和癌相关成纤维细胞（CAF）失活，从而导致小鼠肿瘤生长抑制。