Tumor microenvironment-driven ST6Gal-Ⅰ activation promotes aggressiveness in gastric signet-ring cell carcinoma via ITGβ1/FAK/Paxillin signaling

IF 2.5 4区生物学 Q1 ANATOMY & MORPHOLOGY

Tissue & cell Pub Date : 2025-09-06 DOI:10.1016/j.tice.2025.103130

Shuhong Zeng , Lihuiping Tao , Yingjie Gao , Xueying Yang , Zhiyu Li , Ziwen Li , Luhua Wu , Zhengchen Ping , Qian Zhao , Jiayi Gu , Liu Li , Dongdong Sun , Weixing Shen

{"title":"Tumor microenvironment-driven ST6Gal-Ⅰ activation promotes aggressiveness in gastric signet-ring cell carcinoma via ITGβ1/FAK/Paxillin signaling","authors":"Shuhong Zeng , Lihuiping Tao , Yingjie Gao , Xueying Yang , Zhiyu Li , Ziwen Li , Luhua Wu , Zhengchen Ping , Qian Zhao , Jiayi Gu , Liu Li , Dongdong Sun , Weixing Shen","doi":"10.1016/j.tice.2025.103130","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Poorly cohesive gastric carcinoma, particularly signet-ring cell (SRC) carcinoma, is an aggressive gastric cancer (GC) subtype with high metastatic potential and poor prognosis. Sialylation plays a critical role in tumor progression, but its functional significance in SRC malignancy and microenvironmental regulation remains unclear. This study investigated ST6Gal-Ⅰ’s mechanistic contributions to SRC aggressiveness, focusing on epithelial-mesenchymal transition (EMT), stromal interactions, and metastatic signaling.</div></div><div><h3>Methods</h3><div>Multiple SRC and non-SRC GC cell lines, patient-derived organoids, and stromal cells (MSCs, HUVECs) were utilized. Techniques included co-culture models (transwell and direct contact), immunohistochemistry, western blotting, functional assays (transwell migration, wound healing, sphere/colony formation, EdU proliferation), and lectin staining. ST6Gal-Ⅰ expression was modulated via shRNA knockdown or overexpression. Mechanistic analyses focused on integrin-β1 (ITGβ1)/FAK/Paxillin signaling and stromal reprogramming. Statistical significance was determined using ANOVA with post hoc tests.</div></div><div><h3>Results</h3><div>ST6Gal-Ⅰ exhibited microenvironment-dependent regulation: low <em>in vitro</em> expression in SRC cells was rescued by stromal co-culture or extracellular matrix (ECM) contact, mirroring high <em>in vivo</em> expression. ST6Gal-Ⅰ overexpression promoted EMT, stemness, angiogenesis, and proliferation. It facilitated MSCs differentiation into cancer-associated fibroblasts (CAFs) via α-SMA/FAP upregulation. Mechanistically, ST6Gal-Ⅰ activated the ITGβ1/FAK/Paxillin axis to enhance cell-ECM adhesion. Silencing ST6Gal-Ⅰ reversed these phenotypes, suppressing malignancy and stromal crosstalk.</div></div><div><h3>Conclusion</h3><div>ST6Gal-Ⅰ is a microenvironment-sensitive driver of SRC progression, orchestrating EMT, stemness, angiogenesis, and stromal reprogramming through ITGβ1/FAK/Paxillin signaling. Its dual role in tumor-autonomous behaviors and stromal co-option highlights its potential as a therapeutic target. Targeting ST6Gal-Ⅰ or downstream effectors (e.g., FAK, CAF-derived signals) may disrupt SRC metastasis and improve clinical outcomes.</div></div>","PeriodicalId":23201,"journal":{"name":"Tissue & cell","volume":"98 ","pages":"Article 103130"},"PeriodicalIF":2.5000,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Tissue & cell","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0040816625004124","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ANATOMY & MORPHOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Poorly cohesive gastric carcinoma, particularly signet-ring cell (SRC) carcinoma, is an aggressive gastric cancer (GC) subtype with high metastatic potential and poor prognosis. Sialylation plays a critical role in tumor progression, but its functional significance in SRC malignancy and microenvironmental regulation remains unclear. This study investigated ST6Gal-Ⅰ’s mechanistic contributions to SRC aggressiveness, focusing on epithelial-mesenchymal transition (EMT), stromal interactions, and metastatic signaling.

Methods

Multiple SRC and non-SRC GC cell lines, patient-derived organoids, and stromal cells (MSCs, HUVECs) were utilized. Techniques included co-culture models (transwell and direct contact), immunohistochemistry, western blotting, functional assays (transwell migration, wound healing, sphere/colony formation, EdU proliferation), and lectin staining. ST6Gal-Ⅰ expression was modulated via shRNA knockdown or overexpression. Mechanistic analyses focused on integrin-β1 (ITGβ1)/FAK/Paxillin signaling and stromal reprogramming. Statistical significance was determined using ANOVA with post hoc tests.

Results

ST6Gal-Ⅰ exhibited microenvironment-dependent regulation: low in vitro expression in SRC cells was rescued by stromal co-culture or extracellular matrix (ECM) contact, mirroring high in vivo expression. ST6Gal-Ⅰ overexpression promoted EMT, stemness, angiogenesis, and proliferation. It facilitated MSCs differentiation into cancer-associated fibroblasts (CAFs) via α-SMA/FAP upregulation. Mechanistically, ST6Gal-Ⅰ activated the ITGβ1/FAK/Paxillin axis to enhance cell-ECM adhesion. Silencing ST6Gal-Ⅰ reversed these phenotypes, suppressing malignancy and stromal crosstalk.

Conclusion

ST6Gal-Ⅰ is a microenvironment-sensitive driver of SRC progression, orchestrating EMT, stemness, angiogenesis, and stromal reprogramming through ITGβ1/FAK/Paxillin signaling. Its dual role in tumor-autonomous behaviors and stromal co-option highlights its potential as a therapeutic target. Targeting ST6Gal-Ⅰ or downstream effectors (e.g., FAK, CAF-derived signals) may disrupt SRC metastasis and improve clinical outcomes.

查看原文本刊更多论文

肿瘤微环境驱动的ST6Gal-Ⅰ激活通过ITGβ1/FAK/Paxillin信号传导促进胃印戒细胞癌的侵袭性

背景：低黏结性胃癌，尤其是印戒细胞癌（SRC），是一种侵袭性胃癌（GC）亚型，具有高转移潜力和不良预后。唾液酰化在肿瘤进展中起关键作用，但其在SRC恶性肿瘤和微环境调节中的功能意义尚不清楚。本研究探讨了ST6Gal-Ⅰ对SRC侵袭性的机制贡献，重点关注上皮-间质转化（EMT）、基质相互作用和转移信号。方法利用多种SRC和非SRC GC细胞系、患者源性类器官和基质细胞（MSCs、HUVECs）。技术包括共培养模型（transwell和直接接触）、免疫组织化学、免疫印迹、功能分析（transwell迁移、伤口愈合、球/菌落形成、EdU增殖）和凝集素染色。ST6Gal-Ⅰ的表达可通过shRNA敲低或过表达进行调节。机制分析侧重于整合素-β1 (itg -β1)/FAK/Paxillin信号传导和基质重编程。采用方差分析和事后检验确定统计学显著性。结果st6gal -Ⅰ具有微环境依赖性，在SRC细胞中通过基质共培养或细胞外基质（ECM）接触恢复体外低表达，反映体内高表达。ST6Gal-Ⅰ过表达促进EMT、干性、血管生成和增殖。它通过α-SMA/FAP上调促进MSCs向癌症相关成纤维细胞（CAFs）分化。机制上，ST6Gal-Ⅰ激活itg - β1/FAK/Paxillin轴增强细胞- ecm粘附。沉默ST6Gal-Ⅰ逆转了这些表型，抑制了恶性和间质串扰。结论st6gal -Ⅰ是SRC进展的微环境敏感驱动因子，通过ITGβ1/FAK/Paxillin信号调控EMT、干细胞、血管生成和基质重编程。它在肿瘤自主行为和基质共选择中的双重作用突出了它作为治疗靶点的潜力。靶向ST6Gal-Ⅰ或下游效应物（如FAK、ca衍生信号）可能会破坏SRC转移并改善临床结果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Tissue & cell 医学-解剖学与形态学

CiteScore

3.90

自引率

0.00%

发文量

234

期刊介绍： Tissue and Cell is devoted to original research on the organization of cells, subcellular and extracellular components at all levels, including the grouping and interrelations of cells in tissues and organs. The journal encourages submission of ultrastructural studies that provide novel insights into structure, function and physiology of cells and tissues, in health and disease. Bioengineering and stem cells studies focused on the description of morphological and/or histological data are also welcomed. Studies investigating the effect of compounds and/or substances on structure of cells and tissues are generally outside the scope of this journal. For consideration, studies should contain a clear rationale on the use of (a) given substance(s), have a compelling morphological and structural focus and present novel incremental findings from previous literature.