Tissue & cell · 2025
Tumor microenvironment-driven ST6Gal-Ⅰ activation promotes aggressiveness in gastric signet-ring cell carcinoma via ITGβ1/FAK/Paxillin signaling.
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Zeng Shuhong, Tao Lihuiping, Gao Yingjie, Yang Xueying, Li Zhiyu, Li Ziwen, Wu Luhua, Ping Zhengchen, Zhao Qian, Gu Jiayi, Li Liu, Sun Dongdong, Shen Weixing
Аннотация
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.
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.