Cellular signalling · 2026
β-sitosterol inhibited hypoxia-related colorectal cancer metastasis by regulating HIF-1α/VEGF pathway.
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Dai Lingling, Meng Peng, Hu Jing, Dou Huanhuan, Li Shan, Zhang Xiaoni
Аннотация
OBJECTIVE: This study aimed to investigate how β-sitosterol (SIT) suppresses hypoxia-driven metastasis and angiogenesis in colorectal cancer.
METHODS: We employed hypoxic colorectal cancer cells. The biological functions of SIT were assessed via in vitro assays for cell proliferation, migration, invasion, apoptosis and angiogenesis. A mouse model of colorectal cancer lung metastasis was constructed for grouped SIT intervention. Histopathology, immunofluorescence and Western blot were applied to detect the expression of key molecules.
RESULTS: In vitro, SIT dose-dependently inhibited proliferation, migration and invasion of hypoxic colorectal cancer cells and triggered apoptosis. Additionally, SIT markedly inhibited angiogenesis and reversed the epithelial-mesenchymal transition (EMT). In the lung metastasis mouse model, SIT reduced metastatic foci, relieved lung injury, reversed EMT, decreased CD11b+Gr1+ myeloid cell infiltration, and suppressed FAP, eNOS and DDAH2 (angiogenesis-related factors). Further mechanistic studies revealed that SIT downregulated HIF-1α and VEGFA to mediate its anti-tumor actions.
CONCLUSION: Collectively, SIT blocked hypoxia-induced colorectal cancer metastasis and reversed the EMT through the HIF-1α/VEGF axis. Our findings offer new insights and potential therapeutic approaches for lung metastases from colorectal cancer.
METHODS: We employed hypoxic colorectal cancer cells. The biological functions of SIT were assessed via in vitro assays for cell proliferation, migration, invasion, apoptosis and angiogenesis. A mouse model of colorectal cancer lung metastasis was constructed for grouped SIT intervention. Histopathology, immunofluorescence and Western blot were applied to detect the expression of key molecules.
RESULTS: In vitro, SIT dose-dependently inhibited proliferation, migration and invasion of hypoxic colorectal cancer cells and triggered apoptosis. Additionally, SIT markedly inhibited angiogenesis and reversed the epithelial-mesenchymal transition (EMT). In the lung metastasis mouse model, SIT reduced metastatic foci, relieved lung injury, reversed EMT, decreased CD11b+Gr1+ myeloid cell infiltration, and suppressed FAP, eNOS and DDAH2 (angiogenesis-related factors). Further mechanistic studies revealed that SIT downregulated HIF-1α and VEGFA to mediate its anti-tumor actions.
CONCLUSION: Collectively, SIT blocked hypoxia-induced colorectal cancer metastasis and reversed the EMT through the HIF-1α/VEGF axis. Our findings offer new insights and potential therapeutic approaches for lung metastases from colorectal cancer.
Предметные рубрики MeSH
AnimalsHypoxia-Inducible Factor 1, alpha SubunitColorectal NeoplasmsVascular Endothelial Growth Factor AHumansSitosterolsMiceCell Line, TumorSignal TransductionEpithelial-Mesenchymal TransitionCell MovementCell ProliferationApoptosisLung NeoplasmsNeoplasm MetastasisCell HypoxiaNeovascularization, PathologicMice, Inbred BALB C