Hepatology communications · 2025
IL-8-NF-κB-ALDH1A1 loop promotes the progression of intrahepatic cholangiocarcinoma.
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Song Yinghui, Li Yufeng, Zhou Jia, Yu Jianfeng, Hu Qianwei, Yang Feicheng, Yin Zexi, Wang Yizhi, Wang Yueren, Zhang Xinling, Tao Yuewei, Peng Chuang, Liu Sulai
Аннотация
BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a poor prognosis of malignant cancer with high lymph node metastasis and resistance to systemic therapies. Recent studies suggested that the involvement of IL-8 could promote ICC metastasis through epithelial-mesenchymal transition while the ICC-ALDH1A1high subtype is clarified by multi-omics study. The correlation between ALDH1A1 and IL-8 in ICC remains elusive. This study aims to further explore the roles and regulatory mechanisms of ALDH1A1 and IL-8 in ICC.
METHODS: We analyzed IL-8 and ALDH1A1 expression in ICC patients and cells. CXCR2 inhibitor (SB225002) was applied to inhibit the function of IL-8, and JSH-23 was applied to inhibit the NF-κB signaling pathway. We examined the effects of IL-8 inhibition on NF-κB, ALDH1A1 expression, and cell growth, migration, invasion, and stemness. Moreover, we examined the effects of ALDH1A1 on NF-κB, IL-8 expression, and cell growth, migration, invasion, and stemness. The effects of IL-8 and ALDH1A1 on tumor growth and NF-κB expression were validated using subcutaneous tumors in nude mice.
RESULTS: IL-8-derived tumor cells could promote ICC progression. The high expression of IL-8 in serum was associated with lymph node metastasis. IL-8 could upregulate ALDH1A1 expression by activating the NF-κB signaling pathway, promoting tumor progression. Upregulation of ALDH1A1 could activate NF-κB to promote IL-8 secretion, forming a positive feedback loop to promote tumor invasiveness and cell stemness in ICC.
CONCLUSIONS: IL-8-derived tumor cells could upregulate ALDH1A1 expression by activating the NF-κB signaling pathway, promoting tumor progression. Upregulation of ALDH1A1 could activate NF-κB to promote IL-8 secretion, forming a positive feedback loop to promote tumor invasiveness and cell stemness in ICC.
METHODS: We analyzed IL-8 and ALDH1A1 expression in ICC patients and cells. CXCR2 inhibitor (SB225002) was applied to inhibit the function of IL-8, and JSH-23 was applied to inhibit the NF-κB signaling pathway. We examined the effects of IL-8 inhibition on NF-κB, ALDH1A1 expression, and cell growth, migration, invasion, and stemness. Moreover, we examined the effects of ALDH1A1 on NF-κB, IL-8 expression, and cell growth, migration, invasion, and stemness. The effects of IL-8 and ALDH1A1 on tumor growth and NF-κB expression were validated using subcutaneous tumors in nude mice.
RESULTS: IL-8-derived tumor cells could promote ICC progression. The high expression of IL-8 in serum was associated with lymph node metastasis. IL-8 could upregulate ALDH1A1 expression by activating the NF-κB signaling pathway, promoting tumor progression. Upregulation of ALDH1A1 could activate NF-κB to promote IL-8 secretion, forming a positive feedback loop to promote tumor invasiveness and cell stemness in ICC.
CONCLUSIONS: IL-8-derived tumor cells could upregulate ALDH1A1 expression by activating the NF-κB signaling pathway, promoting tumor progression. Upregulation of ALDH1A1 could activate NF-κB to promote IL-8 secretion, forming a positive feedback loop to promote tumor invasiveness and cell stemness in ICC.