背景：转移是肝细胞肝癌相关死亡的主要原因，目前还没有有效的药物治疗方法。慢性炎症促进肝细胞肝癌的扩散，然而，其潜在机制尚不完全清楚。在本研究中，我们探讨了克鲁普尔样因子7（Krüppel-like factor 7，简称KLF7）在炎症诱发的肝细胞肝癌转移中的作用，并提出了针对KLF7阳性患者的治疗策略。方法：通过免疫组织化学和定量实时PCR检测了人体肝细胞肝癌标本中KLF7的表达。进行了荧光素酶报告基因实验和染色质免疫沉淀实验，以探索与KLF7相关的转录调控。建立了原位异种移植模型和DEN/CCl4诱导的肝细胞肝癌模型，评估了肝细胞肝癌的进展和转移。结果：KLF7过表达通过转激活Toll样受体4（toll-like receptor 4，简称TLR4）和蛋白酪氨酸激酶2（protein tyrosine kinase 2，简称PTK2）的表达来促进肝细胞肝癌的转移。高迁移率群体盒子1（high mobility group box 1，简称HMGB1）通过TLR4/先进糖基化终产物特异性受体（receptor for advanced glycosylation end-products，简称RAGE）-PI3K-AKT-NF-κB通路上调KLF7的表达，形成了HMGB1-KLF7-TLR4正反馈环路。HMGB1-KLF7-TLR4/PTK2轴在炎症-肝细胞肝癌转变过程中逐渐激活。通过AAV基因治疗遗传缺失KLF7可阻碍HMGB1介导的肝细胞肝癌进展和转移。TLR4抑制剂TAK-242和PTK2抑制剂defactinib的联合应用可减轻由HMGB1-KLF7轴引起的肝细胞肝癌进展和转移。在人体肝细胞肝癌中，KLF7的表达与细胞质HMGB1、p-p65、TLR4和PTK2水平呈正相关，同时表达HMGB1/KLF7、p-p65/KLF7、KLF7/TLR4或KLF7/PTK2的患者预后最差。结论：HMGB1诱导的KLF7过表达通过上调TLR4和PTK2促进肝细胞肝癌的进展和转移。通过AAV基因治疗遗传消除KLF7，以及联合阻断TLR4和PTK2，为KLF7阳性肝细胞肝癌患者提供了有希望的治疗策略。©作者。

Background: Metastasis is a major cause of HCC-related deaths with no effective pharmacotherapies. Chronic inflammation promotes HCC dissemination, however, its underlying mechanisms are not fully understood. Here, we investigated the role of Krüppel-like factor 7 (KLF7) in inflammation-provoked HCC metastasis and proposed therapeutic strategies for KLF7-positive patients. Methods: The expression of KLF7 in human HCC specimens were examined by immunohistochemistry and quantitative real-time PCR. The luciferase reporter assays and chromatin immunoprecipitation assays were conducted to explore the transcriptional regulation related to KLF7. Orthotopic xenograft models and DEN/CCl4-induced HCC models were established to evaluate HCC progression and metastasis. Results: KLF7 overexpression promotes HCC metastasis through transactivating toll-like receptor 4 (TLR4) and protein tyrosine kinase 2 (PTK2) expression. High mobility group box 1 (HMGB1) upregulates KLF7 expression through the TLR4/advanced glycosylation end-product specific receptor (RAGE)-PI3K-AKT-NF-κB pathway, forming an HMGB1-KLF7-TLR4 positive feedback loop. The HMGB1-KLF7-TLR4/PTK2 axis is gradually activated during the progression of inflammation-HCC transition. Genetic depletion of KLF7 impedes HMGB1-mediated HCC progression and metastasis. The combined application of TLR4 inhibitor TAK-242 and PTK2 inhibitor defactinib alleviates HCC progression and metastasis induced by the HMGB1-KLF7 axis. In human HCCs, KLF7 expression is positively correlated with cytoplasmic HMGB1, p-p65, TLR4, and PTK2 levels, and patients positively co-expressing HMGB1/KLF7, p-p65/KLF7, KLF7/TLR4 or KLF7/PTK2 exhibit the worst prognosis. Conclusions: HMGB1-induced KLF7 overexpression facilitates HCC progression and metastasis by upregulating TLR4 and PTK2. Genetic ablation of KLF7 via AAV gene therapy and combined blockade of TLR4 and PTK2 represents promising therapy strategies for KLF7-positive HCC patients.© The author(s).