Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University/Affiliated Lishui Hospital of Zhejiang University/The Central Hospital of Zhejiang Lishui, Lishui 323000, China; Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University/Affiliated Lishui Hospital of Zhejiang University/The Central Hospital of Zhejiang Lishui, Lishui 323000, China.
Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University/Affiliated Lishui Hospital of Zhejiang University/The Central Hospital of Zhejiang Lishui, Lishui 323000, China; Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University/Affiliated Lishui Hospital of Zhejiang University/The Central Hospital of Zhejiang Lishui, Lishui 323000, China.
Life Sci. 2021 Jan 1;264:118642. doi: 10.1016/j.lfs.2020.118642. Epub 2020 Oct 24.
Hepatocellular carcinoma (HCC) is an aggressive solid tumor with restricted therapeutics. Lenvatinib is the second approved frontline drug for advanced HCC, however lenvatinib-resistant cases have been reported in clinical. Overexpression of fibroblast growth factor receptor (FGFR1) has been found to be associated with advanced HCC. This study was aimed to investigate the relationship between FGFR1 overexpression and lenvatinib resistance, and explore the potential candidate that can sensitize lenvatinib against FGFR1-overexpressed HCC.
Development of FGFR1 overexpression was accomplished in Hep3B and HepG2 cell lines by pCDH-FGFR1 lentiviral vector. In vitro, cell proliferation, colony formation, cell migration and cell apoptosis assays were used to explore the effect of lenvatinib and Oxysophocarpine. In vivo, BALB/c nude mice were burdened with subcutaneous FGFR1-overexpressed Hep3B tumor to assess the therapeutic effect of lenvatinib and Oxysophocarpine. qRT-PCR and western blotting were further used to identify the underlying mechanism.
Here, we revealed that overexpressed FGFR1 and its downstream AKT/mTOR and ERK signaling activation could induce lenvatinib resistance in HCC. In vivo and in vitro results showed Oxysophocarpine inhibited the proliferation and induced the apoptosis of FGFR1-overexpressed HCC cells. Oxysophocarpine could further sensitize FGFR1-overexpressed HCC cells to lenvatinib treatment. Mechanism studies revealed that Oxysophocarpine downregulated FGFR1 expression along with downstream AKT/mTOR and ERK signaling to sensitize lenvatinib against FGFR1-overexpressed HCC.
These data collectively provided evidence that FGFR1 overexpression could be a potential cause of lenvatinib resistance and Oxysophocarpine could be an ideal combined therapy with lenvatinib in HCC treatment.
肝细胞癌（HCC）是一种侵袭性实体肿瘤，治疗方法有限。仑伐替尼是第二种被批准用于晚期 HCC 的一线药物，然而，临床上已经报道了仑伐替尼耐药的病例。成纤维细胞生长因子受体（FGFR1）的过表达已被发现与晚期 HCC 相关。本研究旨在探讨 FGFR1 过表达与仑伐替尼耐药之间的关系，并探索潜在的候选药物，以增强仑伐替尼对 FGFR1 过表达 HCC 的敏感性。
通过 pCDH-FGFR1 慢病毒载体在 Hep3B 和 HepG2 细胞系中构建 FGFR1 过表达。在体外，使用细胞增殖、集落形成、细胞迁移和细胞凋亡实验来探讨仑伐替尼和氧化槐果碱的作用。在体内，将 BALB/c 裸鼠皮下荷 FGFR1 过表达 Hep3B 肿瘤，以评估仑伐替尼和氧化槐果碱的治疗效果。进一步使用 qRT-PCR 和 Western blot 来确定潜在的机制。
在这里，我们揭示了过表达的 FGFR1 及其下游 AKT/mTOR 和 ERK 信号激活可诱导 HCC 对仑伐替尼产生耐药性。体内和体外结果表明，氧化槐果碱抑制 FGFR1 过表达 HCC 细胞的增殖并诱导其凋亡。氧化槐果碱还可以进一步增强 FGFR1 过表达 HCC 细胞对仑伐替尼治疗的敏感性。机制研究表明，氧化槐果碱下调 FGFR1 表达及其下游 AKT/mTOR 和 ERK 信号，从而增强仑伐替尼对 FGFR1 过表达 HCC 的敏感性。
这些数据共同提供了证据表明，FGFR1 过表达可能是仑伐替尼耐药的潜在原因，氧化槐果碱可能是 HCC 治疗中与仑伐替尼联合应用的理想选择。
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