Cancer-associated fibroblast-derived secreted phosphoprotein 1 contributes to resistance of hepatocellular carcinoma to sorafenib and lenvatinib.
Cancer-associated fibroblast-derived secreted phosphoprotein 1 contributes to resistance of hepatocellular carcinoma to sorafenib and lenvatinib.
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与癌症相关的成纤维细胞衍生的分泌磷蛋白1有助于肝细胞癌对索拉非尼和伦瓦替尼的抗性。
DOI：
10.1002/cac2.12414
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发表时间：
2023-04
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影响因子：
--
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中科院分区：
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--
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癌症相关成纤维细胞（CAF）在诱导化疗耐药性中发挥重要作用。本研究旨在阐明CAF介导的对两种酪氨酸激酶抑制剂（TKI）索拉非尼和乐伐替尼耐药的机制，并确定克服肝细胞癌（HCC）TKI耐药的新治疗靶点。我们对分别从人HCC和癌帕拉组织中分离的9对CAF和癌帕拉成纤维细胞的公开可用基因表达数据集和全转录组测序数据进行了系统的综合分析，以鉴定可能诱导TKI耐药的关键分子。然后，我们进行了体外和体内实验，以验证选定的目标和相关机制。使用Kaplan-Meier和考克斯回归分析评价了54例晚期HCC患者接受索拉非尼/乐伐替尼治疗前血浆分泌型磷蛋白1（SPP 1）表达水平与无进展生存期（PFS）和总生存期（OS）的相关性。生物信息学分析将CAF衍生的SPP 1确定为驱动TKI耐药性的候选分子。SPP 1抑制剂在体外和体内逆转CAF诱导的TKI耐药性。CAF衍生的SPP 1通过整合素蛋白激酶C-α（PKCα）信号通路激活快速加速纤维肉瘤（RAF）/丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇3-激酶（PI 3 K）/蛋白激酶B（AKT）/哺乳动物雷帕霉素靶蛋白（mTOR），并促进上皮-间充质转化（EMT）。TKI治疗前高血浆SPP 1水平被确定为TKI治疗后晚期HCC患者PFS（P = 0. 026）和OS（P = 0. 047）较差的独立预测因子。CAF衍生的SPP 1通过致癌信号的旁路激活和EMT促进增强HCC中的TKI耐药性。其抑制代表了针对HCC中TKI耐药性的有前景的治疗策略。此外，TKI治疗前的血浆SPP 1水平代表了治疗反应预测的潜在生物标志物。
Cancer‐associated fibroblasts (CAFs) play an important role in the induction of chemo‐resistance. This study aimed to clarify the mechanism underlying CAF‐mediated resistance to two tyrosine kinase inhibitors (TKIs), sorafenib and lenvatinib, and to identify a novel therapeutic target for overcoming TKI resistance in hepatocellular carcinoma (HCC). We performed a systematic integrative analysis of publicly available gene expression datasets and whole‐transcriptome sequencing data from 9 pairs of CAFs and para‐cancer fibroblasts isolated from human HCC and para‐tumor tissues, respectively, to identify key molecules that might induce resistance to TKIs. We then performed in vitro and in vivo experiments to validate selected targets and related mechanisms. The associations of plasma secreted phosphoprotein 1 (SPP1) expression levels before sorafenib/lenvatinib treatment with progression‐free survival (PFS) and overall survival (OS) of 54 patients with advanced HCC were evaluated using Kaplan‐Meier and Cox regression analysis. Bioinformatic analysis identified CAF‐derived SPP1 as a candidate molecule driving TKI resistance. SPP1 inhibitors reversed CAF‐induced TKI resistance in vitro and in vivo. CAF‐derived SPP1 activated rapidly accelerated fibrosarcoma (RAF)/mitogen‐activated protein kinase (MAPK) and phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) through the integrin‐protein kinase C‐alpha (PKCα) signaling pathway and promoted epithelial‐to‐mesenchymal transition (EMT). A high plasma SPP1 level before TKI treatment was identified as an independent predictor of poor PFS (P = 0.026) and OS (P = 0.047) in patients with advanced HCC after TKI treatment. CAF‐derived SPP1 enhances TKI resistance in HCC via bypass activation of oncogenic signals and EMT promotion. Its inhibition represents a promising therapeutic strategy against TKI resistance in HCC. Moreover, plasma SPP1 level before TKI treatment represents a potential biomarker for treatment response prediction.
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