Increased Expression of Fibulin-1 Is Associated With Hepatocellular Carcinoma Progression by Regulating the Notch Signaling Pathway
Increased Expression of Fibulin-1 Is Associated With Hepatocellular Carcinoma Progression by Regulating the Notch Signaling Pathway
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Fibulin-1 表达增加通过调节 Notch 信号通路与肝细胞癌进展相关
DOI：
10.3389/fcell.2020.00478
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发表时间：
2020-06-16
影响因子：
5.5
通讯作者：
Chong, Yutian
中科院分区：
文献类型：
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作者：
Gong, Jiao;Jie, Yusheng;Chong, Yutian
Fibulin-1是细胞外基质（ECM）的一种成分，其在肝细胞癌（HCC）的预后、病理生理和诊断中的作用尚不清楚。我们首先发现，无论是Fibulin-1的信使RNA（mRNA）或蛋白质水平在肝癌组织中高度升高与正常组织相比。Fibulin-1与总生存率相关，是一个独立的预后预测因子（p = 0.001）。此外，Fibulin-1的过表达或抑制降低或敏化HCC细胞对凋亡信号的敏感性，并且Fibulin-1沉默抑制HCC细胞在体内形成肿瘤的能力。此外，Fibulin-1通过Notch途径抑制细胞凋亡，而Fibulin-1沉默对p-MAPK、p-c-jun和p-stat 3表达没有明显影响，并且Mcl-1和Bcl-xL都是Fibulin-1的靶点。此外，基于TCGA HCC数据库，使用xCell、TIMER和TISDIB工具，在高Fibulin-1组织中基质和免疫评分升高，并且FBLN 1表达与浸润巨噬细胞增加相关。重要的是，与健康对照、慢性B型肝炎个体和HBV诱导的肝硬化患者相比，HCC患者血清中Fibulin-1的循环无细胞RNA（cfRNA）水平显著升高。Fibulin-1的受试者工作特征曲线下面积（AUC）为0.791，甲胎蛋白为0.640，两种肿瘤标志物的组合为0.868。我们的研究结果表明，Fibulin-1可能是一个潜在的预后指标，一个有前途的血清生物标志物和治疗肝癌患者的目标。
Fibulin-1, a component of the extracellular matrix (ECM), its prognostic, pathophysiologic and diagnostic role in hepatocellular carcinoma (HCC) is still unexplored. We first found that either Fibulin-1 messenger RNA (mRNA) or protein level was highly elevated in HCC tissues compared with normal tissues. Fibulin-1 correlated with poor overall survival, and it was an independent prognostic predictor (p = 0.001). Furthermore, Overexpression or inhibition of Fibulin-1 reduced or sensitized HCC cells to apoptotic signals, and Fibulin-1 silencing suppressed the ability of HCC cells to form tumors in vivo. Moreover, Fibulin-1 inhibited apoptosis via the Notch pathway while Fibulin-1 silencing had no obvious effect on p-MAPK, p-c-jun and p-stat3 expression, and both Mcl-1 and Bcl-xL are targets of Fibulin-1. Furthermore, the stromal and immune score was elevated in high Fibulin-1 tissues, and FBLN1 expression was associated with increased infiltrating macrophages using xCell, TIMER and TISDIB tool based on TCGA HCC database. Importantly, the circulating cell-free RNA (cfRNA) level of Fibulin-1 in the serum were significantly increased in patients with HCC compared with those in healthy controls, individuals with chronic hepatitis B and patients with HBV-induced liver cirrhosis. The area under receiver operating characteristic curves (AUC) was 0.791 for Fibulin-1, 0.640 for α-fetoprotein and 0.868 for the combination of the two tumor markers. Our findings indicate that Fibulin-1 may be a potential prognostic indicator, a promising serum biomarker and a therapeutic target in patients with HCC.