Increased Expression of Fibulin-1 Is Associated With Hepatocellular Carcinoma Progression by Regulating the Notch Signaling Pathway
Jiao Gong, Yusheng Jie, Cuicui Xiao, Wenying Zhou, Xinhua Li, Yaqiong Chen, Yuankai Wu, Jing Cao, Qi Zhang, Zhiliang Gao, Bo Hu, Yutian Chong
Abstract
Fibulin-1, a component of the extracellular matrix (ECM), its prognostic, pathophysiologic and diagnostic role in hepatocellular carcinoma (HCC) has not yet been reported. We first found that either Fibulin-1 messenger RNA (mRNA) or protein expression was highly overexpressed in HCC tissues compared with normal tissues, which was associated with overall survival. Moreover, Fibulin-1 was an independent prognostic predictor for overall survival (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 a-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.