MFAP5 facilitates the aggressiveness of intrahepatic Cholangiocarcinoma by activating the Notch1 signaling pathway

Abstract

BackgroundIntrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer. The dismal outcome of ICC patients is due to lack of early diagnosis, the aggressive biological behavior of ICC and the lack of effective therapeutic options. Early diagnosis and prognosis of ICC by non-invasive methods would be helpful in providing valuable information and developing effective treatment strategies.MethodsExpression of microfibrillar-associated protein 5 (MFAP5) in the serum of ICC patients was detected by ELISA. Human ICC specimens were immunostained by MFAP5 antibodies. The growth rate of human ICC cell lines treated with MFAP5 or MFAP5 shRNAs was examined by CCK8 and colony formation assays. Cell cycle analysis was performed with PI staining. The effect of MFAP5 inhibition was assessed by xenograft models in nude mice. RNA-seq and ATAC-seq analyses were used to dissect the molecular mechanism by which MFAP5 promoted ICC aggressiveness.ResultsWe identified MFAP5 as a biomarker for the diagnosis and prognosis of ICC. Upregulated MFAP5 is a common feature in aggressive ICC patients’ tissues. Importantly, MFAP5 level in the serum of ICC patients and healthy individuals showed significant differential expression profiles. Furthermore, we showed that MFAP5 promoted ICC cell growth and G1 to S-phase transition. Using RNA-seq expression and ATAC-seq chromatin accessibility profiling of ICC cells with suppressed MFAP5 secretion, we showed that MFAP5 regulated the expression of genes involved in the Notch1 signaling pathway. Furthermore, FLI-06, a Notch signaling inhibitor, completely abolished the MFAP5-dependent transcriptional programs.ConclusionsRaised MFAP5 serum level is useful for differentiating ICC patients from healthy individuals, and could be helpful in ICC diagnosis, prognosis and therapies.

Microfibrillar-associated protein 5 regulates osteogenic differentiation by modulating the Wnt/β-catenin and AMPK signaling pathways

“…However, the p-AMPK level fell after MFAP5 knockdown, suggesting that AMPK signaling was involved in the MFAP5 regulation of osteogenesis. Of note, MFAP5 activated Notch 1 signaling in certain tumors, promoting tumor invasion and migration (Chen et al 2020 ; Li et al 2019 ). Notch 1 signaling is also involved in osteogenesis (Díaz-Tocados et al 2017 ; Fan et al 2016 ; Fan et al 2021 ).…”

Notch signalling pathway in development of cholangiocarcinoma

“…It facilitates the aggressiveness of IH-CAA by activating the Notch1 signalling pathway. A gamma secretase inhibitor, FLI-06, has been found to completely abolish the MFAP5- dependent Notch activation in CCA[ 84 ]. Crenigacestat is a LY3039478-specific inhibitor.…”

The preoperative prognostic value of the radiomics nomogram based on CT combined with machine learning in patients with intrahepatic cholangiocarcinoma

“…Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver carcinoma, accounting for 10–15% of all primary liver malignancies [ 1 – 4 ]. In recent years, the incidence and mortality of ICC were increasing worldwide, albeit the incidence was still lower than hepatocellular carcinoma [ 5 , 6 ].…”