miR-200c-3p, miR-222-5p, and miR-512-3p Constitute a Biomarker Signature of Sorafenib Effectiveness in Advanced Hepatocellular Carcinoma

作者：Patricia de la Cruz‐Ojeda, Tobias Schmid, Loreto Boix, M Angeles Galvez Moreno, Víctor Sapena, Juan Manuel Praena‐Fernández, Francisco J. Castell, Juan Manuel Falcón‐Pérez, María Reig, Bernhard Brüne, Miguel Ángel Gómez‐Bravo, Álvaro Giráldez Gallego, Jordi Bruix, M.T. Ferrer, Jordi Muntané · 发表于：Cells · 年份：2022 · DOI：10.3390/cells11172673 · 被引用次数：28 · 研究领域：Extracellular vesicles in disease、Hepatocellular Carcinoma Treatment and Prognosis、MicroRNA in disease regulation

BACKGROUND: Sorafenib constitutes a suitable treatment alternative for patients with advanced hepatocellular carcinoma (HCC) in whom atezolizumab + bevacizumab therapy is contraindicated. The aim of the study was the identification of a miRNA signature in liquid biopsy related to sorafenib response. METHODS: miRNAs were profiled in hepatoblastoma HepG2 cells and tested in animal models, extracellular vesicles (EVs), and plasma from HCC patients. RESULTS: Sorafenib altered the expression of 11 miRNAs in HepG2 cells. miR-200c-3p and miR-27a-3p exerted an anti-tumoral activity by decreasing cell migration and invasion, whereas miR-122-5p, miR-148b-3p, miR-194-5p, miR-222-5p, and miR-512-3p exerted pro-tumoral properties by increasing cell proliferation, migration, or invasion, or decreasing apoptosis. Sorafenib induced a change in EVs population with an increased number of larger EVs, and promoted an accumulation of miR-27a-3p, miR-122-5p, miR-148b-3p, miR-193b-3p, miR-194-5p, miR-200c-3p, and miR-375 into exosomes. In HCC patients, circulating miR-200c-3p baseline levels were associated with increased survival, whereas high levels of miR-222-5p and miR-512-3p after 1 month of sorafenib treatment were related to poor prognosis. The RNA sequencing revealed that miR-200c-3p was related to the regulation of cell growth and death, whereas miR-222-5p and miR-512-3p were related to metabolic control. CONCLUSIONS: The study showed that Sorafenib regulates a specific miRNA signature in ...