Filamin A is involved in human intrahepatic cholangiocarcinoma aggressiveness and progression.

Autor: Vitali E; Laboratory of Cellular and Molecular Endocrinology, IRCCS Humanitas Research Hospital, Milan, Italy., Franceschini B; Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, Milan, Italy., Milana F; Division of Hepatobiliary and General Surgery, Department of Surgery, IRCCS Humanitas Research Hospital, Milan, Italy., Soldani C; Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, Milan, Italy., Polidoro MA; Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, Milan, Italy., Carriero R; Bioinformatics Unit, IRCCS Humanitas Research Hospital, Milan, Italy., Kunderfranco P; Bioinformatics Unit, IRCCS Humanitas Research Hospital, Milan, Italy., Trivellin G; Laboratory of Cellular and Molecular Endocrinology, IRCCS Humanitas Research Hospital, Milan, Italy., Costa G; Division of Hepatobiliary and General Surgery, Department of Surgery, IRCCS Humanitas Research Hospital, Milan, Italy., Milardi G; Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, Milan, Italy., Di Tommaso L; Department of Biomedical Sciences, Humanitas University, Milan, Italy.; Pathology Department, Humanitas Clinical and Research Center-IRCCS, Milan, Italy., Torzilli G; Division of Hepatobiliary and General Surgery, Department of Surgery, IRCCS Humanitas Research Hospital, Milan, Italy.; Department of Biomedical Sciences, Humanitas University, Milan, Italy., Lleo A; Department of Biomedical Sciences, Humanitas University, Milan, Italy.; Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy., Lania AG; Department of Biomedical Sciences, Humanitas University, Milan, Italy.; Endocrinology, Diabetology and Medical Andrology Unit, IRCCS Humanitas Research Hospital, Milan, Italy., Donadon M; Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy.; Department of General Surgery, University Maggiore Hospital, Novara, Italy.
Jazyk: angličtina
Zdroj: Liver international : official journal of the International Association for the Study of the Liver [Liver Int] 2024 Feb; Vol. 44 (2), pp. 518-531. Date of Electronic Publication: 2023 Nov 27.
DOI: 10.1111/liv.15800
Abstrakt: Background & Aims: Intrahepatic cholangiocarcinoma (iCCA) is a primary liver tumour, characterized by poor prognosis and lack of effective therapy. The cytoskeleton protein Filamin A (FLNA) is involved in cancer progression and metastasis, including primary liver cancer. FLNA is cleaved by calpain, producing a 90 kDa fragment (FLNA CT ) that can translocate to the nucleus and inhibit gene transcription. We herein aim to define the role of FLNA and its cleavage in iCCA carcinogenesis.
Methods & Results: We evaluated the expression and localization of FLNA and FLNA CT in liver samples from iCCA patients (n = 82) revealing that FLNA expression was independently correlated with disease-free survival. Primary tumour cells isolated from resected iCCA patients expressed both FLNA and FLNA CT , and bulk RNA sequencing revealed a significant enrichment of cell proliferation and cell motility pathways in iCCAs with high FLNA expression. Further, we defined the impact of FLNA and FLNA CT on the proliferation and migration of primary iCCA cells (n = 3) and HuCCT1 cell line using silencing and Calpeptin, a calpain inhibitor. We observed that FLNA silencing decreased cell proliferation and migration and Calpeptin was able to reduce FLNA CT expression in both the HuCCT1 and iCCA cells (p < .05 vs. control). Moreover, Calpeptin 100 μM decreased HuCCT1 and primary iCCA cell proliferation (p <.00001 vs. control) and migration (p < .05 vs. control).
Conclusions: These findings demonstrate that FLNA is involved in human iCCA progression and calpeptin strongly decreased FLNA CT expression, reducing cell proliferation and migration.
(© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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