Filamin A is involved in human intrahepatic cholangiocarcinoma aggressiveness and progression
Eleonora Vitali, Barbara Franceschini, Flavio Milana, Cristiana Soldani, Michela Anna Polidoro, Roberta Carriero, Paolo Kunderfranco, Giampaolo Trivellin, Guido Costa, Giulia Milardi, Luca Di Tommaso, Guido Torzilli, Ana Lleò, Andrea Lania, Matteo Donadon
Abstract
Abstract 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.