Filamin A is involved in human intrahepatic cholangiocarcinoma aggressiveness and progression

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.