Laminin β1 stimulates the Hippo-YAP1 pathway to advance the progression and lenvatinib resistance in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common and fatal solid cancers worldwide, particularly in Asian countries. Alterations in extracellular matrix (ECM) contribute to HCC development, yet the precise underlying mechanisms remain unclear. Laminin β1 (LAMB1), which is an ECM component, plays a central role in regulating ECM dynamics. Herein, we aim to explore the role of LAMB1 in HCC progression and its therapeutic potential. LAMB1 levels in HCC and paired normal tissues recorded in publicly available databases were statistically compared. Immunohistochemistry and enzyme-linked immunosorbent assay were performed to examine the correlation between LAMB1 expression and HCC progression. Cell growth assays and animal tumor models were employed to demonstrate the oncogenic role of LAMB1. Dual-luciferase reporter assays were conducted to study the regulatory mechanism of LAMB1 expression. RNA sequencing analysis was used to identify the LAMB1-modulated signaling effectors, which were further validated by quantitative real-time PCR, Western blotting, co-immunoprecipitation, and confocal fluorescence microscopy. We found that LAMB1 is upregulated in HCC and significantly correlated with advanced tumor stage and poor patient prognosis. LAMB1 promoted HCC cell proliferation both in vitro and in vivo. Mechanistically, LAMB1 induces FAK and SRC phosphorylation via its engagement with integrin beta 1 on the cell surface, leading to the nuclear translocation of YAP1, a transcriptional co-activator of Hippo pathway. Nuclear YAP1 subsequently binds TEAD4, which is an upstream transcription factor for LAMB1, and thus constituting a positive feedback loop in HCC progression. Notably, administration with LAMB1 C-peptide, a LAMB1 C-terminal fragment that competes for integrin binding, markedly enhances the efficacy of lenvatinib in treating HCC. Additionally, serum LAMB1 demonstrates superior diagnostic performance compared to the classic HCC marker alpha-fetoprotein. LAMB1 represents a promising therapeutic target for HCC, and also serves as a potential circulating biomarker for liver cancer screening in clinics.