ROLE OF KIF4A IN THE FXa-INDUCED PHENOTYPIC MODULATION OF PLEURAL MESOTHELIAL CELLS

Pleural injuries can disrupt the organization of the pleural surface, leading to pleural remodeling and fibrosis (PF), characterized by the proliferation of myofibroblasts expressing alpha-smooth muscle actin (α-SMA) and the deposition of extracellular matrix proteins, primarily due to the mesenchymal transition of pleural mesothelial cells (PMCs) (MesoMT). It is well established that various external stimuli, such as TGF-β, thrombin, and factor Xa (FXa), induce MesoMT. Our laboratory found that myocardin, a transcriptional co-activator, was dramatically up-regulated during MesoMT, and that gene silencing of myocardin (MyoCD) diminished MesoMT. RNA sequencing data showed that FXa activated a set of genes not upregulated by TGF-β or thrombin, and this activation was diminished by MyoCD knockdown (KD), among which KIF4A was identified as a novel effector gene. Moreover, we found that KIF4A was overexpressed in the pleura of mouse disease models. We studied the effect of FXa and KIF4A KD on the mRNA and protein expression of profibrotic markers. KIF4A gene silencing markedly downregulated MyoCD expression, suggesting a functional association or interaction between KIF4A and MyoCD. KIF4A gene silencing diminished the expression of alpha-SMA and calponin, which are critical components of stress fibers and markers of MesoMT. Consistently, KIF4A KD diminished stress fiber formation of HPMCs. Our results suggest that the interaction of MyoCD and KIF4A may play a role in the development of MesoMT and pleural fibrosis.