ACTL6A accelerates the progression of NSCLC through hippo/YAP signaling axis and TAMs-mediated immune regulation.

Lung cancer is one of the deadliest cancers in the world with non-small cell lung cancer (NSCLC) being the most common subtype. Although advanced NSCLC patients undergone comprehensive treatment, their prognosis remains poor. Recent studies have elucidated that actin-like 6 A (ACTL6A) is aberrantly elevated in various cancers and acts as a driver of tumor progression. However, the main effect and mechanism of ACTL6A on NSCLC remains obscure. Databases, NSCLC tissue samples and cell lines were employed to investigate the ACTL6A expression levels in NSCLC using immunohistochemistry, western blot and qRT-PCR assays. CCK-8, wound healing assay, transwell assay, cell cycle analysis, in vivo animal experiment and other assays were performed to determine the effect of ACTL6A on NSCLC and uncover its underlying mechanism. Finally, the effect of NSCLC cell lines and tissues with varying ACTL6A expression levels on tumor-associated macrophages (TAMs) was determined. ACTL6A was overexpressed in both NSCLC cells and tissues. Furthermore, the elevated ACTL6A expression induced cell proliferation, migration, epithelial-to-mesenchymal transition and in vivo tumorigenicity of NSCLC cells to increase. The knockdown of ACTL6A induced G1 phase cell cycle arrest. And the Hippo signaling pathway was inactivated in ACTL6A-overexpressing NSCLC cells with the suppression p-YAP expression, resulting in the translocation of YAP to the nucleus, while ACTL6A knockdown cells resulted in opposite changes. What's more, ACTL6A-interfered NSCLC cells mainly regulate the expression of TEAD1 and TEAD4 to affect the migration capabilities. Interestingly, the high ACTL6A expressions in NSCLC tissues were correlated with the levels of MRC1+CD68+ TAMs, while deleting macrophages could inhibit ACTL6A-driven tumor progression. Moreover, the condition mediums from ACTL6A-overexpressing NSCLC cells promoted TAMs to present the M2 phenotype and facilitated the migration of M2-TAMs through CSF1. This means that ACTL6A-overexpressing NSCLC cells may induce TAMs into M2 polarization and recruit M2-TAMs to the tumor microenvironment, which in turn, may promote the development of NSCLC. ACTL6A accelerates the progression of NSCLC by modulating the Hippo/YAP signaling axis and influencing TAMs-mediated immune regulation through CSF1.