MiR-135a-5p/STAT6-mediated EMT regulates IL-4 secretion in non-small cell lung cancer to affect M2-like TAM polarization

Abstract

Arginase 1 (Arg1), a key indicator of M2 polarization in tumor-associated macrophages (TAMs), plays a crucial role in inhibiting T-cell activation and proliferation by depleting local arginine levels, thereby facilitating tumor immune escape. The epithelial–mesenchymal transition (EMT), a fundamental biological process in cancer proliferation and progression, is intricately linked to the interactions between TAMs and cancer cells. However, the underlying mechanisms of EMT and how EMT-programmed cancer cells specifically modulate Arg1 expression in M2-like TAMs remain incompletely understood. Our comprehensive analysis confirmed that Arg1 expression was significantly upregulated in non-small cell lung cancer (NSCLC) tissues, and patients with elevated Arg1 levels exhibited a notably shorter overall survival. Furthermore, alterations in miR-135a-5p expression were found to profoundly influence the proliferation, migration, invasion, EMT, and apoptotic processes of NSCLC cells. Mechanistically, miR-135a-5p post-transcriptionally inhibited STAT6 expression by regulating its 3′-untranslated region (3’-UTR). Subsequently, the miR-135a-5p/STAT6 axis inhibited GATA3-mediated interleukin-4 (IL-4) secretion from NSCLC cells, ultimately suppressing Arg1 expression in M2-like TAMs. MiR-135a-5p may exert pivotal roles in modulating STAT6-induced EMT in tumor cells, which subsequently impacts IL-4-related Arg1 expression and M2 polarization of TAMs in NSCLC. This, in turn, reduced the capacity of M2-like TAMs to secrete tumor-promoting cytokines. Therefore, Arg1 holds potential as a diagnostic biomarker for NSCLC, and miR-135a-5p may emerge as a promising target for inhibiting NSCLC progression.