HSP27/IL-6 axis promotes OSCC chemoresistance of cisplatin, migration and invasion by orchestrating macrophages via a positive feedback loop

The mechanisms of interaction and crosstalk between tumor cells and tumor-associated macrophages (TAMs) have provided novel options for intervening in tumor progression. However, the molecular mechanisms of the interaction between the tumor cells and TAMs underlying oral squamous cell carcinoma (OSCC) invasio, migration and chemoresistance remain unclear. This study sought to specifically investigate the role of the tumor-cell-derived paracrine heat shock protein 27 (HSP27) in OSCC invasion, migration and chemoresistance and the potential molecular mechanisms of the interaction between the tumor cells and TAMs. In this study, bioinformatic analysis and IHC results demonstrated that the expression level of HSP27 was higher in the tissues of patients with advanced lymph node metastasis of OSCC than that in early stage non-metastatic patients, and that its expression level was positively correlated with the levels of multidrug resistance-associated proteins and macrophage infiltration. In vivo, Survival of low-expressing HSP27 xenograft model mice was inferior to that of controls. In vitro, TAMs-CM significantly up-regulated the expression level of HSP27 in the two types of OSCC tumor cells including CAL27 and SCC9 cells. The OSCC tumor cell-derived HSP27 regulated TAMs through paracrine mode and reduced the level of apoptosis induced by the chemotherapeutic drug cisplatin in tumor cells, thus promoting chemoresistance in OSCC. HSP27 promoted the secretion of cytokine IL-6 from TAMs, whereas TAMs-derived IL-6 up-regulated the expression of HSP27 and enhanced the chemoresistance, migration and invasion of OSCC in tumor cells through an autocrine mode and activates the β-catenin pathway during this process, additionally up-regulated the stem cell properties of tumor cells through an autocrine manner. Tumor-cell-derived paracrine HSP27 promoted OSCC invasion and migration through enhancing the epithelial–mesenchymal transition (EMT) of tumor cells via binding to toll-like receptor 4 (TLR4) on the surface of the TAMs. HSP27/TLR4 induced polarization of the TAMs to an M2-like phenotype and the secretion of IL-6 in the TAMs. Respectively, TAMs-derived IL-6 enhanced OSCC invasion and migration via autocrine HSP27/TLR4 signaling in tumor cells while IL-6 promoted the EMT of tumor cells via autocrine HSP27. Collectively, tumor-cell-derived paracrine HSP27 promoted OSCC migration, invasion and chemoresistance by orchestrating macrophage M2 polarization and IL-6 secretion from macrophages via a positive feedback loop . TAM-derived IL-6 enhanced these progressions via autocrine HSP27/IL-6 signaling in tumor cells. Targeting HSP27/IL-6 may be an effective treatment strategy for OSCC patients, and it is expected to control OSCC progression and improve its prognosis and recurrence in patients.