ALDH3A1 overexpression in OSCC inhibits inflammation via phospho-Ser727 at STAT3 in tumor-associated macrophages.

OBJECTIVES

Cancer-related inflammation (CRI) significantly increases the difficulty of treating oral squamous cell carcinoma (OSCC) and remains a major treatment challenge. Our objective was to determine whether tumor ALDH3A1 could attenuate OSCC tumorigenesis by inhibiting tumor-associated macrophages (TAMs) that promoted CRI.

MATERIALS AND METHODS

ALDH3A1 in Cal27 cells was overexpressed, and the tumor-conditioned medium (TCM) was collected. We induced THP-1 cells with TCM and recombinant human IL-6. The phosphorylation of STAT3 and the TLR4/TRAF6/TBK1 cascade reaction in TAMs was analyzed using Western blotting, and mitochondrial ROS (mtROS) production was measured using a MitoSox kit. A tumorigenicity assay was performed to examine the tumor volume and weight, and the expression of CD68, CD11b, IL-6, Ki67, and CD31 was analyzed via immunohistochemistry.

RESULTS

ALDH3A1 attenuated STAT3 phosphorylation at Ser727 rapidly and mtROS production earlier in TAMs via inhibiting TLR4/TRAF6/TBK1 cascade reaction. MtROS reduction inhibited IL-1β and IL-8 secretions by NLRP3/caspase-1/IL-1β/IL-8 pathway. Meanwhile, the inhibition of pro-tumor phenotypes of TAMs, tumor proliferation, and tumor angiogenesis during the process was proved in vivo.

CONCLUSION

ALDH3A1 was associated closely with CRI and inhibited CRI regulated by TAMs. This finding may achieve clinical transformation and open new therapeutic options for targeting CRI regulated by TAMs.