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.