SYVN1 aggravates esophageal squamous cell carcinoma development by activating NF-κB pathway to facilitate macrophage...

Esophageal squamous cell carcinoma (ESCC) is a leading lethal cancer in the digestive system. Tumor-associated macrophages (TAMs) are key participators in ESCC progression. Mounting evidence has testified the regulatory function of synoviolin (SYVN1) in cancer development. However, the correlation between SYVN1 and TAM polarization remains unclear. As a result, the goal of the present study was to shed light on the new mechanism of SYVN1 in ESCC.

Collect clinical samples and culture ESCC cell lines to detect SYVN1 expression in ESCC. Construct small interfering RNA targeting SYVN1 and transfect it into ESCC cells to observe its effects on malignant biological processes in cancer cells and macrophage polarization. Use a co-culture system to observe the effects of si-SYVN1 and macrophage polarization on pyroptosis levels in ESCC cells. In addition, we explored the relationship between SYVN1 and pivotal modulatory factors of nuclear factor kappa B (NF-κB) signaling pathway. In plus, we used a xenograft model to observe the effect of si-SYVN1 on subcutaneous tumor growth.

It was found that SYVN1 was upregulated at messenger RNA (mRNA) and protein levels in tissue samples and cells of ESCC. Knocking down of SYVN1 attenuated the malignant behaviors of ESCC cells in vitro and in vivo. Of note, we verified that silencing SYVN1 contributed to the polarization of TAMs into M1 subtype. Moreover, our findings demonstrated that SYVN1 mediated cell pyroptosis through modulating TAM polarization. Our observations revealed that SYVN1 directly bound with DEAD-box helicase 5 (DDX5) and eukaryotic translation elongation factor 1 alpha 2 (eEF1A2) to enhance their expression. Besides, silencing of SYVN1 inhibited the activation of NF-κB pathway, and overexpression of DDX5 or eEF1A2 abolished the role of SYVN1 deficiency in NF-κB pathway. Furthermore, our findings clarified that DDX5 and eEF1A2 mediated the stimulative function of SYVN1 in ESCC progression and NF-κB pathway was responsible for the effects of SYVN1/DDX5/eEF1A2 axis on ESCC.

Overall, this study illustrated that SYVN1 promoted the M2 polarization of TAMs to induce ESCC progression by targeting DDX5 and eEF1A2 to activate NF-κB pathway.