Hsa_circ_0073453 modulates IL-8 secretion by GC-MSCs to promote gastric cancer progression by sponging miR-146a-5p

Abstract

Gastric cancer associated mesenchymal stem cells (GC-MSCs) have been demonstrated to promote gastric cancer progression in a paracrine manner. IL-8 is highly secreted by GC-MSCs and is crucial for their oncogenic function. However, the mechanism underlying the modulation of IL-8 secretion by GC-MSCs has not been well elucidated. In this study, Shbio-human ceRNA array was used to identify dysregulated mRNAs and circRNAs between GC-MSCs and bone marrow derived mesenchymal stem cells (BM-MSCs). IL-8 was validated to be a critical paracrine cytokine for GC-MSCs promoting migration and invasion of gastric cancer cells. circ_0073453 was identified as a novel GC-MSC-derived circRNA which acted as a sponge of miR-146a-5p, thus increasing IL-8 expression and secretion to promote gastric cancer cell metastasis. Furthermore, circ_0073453 modulated IL-8 secretion by GC-MSCs to enhance gastric cancer cells PD-L1 expression to resist cytotoxic CD8⁺ T cell-killing. circ_0073453/miR-146a-5p/IL-8 axis was deregulated in gastric cancer tissues and associated with prognosis depending on MSC abundance in cancer tissues. Taken together, our findings suggest that circ_0073453/miR-146a-5p/IL-8 axis is critical for GC-MSCs promoting gastric cancer progression. Hence, hsa_circ_0073453 may be a potential therapeutic target for gastric cancer.

Keywords: Gastric cancer; Hsa_circ_0073435; IL-8; Mesenchymal stem cells; miR-146a-5p.