Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, PR China.
Department of Laboratory Medicine, Affiliated Tumor Hospital of Nantong University, Nantong, Jiangsu Province, PR China.
Int Immunopharmacol. 2023 Jun;119:110121. doi: 10.1016/j.intimp.2023.110121. Epub 2023 Apr 10.
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.
胃癌相关间充质干细胞（GC-MSCs）已被证明以旁分泌的方式促进胃癌的进展。GC-MSCs 高度分泌 IL-8，这对于其致癌功能至关重要。然而，GC-MSCs 中 IL-8 分泌的调节机制尚未得到充分阐明。在这项研究中，使用 Shbio-human ceRNA 芯片鉴定了 GC-MSCs 和骨髓间充质干细胞（BM-MSCs）之间失调的 mRNAs 和 circRNAs。IL-8 被验证为 GC-MSCs 促进胃癌细胞迁移和侵袭的关键旁分泌细胞因子。circ_0073453 被鉴定为一种新型 GC-MSC 衍生的 circRNA，它作为 miR-146a-5p 的海绵，从而增加 IL-8 的表达和分泌，促进胃癌细胞转移。此外，circ_0073453 通过 GC-MSCs 调节 IL-8 的分泌，增强胃癌细胞 PD-L1 的表达，以抵抗细胞毒性 CD8 T 细胞的杀伤。circ_0073453/miR-146a-5p/IL-8 轴在胃癌组织中失调，并根据肿瘤组织中 MSC 丰度与预后相关。总之，我们的研究结果表明，circ_0073453/miR-146a-5p/IL-8 轴对于 GC-MSCs 促进胃癌进展至关重要。因此，hsa_circ_0073453 可能是胃癌的潜在治疗靶点。
