Abstract

Tumour microenvironment (TME) is frequently remodelled and deregulated in cancer development and progression. The underlying mechanisms are complex, multifactorial and largely unknown. Circular RNA (circRNA) is an endogenous RNA with a covalently closed loop that plays critical roles in the pathological and physiological processes of the organism. Here, we identified a TME-associated circRNA, circ-TPGS2, which promoted breast cancer (BC) cell dissemination via altering TME. High circ-TPGS2 was observed in metastatic BC tissues and cell lines in comparison to respective normal controls, which was linked to poor overall and recurrence-free survival. Overexpression of circ-TPGS2 notably promoted cell migration, while silencing of circ-TPGS2 resulted in an opposite trend. Moreover, circ-TPGS2 increased pro-inflammatory chemokine production and evoked tumour-associated inflammation by recruiting neutrophils via autocrine and paracrine manners. In terms of mechanism, circ-TPGS2 acted as a sponge of miR-7 and elevated TRAF6, leading to p65 phosphorylation and nuclear translocation, ultimately activating NF-κB signalling. In addition, p65 was abundantly occupied on circ-TPGS2 promoter, activating circ-TPGS2 transcription, thus, forming a positive feedback loop that amplified the pro-metastasis effect of circ-TPGS2. Taken together, our data for the first time reveal the biological implication of circ-TPGS2 in BC, it triggers TME reshaping that facilitates BC metastasis through the miR-7/TRAF6/NF-κB signalling cascade.

摘要

肿瘤微环境 (TME) 在癌症的发展和进展中经常被重塑和解除管制。潜在的机制是复杂的、多因素的并且在很大程度上是未知的。环状RNA（circRNA）是一种具有共价闭合环的内源性RNA，在生物体的病理和生理过程中起关键作用。在这里，我们发现了一种 TME 相关的 circRNA，circ-TPGS2，它通过促进乳腺癌 (BC) 细胞传播改变 TME。与各自的正常对照相比，在转移性 BC 组织和细胞系中观察到高 circ-TPGS2，这与较差的总体生存率和无复发生存率有关。circ-TPGS2 的过表达显着促进了细胞迁移，而 circ-TPGS2 的沉默导致了相反的趋势。此外，circ-TPGS2通过募集中性粒细胞增加促炎趋化因子的产生并诱发肿瘤相关炎症。自分泌和旁分泌方式。就机制而言，circ-TPGS2 充当 miR-7 的海绵并升高 TRAF6，导致 p65 磷酸化和核转位，最终激活 NF-κB 信号传导。此外，p65 大量占据 circ-TPGS2 启动子，激活 circ-TPGS2 转录，从而形成正反馈环，放大 circ-TPGS2 的促转移作用。总之，我们的数据首次揭示了 circ-TPGS2 在 BC 中的生物学意义，它触发了 TME 重塑，通过 miR-7/TRAF6/NF-κB 信号级联促进 BC 转移。