Purpose

Circular RNAs (circRNAs) constitute a class of regulatory RNAs that are thought to play important roles in tumor initiation and progression. Several studies have reported that circRNAs may be involved in various biological processes via networks of competing endogenous RNAs (ceRNAs). However, the regulatory roles and underlying mechanisms of circRNAs in cervical cancer (CC) still largely remain to be resolved.

Methods

CircNFATC3 (hsa_circ_0005615) expression was assessed in CC cell lines (SiHa, H8) using circRNA microarray analysis, whereas qRT-PCR was used to detect circNFATC3 and miR-9-5p expression in primary human CC tissues and cell lines. The tumor promoting role of circNFATC3 was verified in CC cells using a series of functional assays, and interactions between circNFATC3, miR-9-5p and syndecan-2 (SDC2) were investigated using dual-luciferase reporter assays. SDC2 protein expression was detected using Western blotting and immunohistochemistry. The tumor promoting role of circNFATC3 was confirmed in vivo using a CC xenograft model.

Results

We found that circNFATC3 expression was upregulated in primary CC tissues and positively correlated with CC tumor size and stromal invasion. In addition, we found that exogenous circNFATC3 overexpression enhanced the proliferation, migration and invasion of HeLa cells, while its knockdown reduced the malignancy of SiHa cells. We also found that circNFATC3 may act directly as a miR-9-5p sponge to regulate SDC2 expression and its downstream signaling pathways, thereby enhancing CC development.

Conclusion

Our data indicate that circNFATC3 sponges miR-9-5p to regulate SDC2 expression and, thereby, to promote CC tumor development.

中文翻译：

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环状 RNA circNFATC3 作为 miR-9-5p 海绵，通过上调 SDC2 促进宫颈癌的发展。

 目的

环状RNA（circRNA）构成一类调节RNA，被认为在肿瘤的发生和进展中发挥重要作用。多项研究表明，circRNA 可能通过竞争性内源 RNA (ceRNA) 网络参与各种生物过程。然而，circRNA在宫颈癌（CC）中的调控作用和潜在机制在很大程度上仍有待解决。

 方法

使用circRNA微阵列分析评估CC细胞系（SiHa，H8）中的CircNFATC3（hsa_circ_0005615）表达，而qRT-PCR用于检测原代人CC组织和细胞系中的circNFATC3和miR-9-5p表达。使用一系列功能测定在 CC 细胞中验证了 circNFATC3 的肿瘤促进作用，并使用双荧光素酶报告基因测定研究了 circNFATC3、miR-9-5p 和 syndecan-2 (SDC2) 之间的相互作用。使用蛋白质印迹和免疫组织化学检测SDC2蛋白表达。使用 CC 异种移植模型在体内证实了 circNFATC3 的肿瘤促进作用。

 结果

我们发现 circNFATC3 表达在原发性 CC 组织中上调，并且与 CC 肿瘤大小和间质侵袭呈正相关。此外，我们发现外源性circNFATC3过表达增强了HeLa细胞的增殖、迁移和侵袭，而其敲低则降低了SiHa细胞的恶性程度。我们还发现，circNFATC3可能直接作为miR-9-5p海绵来调节SDC2表达及其下游信号通路，从而促进CC的发育。

 结论

我们的数据表明，circNFATC3 海绵 miR-9-5p 来调节 SDC2 表达，从而促进 CC 肿瘤的发展。