SP1 诱导的长链非编码 RNA-ZFAS1 通过 miR-150-5p/VEGFA 轴促进结直肠癌的进展。

SP1-induced lncRNA-ZFAS1 contributes to colorectal cancer progression via the miR-150-5p/VEGFA axis.

机构信息

General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, China.

Medical College, Southeast University, Nanjing, 210009, Jiangsu, China.

出版信息

Cell Death Dis. 2018 Sep 24;9(10):982. doi: 10.1038/s41419-018-0962-6.

Increasing long non-coding RNAs (lncRNAs) have been reported to play key roles in the development and progression of various malignancies. ZNFX1 antisense RNA1 (ZFAS1) has been reported to be aberrant expression and suggested as a tumor suppressor or oncogene in many cancers. However, the biological role and underlying molecular mechanism of ZFAS1, especially the miRNA sponge role of which in CRC remain largely unknown. We found that ZFAS1 expression was higher in CRC tissues, where it was associated with poor overall survival (OS), we also showed that ZFAS1 upregulation was induced by nuclear transcription factor SP1. Moreover, ZFAS1 and VEGFA are both targets of miR-150-5p, while ZFAS1 binds to miR-150-5p in an AGO2-dependent manner. Additionally, ZFAS1 upregulation markedly promoted as well as ZFAS1 knockdown significantly suppressed CRC cell proliferation, migration, invasion and angiogenesis, and the inhibitory effect caused by ZFAS1 knockdown could be reversed by antagomiR-150-5p. Lastly, we demonstrated that ZFAS1 knockdown inhibited EMT process and inactivated VEGFA/VEGFR2 and downstream Akt/mTOR signaling pathway in CRC. Our data demonstrated that SP1-induced ZFAS1 contributed to CRC progression by upregulating VEGFA via competitively binding to miR-150-5p, which acts as a tumor suppressor by targeting VEGFA in CRC.

越来越多的长非编码 RNA（lncRNA）被报道在各种恶性肿瘤的发生和发展中发挥关键作用。ZNFX1 反义 RNA1（ZFAS1）的表达异常，并被认为是许多癌症中的肿瘤抑制因子或癌基因。然而，ZFAS1 的生物学功能及其潜在的分子机制，尤其是其在 CRC 中的 miRNA 海绵作用，在很大程度上仍然未知。我们发现 ZFAS1 在 CRC 组织中的表达较高，与总体生存（OS）不良相关，我们还表明 ZFAS1 的上调是由核转录因子 SP1 诱导的。此外，ZFAS1 和 VEGFA 都是 miR-150-5p 的靶标，而 ZFAS1 以依赖 AGO2 的方式结合 miR-150-5p。此外，ZFAS1 的上调显著促进了 CRC 细胞的增殖、迁移、侵袭和血管生成，而 ZFAS1 下调引起的抑制作用可以被 miR-150-5p 的拮抗剂逆转。最后，我们证明 ZFAS1 下调通过竞争性结合 miR-150-5p 来上调 VEGFA，从而抑制 EMT 过程并使 VEGFA/VEGFR2 和下游 Akt/mTOR 信号通路失活，从而抑制 CRC 中的 EMT 过程和 VEGFA/VEGFR2 和下游 Akt/mTOR 信号通路。我们的数据表明，SP1 诱导的 ZFAS1 通过竞争性结合 miR-150-5p 上调 VEGFA 促进 CRC 进展，在 CRC 中通过靶向 VEGFA 发挥肿瘤抑制作用。