Department of Biomedical Sciences, JCC College of Veterinary Medicine and Life Science, City University of Hong Kong, Hong Kong SAR, China.
CityU Shenzhen Research Institute, Shenzhen, China.
Int J Biol Sci. 2022 May 21;18(9):3697-3713. doi: 10.7150/ijbs.70013. eCollection 2022.
It is still a big puzzle how ovarian cancer cells and the tumor microenvironment (TME) attract lymphocytes infiltration for facilitating metastasis, a leading cause of death from gynecological malignancies. Using genome-wide LncRNA microarray assay, here we report that a LncRNA associated with ovarian cancer metastasis (LncOVM) is highly correlated with poor prognosis and survival. LncOVM interacts with and stabilizes PPIP5K2 by suppressing ubiquitinated degradation to promote complement C5 secretion from ovarian cancer cells. The TME-enriched complement C5 attracts myeloid-derived suppressor cells (MDSCs) infiltration in TME to facilitate metastasis. Knockdown of LncOVM or PPIP5K2 inhibits tumor progression in xenograft models. Application of C5aR antibody or inhibitor (CCX168) inhibits MDSC recruitment and restores the suppression of tumorigenesis and metastasis . Our study reveals that suppression of ovarian cancer metastasis can be achieved by targeting MDSC infiltration in TME through disrupting LncOVM-PPIP5K2-complement axis, providing an option for treating ovarian cancer patients.
卵巢癌细胞和肿瘤微环境（TME）如何吸引淋巴细胞浸润以促进转移仍然是一个大难题，转移是妇科恶性肿瘤死亡的主要原因。在这里，我们使用全基因组长非编码 RNA 微阵列分析，报告了一个与卵巢癌转移相关的长非编码 RNA（LncOVM）与不良预后和生存高度相关。LncOVM 通过抑制泛素化降解与 PPIP5K2 相互作用并稳定其表达，从而促进卵巢癌细胞中补体 C5 的分泌。富含 TME 的补体 C5 吸引髓系来源的抑制细胞（MDSCs）浸润到 TME 中，促进转移。敲低 LncOVM 或 PPIP5K2 可抑制异种移植模型中的肿瘤进展。应用 C5aR 抗体或抑制剂（CCX168）可抑制 MDSC 募集并恢复对肿瘤发生和转移的抑制作用。我们的研究表明，通过破坏 LncOVM-PPIP5K2-补体轴靶向 TME 中的 MDSC 浸润，可以实现对卵巢癌转移的抑制，为治疗卵巢癌患者提供了一种选择。
