Abstract
Ovarian cancer is a leading cause of death from gynecological malignancies worldwide. Due to the asymptomatic nature and lack of effective screening options in early stage, over 75% of ovarian cancer patients are diagnosed at advanced stages (stage III/IV). It is urgently needed to identify biomarkers and therapeutic targets for treating ovarian cancer patients.Current studies indicate that many lncRNAs are involved in various physiologic and pathologic processes including development, immune response, and tumorigenesis, and play a crucial functional role in dysregulated cancer cell signaling pathways. A bifunctional inositol kinase, inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 2 (PPIP5K2), has been reported to regulate various biological processes, including apoptosis, vesicle trafficking, cytoskeletal dynamics, exocytosis, and so on. However, few studies have discussed the role of PPIP5K2 in cancer cells.
In this study, we have revealed an important role of the lncRNA of ovary cancer metastasis (lncOVM). Employed with LncRNA microarray analysis, we show that the elevated lncOVM is highly correlated with metastasis and poor prognosis/survival in ovary cancer patients. Then we performed the Immunoprecipitation (IP) and mass spectrometry (MS), RNA pull-down assay, immunofluorescence analysis and Fluorescent in situ hybridzation (FISH) to identify the interaction and location of LncOVM and PPIP5K2. Data show LncOVM forms a complex with PPIP5K2. LncOVM deficiency induces PPIP5K2 ubiquitination and degradation, and suppression of cancer metastasis. LncOVM/PPIP5K2 complex localizes and remodels the Golgi complex, leading to enhanced cytokine secretion including complement C5, which identified by ITRAQ assay and western bolt assay. Moreover, we report that the up-regulated secreted complement C5 promotes local MDSC recruitment for cancer metastasis. In xenografted nude mice models, depletion of LncOVM or PPIP5K2 inhibits tumor growth and metastasis. In addition, we treat the C5aR antibody and C5aR inhibitor CCX168 on C57BL/6 mice bearing ID8 tumor. The both treatments inhibit MDSC recruitment and restores the suppression of tumorigenesis in immunocompetent mice.
Results from our study demonstrates a novel mechanism of cytosol lncRNA-protein complex in modifying Golgi structure for regulating local immunity on cancer metastasis.
| Date of Award | 14 Jun 2022 |
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| Original language | English |
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| Supervisor | Mingliang HE (Supervisor) |