Abstract 1526: KPNA4 promotes prostate cancer metastasis through TNFα/β mediated cytokine crosstalk in tumor microenvironment

Abstract

Abstract Prostate cancer (PCa) is one of the most common types of cancer for man in worldwide. Distant metastasis to multiple organs is the key lethal factor for PCa patients, still, little is known about the molecular mechanism. Here, we reveal that Karyophorin α4 (KPNA4), an importin family member, mediated cytokine crosstalk plays a critical role in PCa skeletal metastasis. Both IHC staining of KNNA4 on human PCa tissue microarray slides and KPNA4 expression in a TCGA (The Cancer Genome Atlas) dataset demonstrates a positive association between KPNA4 and the pathological stages as well as the Gleason scorse of human prostate cancer. Accordingly, transient knockdown of KPNA4 in multiple PCa cell lines reduces cell migration in vitro. Furthermore, stable knockdown of KPNA4 in PC3 cell line (PC3-shKPNA4) significantly attenuates the primary tumor invasion and bone metastasis in our experimental orthotopic and metastatic mouse models. Cytokines array assays reveal that KPNA4 knockdown reduces to the production of primary cytokines TNF-α and β in PCa cells. Since TNF α and β are the central inflammatory cytokines in the complicated cytokines network as well as immune response, TNF α and β could mediate the effects of KPNA4 on PCa metastasis through priming tumor microenvironment. As expected, TNF-α/β can rescue the migration capacity of PC3-shKPNA4 as well as the M2 polarization of tumor-associated macrophages. Furthermore, PC3-shKPNA4 derived conditioned medium suppresses the inflammatory response of RAW264.7 cells, supporting the critical role of KPNA4 in regulating the tumor-microenvironment. It is known that the formation of metastatic lesion in bone environment is enhanced by activated bone resorption. In addition to modulating the tumor microenvironment adjacent to the primary tumors, TNF-α/β also favor PCa metastasis by restoring the osteoclast formation and activity suppressed by PC3-shKPNA4. Interestingly, only the protein but not the RNA level of KPNA4 is dramatically increased in PCa cells. Therefore, the dysregulation of KPNA4 in PCa cells could be mediated by a post-transcriptional process. Indeed, through bioinformatical screening and transient infection, KPNA4 is identified as a target of miR-708, a tumor suppressive miRNA reported in multiple types of cancer. Supporting the increased expression of KPNA4, miR-708 level is radically inhibited in PCa cells. Collectively, our data reveal a novel mechanism mediated by KPNA4 that links the loss function of miR-708 and the activation of cytokines in facilitating the metastasis of prostate cancer. The KPNA4/TNF axis stimulates PCa metastasis by promoting cancer cell mobility, priming tumor micro-environment nearby and distantly. These findings shed light on the molecular mechanism of prostate cancer metastasis in terms of the regulation of cytokines crosstalk which provides a potential new diagnosis biomarker and therapeutic target for prostate cancer treatment. Citation Format: Jian Yang, Cuijie Lu, Juncheng Wei, Wendi Liu, Yuqi Guo, Xin Li. KPNA4 promotes prostate cancer metastasis through TNFα/β mediated cytokine crosstalk in tumor microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1526.