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ApoC1 promotes the metastasis of clear cell renal cell carcinoma via activation of STAT3

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer and frequently diagnosed at an advanced stage. It is prone to develop unpredictable metastases even with proper treatment. Antiangiogenic therapy is the most effective medical treatment for metastatic ccRCC. Thus, exploration of novel approaches to inhibit angiogenesis and metastasis may potentially lead to a better therapeutic option for ccRCC. Among all the types of cancer, renal cancer samples exhibited the maximum upregulation of ApoC1 as referred to in the Oncomine database. The expression of ApoC1 was increased accompanied by ccRCC progression. A high level of ApoC1 was closely related to poor survival time in ccRCC patients. Furthermore, ApoC1 was over-expressed in the highly invasive ccRCC cells as compared to that in the low-invasive ccRCC cells. Besides, ApoC1 promoted metastasis of ccRCC cells via EMT pathway, whereas depletion of ApoC1 alleviated these effects. ApoC1 as a novel pro-metastatic factor facilitates the activation of STAT3 and enhances the metastasis of ccRCC cells. Meanwhile, ApoC1 in the exosomes were transferred from the ccRCC cells to the vascular endothelial cells and promoted metastasis of the ccRCC cells via activating STAT3. Finally, the metastatic potential of the ccRCC cells driven by ApoC1 was suppressed by DPP-4 inhibition. Our study not only identifies a novel ApoC1-STAT3 pathway in ccRCC metastasis but also provides direction for the exploration of novel strategies to predict and treat metastatic ccRCC in the future.

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Fig. 1: High expression levels of ApoC1 were observed in the ccRCC clinical samples and predicted poor prognosis.
Fig. 2: ApoC1 knock-down suppressed the metastatic ability of ccRCC via inactivation of EMT pathway.
Fig. 3: ApoC1 promoted ccRCC metastasis both in vitro and in vivo.
Fig. 4: The hyperactivation of ApoC1-STAT3 signaling in the ccRCC patients correlated with poor overall survival.
Fig. 5: ApoC1 increased the transcriptional activity of STAT3 by directly interacting with STAT3.
Fig. 6: The inhibition of STAT3 suppressed the enhanced metastatic ability of ccRCC cells induced by ApoC1.
Fig. 7: ApoC1 in exosomes were transferred from ccRCC cells to vascular endothelial cells and promoted the metastasis of ccRCC cells via activating STAT3.
Fig. 8: The metastatic potential of the ccRCC cells driven by ApoC1 was suppressed by DPP-4 inhibition.

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Acknowledgements

This study was funded by National Natural Science Foundation of China (81702887, 81272473), Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province (2020E10021), Key Medical Discipline of Zhejiang Province (2018–2–3), Key Medical Discipline of Hangzhou City (2017–51–07), Zhejiang Provincial Foundation of Natural Science (LY19H310004), Hangzhou Major Science and Technology Project (20172016A01), High‑level Talents Coming Back from Abroad Innovation and Entrepreneurship Program in Hangzhou, Scientific and Technological Developing Scheme of Hangzhou City (20191203B49), Science Research Foundation of Zhejiang Health Bureau (2020RC026), and Teachers Research Fund of Zhejiang University City College (J-19006).

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Li, Yl., Wu, Lw., Zeng, Lh. et al. ApoC1 promotes the metastasis of clear cell renal cell carcinoma via activation of STAT3. Oncogene 39, 6203–6217 (2020). https://doi.org/10.1038/s41388-020-01428-3

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