Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1.

    Barata PC, Rini BI. Treatment of renal cell carcinoma: current status and future directions. CA Cancer J Clin. 2017;67:507–24.

    PubMed  Google Scholar 

  2. 2.

    Hsieh JJ, Purdue MP, Signoretti S, Swanton C, Albiges L, Schmidinger M, et al. Renal cell carcinoma. Nat Rev Dis Prim. 2017;3:17009.

    PubMed  Google Scholar 

  3. 3.

    Choueiri TK, Motzer RJ. Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med. 2017;376:354–66.

    CAS  PubMed  Google Scholar 

  4. 4.

    Bouillet B, Gautier T, Blache D, Pais de Barros JP, Duvillard L, Petit JM, et al. Glycation of apolipoprotein C1 impairs its CETP inhibitory property: pathophysiological relevance in patients with type 1 and type 2 diabetes. Diabetes Care. 2014;37:1148–56.

    CAS  PubMed  Google Scholar 

  5. 5.

    Bus P, Pierneef L, Bor R, Wolterbeek R, van Es LA, Rensen PC, et al. Apolipoprotein C-I plays a role in the pathogenesis of glomerulosclerosis. J Pathol. 2017;241:589–99.

    CAS  PubMed  Google Scholar 

  6. 6.

    Zhou Q, Zhao F, Lv ZP, Zheng CG, Zheng WD, Sun L, et al. Association between APOC1 polymorphism and Alzheimer’s disease: a case-control study and meta-analysis. PLoS ONE. 2014;9:e87017.

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Zhang R, Liu Q, Liu H, Bai H, Zhang Y, Guan L, et al. Effects of apoC1 genotypes on the hormonal levels, metabolic profile and PAF-AH activity in Chinese women with polycystic ovary syndrome. Lipids Health Dis. 2018;17:77.

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Ko HL, Wang YS, Fong WL, Chi MS, Chi KH, Kao SJ. Apolipoprotein C1 (APOC1) as a novel diagnostic and prognostic biomarker for lung cancer: a marker phase I trial. Thorac Cancer. 2014;5:500–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Su WP, Sun LN, Yang SL, Zhao H, Zeng TY, Wu WZ, et al. Apolipoprotein C1 promotes prostate cancer cell proliferation in vitro. J Biochem Mol Toxicol. 2018;32:e22158.

    PubMed Central  Google Scholar 

  10. 10.

    Huang Y, Zhang X, Jiang W, Wang Y, Jin H, Liu X, et al. Discovery of serum biomarkers implicated in the onset and progression of serous ovarian cancer in a rat model using iTRAQ technique. Eur J Obstet Gynecol Reprod Biol. 2012;165:96–103.

    CAS  PubMed  Google Scholar 

  11. 11.

    Hsieh JJ, Le VH, Oyama T, Ricketts CJ, Ho TH, Cheng EH. Chromosome 3p loss-orchestrated VHL, HIF, and epigenetic deregulation in clear cell renal cell carcinoma. J Clin Oncol. 2018;36:JCO2018792549.

  12. 12.

    Schokrpur S, Hu J, Moughon DL, Liu P, Lin LC, Hermann K, et al. CRISPR-mediated VHL knockout generates an improved model for metastatic renal cell carcinoma. Sci Rep. 2016;6:29032.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Ferrara N. Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol. 2001;280:C1358–66.

    CAS  PubMed  Google Scholar 

  14. 14.

    Bielecka ZF, Czarnecka AM, Solarek W, Kornakiewicz A, Szczylik C. Mechanisms of acquired resistance to tyrosine kinase inhibitors in clear - cell renal cell carcinoma (ccRCC). Curr Signal Transduct Ther. 2014;8:218–28.

    PubMed  Google Scholar 

  15. 15.

    Patard JJ, Rioux-Leclercq N, Masson D, Zerrouki S, Jouan F, Collet N, et al. Absence of VHL gene alteration and high VEGF expression are associated with tumour aggressiveness and poor survival of renal-cell carcinoma. Br J Cancer. 2009;101:1417–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Harshman LC, Xie W, Bjarnason GA, Knox JJ, MacKenzie M, Wood L, et al. Conditional survival of patients with metastatic renal-cell carcinoma treated with VEGF-targeted therapy: a population-based study. Lancet Oncol. 2012;13:927–35.

    CAS  PubMed  Google Scholar 

  17. 17.

    Shen C, Kaelin WG Jr. The VHL/HIF axis in clear cell renal carcinoma. Semin Cancer Biol. 2013;23:18–25.

    CAS  PubMed  Google Scholar 

  18. 18.

    Yusenko MV, Kuiper RP, Boethe T, Ljungberg B, van Kessel AG, Kovacs G. High-resolution DNA copy number and gene expression analyses distinguish chromophobe renal cell carcinomas and renal oncocytomas. BMC Cancer. 2009;9:152.

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi B, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 2017;19:649–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Aguirre-Gamboa R, Gomez-Rueda H, Martinez-Ledesma E, Martinez-Torteya A, Chacolla-Huaringa R, Rodriguez-Barrientos A, et al. SurvExpress: an online biomarker validation tool and database for cancer gene expression data using survival analysis. PLoS ONE. 2013;8:e74250.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347:1260419.

    Google Scholar 

  22. 22.

    McPherson A, Larson SB. The structure of human apolipoprotein C-1 in four different crystal forms. J Lipid Res. 2019;60:400–11.

    CAS  PubMed  Google Scholar 

  23. 23.

    Horiguchi A, Oya M, Shimada T, Uchida A, Marumo K, Murai M. Activation of signal transducer and activator of transcription 3 in renal cell carcinoma: a study of incidence and its association with pathological features and clinical outcome. J Urol. 2002;168:762–5.

    CAS  PubMed  Google Scholar 

  24. 24.

    Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Sirkisoon SR, Carpenter RL, Rimkus T, Anderson A, Harrison A, Lange AM, et al. Interaction between STAT3 and GLI1/tGLI1 oncogenic transcription factors promotes the aggressiveness of triple-negative breast cancers and HER2-enriched breast cancer. Oncogene. 2018;37:2502–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Sanchez-Gastaldo A, Kempf E, Gonzalez Del Alba A, Duran I. Systemic treatment of renal cell cancer: a comprehensive review. Cancer Treat Rev. 2017;60:77–89.

    CAS  PubMed  Google Scholar 

  27. 27.

    Zheng P, Luo Q, Wang W, Li J, Wang T, Wang P, et al. Tumor-associated macrophages-derived exosomes promote the migration of gastric cancer cells by transfer of functional Apolipoprotein E. Cell Death Dis. 2018;9:434.

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Skinner NE, Wroblewski MS, Kirihara JA, Nelsestuen GL, Seaquist ER. Sitagliptin results in a decrease of truncated apolipoprotein C1. Diabetes Ther. 2015;6:395–401.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Bouillet B, Gautier T, Aho LS, Duvillard L, Petit JM, Lagrost L, et al. Plasma apolipoprotein C1 concentration is associated with plasma triglyceride concentration, but not visceral fat, in patients with type 2 diabetes. Diabetes Metab. 2016;42:263–6.

    CAS  PubMed  Google Scholar 

  30. 30.

    Wang X, Wang T, Chen C, Wu Z, Bai P, Li S. et al. Serum exosomal miR-210 as a potential biomarker for clear cell renal cell carcinoma. J Cell Biochem. 2019;120:1492–1502.

    CAS  Google Scholar 

  31. 31.

    Ren H, Chen Z, Yang L, Xiong W, Yang H, Xu K, et al. Apolipoprotein C1 (APOC1) promotes tumor progression via MAPK signaling pathways in colorectal cancer. Cancer Manag Res. 2019;11:4917–30.

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Wang X, Gong Y, Deng T, Zhang L, Liao X, Han C, et al. Diagnostic and prognostic significance of mRNA expressions of apolipoprotein A and C family genes in hepatitis B virus-related hepatocellular carcinoma. J Cell Biochem. 2019;120:18246–65.

    CAS  PubMed  Google Scholar 

  33. 33.

    De Palma M, Biziato D, Petrova TV. Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer. 2017;17:457–74.

    PubMed  Google Scholar 

  34. 34.

    Mathieu M, Martin-Jaular L, Lavieu G, Thery C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol. 2019;21:9–17.

    CAS  PubMed  Google Scholar 

  35. 35.

    Huynh J, Chand A, Gough D, Ernst M. Therapeutically exploiting STAT3 activity in cancer-using tissue repair as a road map. Nat Rev Cancer. 2019;19:82–96.

    CAS  PubMed  Google Scholar 

  36. 36.

    Srivastava J, DiGiovanni J. Non-canonical Stat3 signaling in cancer. Mol Carcinog. 2016;55:1889–98.

    CAS  PubMed  Google Scholar 

  37. 37.

    Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol. 2007;7:41–51.

    CAS  PubMed  Google Scholar 

  38. 38.

    Desroses M, Busker S, Astorga-Wells J, Attarha S, Kolosenko I, Zubarev RA, et al. STAT3 differential scanning fluorimetry and differential scanning light scattering assays: Addressing a missing link in the characterization of STAT3 inhibitor interactions. J Pharm Biomed Anal. 2018;160:80–8.

    CAS  PubMed  Google Scholar 

  39. 39.

    Zhao W, Jaganathan S, Turkson J. A cell-permeable Stat3 SH2 domain mimetic inhibits Stat3 activation and induces antitumor cell effects in vitro. J Biol Chem. 2010;285:35855–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Li X, Ma H, Li L, Chen Y, Sun X, Dong Z, et al. Novel synthetic bisindolylmaleimide alkaloids inhibit STAT3 activation by binding to the SH2 domain and suppress breast xenograft tumor growth. Oncogene. 2018;37:2469–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Beebe JD, Liu JY, Zhang JT. Two decades of research in discovery of anticancer drugs targeting STAT3, how close are we? Pharm Ther. 2018;191:74–91.

    CAS  Google Scholar 

  42. 42.

    Wu LW, Zhou DM, Zhang ZY, Zhang JK, Zhu HJ, Lin NM, et al. Suppression of LSD1 enhances the cytotoxic and apoptotic effects of regorafenib in hepatocellular carcinoma cells. Biochem Biophys Res Commun. 2019;512:852–8.

    CAS  PubMed  Google Scholar 

Download references


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).

Author information



Corresponding authors

Correspondence to Chong Zhang or Neng-ming Lin.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

Further reading


Quick links