By Increasing the Expression and Activation of STAT3, Sustained C5a Stimulation Increases the Proliferation, Migration, and Invasion of RCC Cells and Promotes the Growth of Transgrafted Tumors

References

• Srivastava A, Rivera-Núñez Z, Kim S, et al. Impact of pathologic lymph node-positive renal cell carcinoma on survival in patients without metastasis: evidence in support of expanding the definition of stage IV kidney cancer. Cancer. 2020;126(13):2991–3001. doi:10.1002/cncr.3291232329899
   PubMed Web of Science ®Google Scholar
• Roumenina LT, Daugan MV, Noé R, et al. Tumor cells hijack macrophage-produced complement C1q to promote tumor growth. Cancer Immunol Res. 2019;7(7):1091–1105. doi:10.1158/2326-6066.Cir-18-089131164356
   PubMed Web of Science ®Google Scholar
• Roncati L, Maiorana A. Biological characterization of metastatic renal cell carcinoma. Urologia. 2010;77(Suppl 16):37–41. doi:10.1177/0391560310077016S09
   PubMedGoogle Scholar
• Netti GS, Lucarelli G, Spadaccino F, et al. PTX3 modulates the immunoflogosis in tumor microenvironment and is a prognostic factor for patients with clear cell renal cell carcinoma. Aging. 2020;12(8):7585–7602. doi:10.18632/aging.10316932345771
   PubMedGoogle Scholar
• Battaglia M, Lucarelli G. The role of renal surgery in the era of targeted therapy: the urologist’s perspective. Urologia. 2015;82(3):137–138. doi:10.5301/uro.500010525704789
   PubMedGoogle Scholar
• Di Lorenzo G, De Placido S, Pagliuca M, et al. The evolving role of monoclonal antibodies in the treatment of patients with advanced renal cell carcinoma: a systematic review. Expert Opin Biol Ther. 2016;16(11):1387–1401. doi:10.1080/14712598.2016.121696427463642
   PubMed Web of Science ®Google Scholar
• Liu Y, Xu SQ, Long WJ, Zhang XY, Lu HL. C5aR antagonist inhibits occurrence and progression of complement C5a induced inflammatory response of microglial cells through activating p38MAPK and ERK1/2 signaling pathway. Eur Rev Med Pharmacol Sci. 2018;22(22):7994–8003. doi:10.26355/eurrev_201811_1642830536348
   PubMed Web of Science ®Google Scholar
• Ajona D, Ortiz-Espinosa S, Pio R. Complement anaphylatoxins C3a and C5a: emerging roles in cancer progression and treatment. Semin Cell Dev Biol. 2019;85:153–163. doi:10.1016/j.semcdb.2017.11.02329155219
   PubMed Web of Science ®Google Scholar
• Maeda Y, Kawano Y, Wada Y, et al. C5aR is frequently expressed in metastatic renal cell carcinoma and plays a crucial role in cell invasion via the ERK and PI3 kinase pathways. Oncol Rep. 2015;33(4):1844–1850. doi:10.3892/or.2015.380025682807
   PubMed Web of Science ®Google Scholar
• Xi W, Liu L, Wang J, et al. High level of anaphylatoxin C5a predicts poor clinical outcome in patients with clear cell renal cell carcinoma. Sci Rep. 2016;6:29177. doi:10.1038/srep2917727381421
   PubMed Web of Science ®Google Scholar
• Xi W, Liu L, Wang J, et al. Enrichment of C5a-C5aR axis predicts poor postoperative prognosis of patients with clear cell renal cell carcinoma. Oncotarget. 2016;7(49):80925–80934. doi:10.18632/oncotarget.1310827821813
   PubMedGoogle Scholar
• Bokisch VA, Müller-Eberhard HJ. Anaphylatoxin inactivator of human plasma: its isolation and characterization as a carboxypeptidase. J Clin Invest. 1970;49(12):2427–2436. doi:10.1172/jci1064624098172
   PubMed Web of Science ®Google Scholar
• Matthews KW, Mueller-Ortiz SL, Wetsel RA. Carboxypeptidase N: a pleiotropic regulator of inflammation. Mol Immunol. 2004;40(11):785–793. doi:10.1016/j.molimm.2003.10.00214687935
   PubMed Web of Science ®Google Scholar
• Li XX, Lee JD, Kemper C, Woodruff TM. The complement receptor C5aR2: a powerful modulator of innate and adaptive immunity. J Immunol. 2019;202(12):3339–3348. doi:10.4049/jimmunol.190037131160390
   PubMed Web of Science ®Google Scholar
• Garcia-Pardo J, Tanco S, Garcia-Guerrero MC, et al. Substrate specificity and structural modeling of human carboxypeptidase Z: a unique protease with a frizzled-like domain. Int J Mol Sci. 2020;21(22):8687. doi:10.3390/ijms21228687
   PubMed Web of Science ®Google Scholar
• MacDonald TM, Thomas LN, Gupta A, Barnes PJ, Too CK. Prolactin and androgen R1881 induce pro-survival carboxypeptidase-D and EDD E3 ligase in triple-negative and HER2+ breast cancer. Am J Cancer Res. 2020;10(5):1321–1343.32509382
   PubMed Web of Science ®Google Scholar
• Skidgel RA, Erdös EG. Cellular carboxypeptidases. Immunol Rev. 1998;161:129–141. doi:10.1111/j.1600-065x.1998.tb01577.x9553770
   PubMed Web of Science ®Google Scholar
• Song L, Fricker LD. Purification and characterization of carboxypeptidase D, a novel carboxypeptidase E-like enzyme, from bovine pituitary. J Biol Chem. 1995;270(42):25007–25013. doi:10.1074/jbc.270.42.250077559630
   PubMed Web of Science ®Google Scholar
• Zhao C, Li Y, Qiu W, et al. C5a induces A549 cell proliferation of non-small cell lung cancer via GDF15 gene activation mediated by GCN5-dependent KLF5 acetylation. Oncogene. 2018;37(35):4821–4837. doi:10.1038/s41388-018-0298-929773900
   PubMed Web of Science ®Google Scholar
• Zhang Y, Cao Y, Zhang L, et al. Apigenin inhibits C5a-induced proliferation of human nasopharyngeal carcinoma cells through down-regulation of C5aR. Biosci Rep. 2018;38(3). doi:10.1042/bsr20180456
   Web of Science ®Google Scholar
• Lu Y, Hu XB. C5a stimulates the proliferation of breast cancer cells via Akt-dependent RGC-32 gene activation. Oncol Rep. 2014;32(6):2817–2823. doi:10.3892/or.2014.348925230890
   PubMed Web of Science ®Google Scholar
• Cho MS, Vasquez HG, Rupaimoole R, et al. Autocrine effects of tumor-derived complement. Cell Rep. 2014;6(6):1085–1095. doi:10.1016/j.celrep.2014.02.01424613353
   PubMed Web of Science ®Google Scholar
• Ajona D, Zandueta C, Corrales L, et al. Blockade of the complement C5a/C5aR1 axis impairs lung cancer bone metastasis by CXCL16-mediated effects. Am J Respir Crit Care Med. 2018;197(9):1164–1176. doi:10.1164/rccm.201703-0660OC29327939
   PubMed Web of Science ®Google Scholar
• Nabizadeh JA, Manthey HD, Panagides N, et al. C5a receptors C5aR1 and C5aR2 mediate opposing pathologies in a mouse model of melanoma. FASEB J. 2019;33(10):11060–11071. doi:10.1096/fj.201800980RR31298935
   PubMed Web of Science ®Google Scholar
• Zha H, Wang X, Zhu Y, et al. Intracellular activation of complement C3 leads to PD-L1 antibody treatment resistance by modulating tumor-associated macrophages. Cancer Immunol Res. 2019;7(2):193–207. doi:10.1158/2326-6066.Cir-18-027230514794
   PubMed Web of Science ®Google Scholar
• Bergdolt S, Kovtun A, Hägele Y, et al. Osteoblast-specific overexpression of complement receptor C5aR1 impairs fracture healing. PLoS One. 2017;12(6):e0179512. doi:10.1371/journal.pone.017951228614388
   PubMed Web of Science ®Google Scholar
• Perianayagam MC, Balakrishnan VS, King AJ, Pereira BJ, Jaber BL. C5a delays apoptosis of human neutrophils by a phosphatidylinositol 3-kinase-signaling pathway. Kidney Int. 2002;61(2):456–463. doi:10.1046/j.1523-1755.2002.00139.x11849385
   PubMed Web of Science ®Google Scholar
• Chen J, Li GQ, Zhang L, et al. Complement C5a/C5aR pathway potentiates the pathogenesis of gastric cancer by down-regulating p21 expression. Cancer Lett. 2018;412:30–36. doi:10.1016/j.canlet.2017.10.00329031586
   PubMed Web of Science ®Google Scholar
• Chen J, Sun ZH, Chen LY, et al. C5aR deficiency attenuates the breast cancer development via the p38/p21 axis. Aging. 2020;12(14):14285–14299. doi:10.18632/aging.10346832669478
   PubMedGoogle Scholar
• Lim EJ, Kim S, Oh Y, et al. Crosstalk between GBM cells and mesenchymal stemlike cells promotes the invasiveness of GBM through the C5a/p38/ZEB1 axis. Neuro-Oncology. 2020;22(10):1452–1462. doi:10.1093/neuonc/noaa06432179921
   PubMed Web of Science ®Google Scholar
• Huang Q, Zhong Y, Dong H, et al. Revisiting signal transducer and activator of transcription 3 (STAT3) as an anticancer target and its inhibitor discovery: where are we and where should we go? Eur J Med Chem. 2020;187:111922. doi:10.1016/j.ejmech.2019.11192231810784
   PubMed Web of Science ®Google Scholar
• Hillmer EJ, Zhang H, Li HS, Watowich SS. STAT3 signaling in immunity. Cytokine Growth Factor Rev. 2016;31:1–15. doi:10.1016/j.cytogfr.2016.05.00127185365
   PubMed Web of Science ®Google Scholar
• Kujawski M, Kortylewski M, Lee H, et al. Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. J Clin Invest. 2008;118(10):3367–3377. doi:10.1172/jci3521318776941
   PubMed Web of Science ®Google Scholar
• 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(2):82–96. doi:10.1038/s41568-018-0090-830578415
   PubMed Web of Science ®Google Scholar
• Beebe JD, Liu JY, Zhang JT. Two decades of research in discovery of anticancer drugs targeting STAT3, how close are we? Pharmacol Ther. 2018;191:74–91. doi:10.1016/j.pharmthera.2018.06.00629933035
   PubMed Web of Science ®Google Scholar
• Laudisi F, Cherubini F, Monteleone G, Stolfi C. STAT3 interactors as potential therapeutic targets for cancer treatment. Int J Mol Sci. 2018;19(6). doi:10.3390/ijms19061787
   PubMed Web of Science ®Google Scholar
• O’Sullivan KE, Michielsen AJ, O’Regan E, et al. pSTAT3 levels have divergent expression patterns and associations with survival in squamous cell carcinoma and adenocarcinoma of the oesophagus. Int J Mol Sci. 2018;19(6):1720. doi:10.3390/ijms19061720
   PubMed Web of Science ®Google Scholar
• Chong PSY, Chng WJ, de Mel S. STAT3: a promising therapeutic target in multiple myeloma. Cancers. 2019;11(5):731. doi:10.3390/cancers11050731
   PubMed Web of Science ®Google Scholar
• Qin JJ, Yan L, Zhang J, Zhang WD. STAT3 as a potential therapeutic target in triple negative breast cancer: a systematic review. J Exp Clin Cancer Res. 2019;38(1):195. doi:10.1186/s13046-019-1206-z31088482
   PubMed Web of Science ®Google Scholar
• Horiguchi A, Oya M, Shimada T, et al. 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(2):762–765. doi:10.1016/S0022-5347(05)64741-612131365
   PubMed Web of Science ®Google Scholar
• Siveen KS, Sikka S, Surana R, et al. Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. Biochim Biophys Acta. 2014;1845(2):136–154. doi:10.1016/j.bbcan.2013.12.00524388873
   PubMed Web of Science ®Google Scholar
• Khan MW, Saadalla A, Ewida AH, et al. The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer. Cancer Immunol Immunother. 2018;67(1):13–23. doi:10.1007/s00262-017-2057-028875329
   PubMed Web of Science ®Google Scholar