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Overexpression of CXCL2 inhibits cell proliferation and promotes apoptosis in hepatocellular carcinoma

  • Ding, Jun (Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital School of Medicine, Zhejiang University) ;
  • Xu, Kangdi (Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital School of Medicine, Zhejiang University) ;
  • Zhang, Jie (Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital School of Medicine, Zhejiang University) ;
  • Lin, Bingyi (Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital School of Medicine, Zhejiang University) ;
  • Wang, Yubo (Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital School of Medicine, Zhejiang University) ;
  • Yin, Shengyong (Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health) ;
  • Xie, Haiyang (Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health) ;
  • Zhou, Lin (Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Chinese Academy of Medical Sciences) ;
  • Zheng, Shusen (Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital School of Medicine, Zhejiang University)
  • Received : 2018.07.05
  • Accepted : 2018.10.02
  • Published : 2018.12.31

Abstract

C-X-C motif chemokine ligand 2 (CXCL2) is a small secreted protein that exhibits a structure similar to the proangiogenic subgroup of the CXC chemokine family. Recently, accumulating evidence suggests that chemokines play a pivotal role in cancer progression and carcinogenesis. We examined the expression levels of 7 types of $ELR^+$ CXCLs messenger RNA (mRNA) in 264 clinical samples. We found that CXCL2 expression was stably down-regulated in 94% of hepatocellular carcinoma (HCC) specimens compared with paired adjacent normal liver tissues and some HCC cell lines. Moreover, CXCL2 overexpression profoundly attenuated HCC cell proliferation and growth and induced apoptosis in vitro. In animal studies, we found that overexpressing CXCL2 by lentivirus also apparently inhibited the size and weight of subcutaneous tumours in nude mice. Furthermore, we demonstrated that CXCL2 induced HCC cell apoptosis via both nuclear and mitochondrial apoptosis pathways. Our results indicate that CXCL2 negatively regulates the cell cycle in HCC cells via the ERK1/2 signalling pathway. These results provide new insights into HCC and may ultimately lead to the discovery of innovative therapeutic approaches of HCC.

Keywords

References

  1. Altekruse SF, McGlynn KA and Reichman ME (2009) Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 27, 1485-1491 https://doi.org/10.1200/JCO.2008.20.7753
  2. Siegel RL, Miller KD and Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68, 7-30 https://doi.org/10.3322/caac.21442
  3. Yuen MF, Hou JL, Chutaputti A and Asia Pacific Working Party on Prevention of Hepatocellular C (2009) Hepatocellular carcinoma in the Asia pacific region. J Gastroenterol Hepatol 24, 346-353 https://doi.org/10.1111/j.1440-1746.2009.05784.x
  4. Toso C, Mentha G and Majno P (2011) Liver transplantation for hepatocellular carcinoma: five steps to prevent recurrence. Am J Transplant 11, 2031-2035 https://doi.org/10.1111/j.1600-6143.2011.03689.x
  5. Bruix J, Sherman M and Practice Guidelines Committee AAftSoLD (2005) Management of hepatocellular carcinoma. Hepatology 42, 1208-1236 https://doi.org/10.1002/hep.20933
  6. Mantovani A (2009) Cancer: Inflaming metastasis. Nature 457, 36
  7. Mantovani A, Allavena P, Sica A and Balkwill F (2008) Cancer-related inflammation. J Clin Immol 454, 436-444
  8. Li YW, Qiu SJ, Fan J et al (2011) Intratumoral neutrophils: a poor prognostic factor for hepatocellular carcinoma following resection. J Hepatol 54, 497-505 https://doi.org/10.1016/j.jhep.2010.07.044
  9. Reaux-Le Goazigo A, Van Steenwinckel J, Rostene W and Melik Parsadaniantz S (2013) Current status of chemokines in the adult CNS. Prog Neurobiol 104, 67-92 https://doi.org/10.1016/j.pneurobio.2013.02.001
  10. Balkwill F (2004) Cancer and the chemokine network. Nat Rev Cancer 4, 540-550 https://doi.org/10.1038/nrc1388
  11. Smyth MJ, Cretney E, Kershaw MH and Hayakawa Y (2004) Cytokines in cancer immunity and immunotherapy. Immol Rev 202, 275-293 https://doi.org/10.1111/j.0105-2896.2004.00199.x
  12. Acharyya S, Oskarsson T, Vanharanta S et al (2012) A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150, 165-178 https://doi.org/10.1016/j.cell.2012.04.042
  13. Kollmar O, Scheuer C, Menger MD and Schilling MK (2006) Macrophage Inflammatory Protein-2 Promotes Angiogenesis, Cell Migration, and Tumor Growth in Hepatic Metastasis. Ann Surg Oncol 13, 263-275 https://doi.org/10.1245/ASO.2006.03.096
  14. Hardaway AL, Herroon MK, Rajagurubandara E and Podgorski I (2015) Marrow adipocyte-derived CXCL1 and CXCL2 contribute to osteolysis in metastatic prostate cancer. Clin Exp Metastasis 32, 353-368 https://doi.org/10.1007/s10585-015-9714-5
  15. Zhang H, Ye YL, Li MX et al (2017) CXCL2/MIF-CXCR2 signaling promotes the recruitment of myeloid-derived suppressor cells and is correlated with prognosis in bladder cancer. Oncogene 36, 2095-2104 https://doi.org/10.1038/onc.2016.367
  16. Lu Y, Li S, Ma L et al (2016) Type conversion of secretomes in a 3D TAM2 and HCC cell co-culture system and functional importance of CXCL2 in HCC. Sci Rep 6, 24558 https://doi.org/10.1038/srep24558
  17. Fang LY, Izumi K, Lai KP et al (2013) Infiltrating macrophages promote prostate tumorigenesis via modulating androgen receptor-mediated CCL4-STAT3 signaling. Cancer Res 73, 5633-5646 https://doi.org/10.1158/0008-5472.CAN-12-3228
  18. Dubois RN (2014) Role of Inflammation and Inflammatory Mediators in Colorectal Cancer. Trans Am Clin Climatol Assoc 125, 358
  19. Wolpe SD, Sherry B, Juers D, Davatelis G, Yurt RW and Cerami A (1989) Identification and characterization of macrophage inflammatory protein 2. Proc Natl Acad Sci U S A 86, 612-616 https://doi.org/10.1073/pnas.86.2.612
  20. Oppenheim JJ, Zachariae COC, N Mukaida A and Matsushima K (1991) Properties of the Novel Proinflammatory Supergene "Intercrine" Cytokine Family. Annu Rev Immunol 9, 617-648 https://doi.org/10.1146/annurev.iy.09.040191.003153
  21. Ness TL, Hogaboam CM, Strieter RM and Kunkel SL (2003) Immunomodulatory role of CXCR2 during experimental septic peritonitis. J Immol 171, 3775 https://doi.org/10.4049/jimmunol.171.7.3775
  22. Song X, Wang Z, Jin Y, Wang Y and Duan W (2015) Loss of miR-532-5p in vitro promotes cell proliferation and metastasis by influencing CXCL2 expression in HCC. AmJ Trans Res 7, 2254-2261
  23. Filmus J, Robles AI, Shi W, Wong MJ, Colombo LL and Conti CJ (1994) Induction of cyclin D1 overexpression by activated ras. Oncogene 9, 3627-3633
  24. Paternot S, Bockstaele L, Bisteau X, Kooken H, Coulonval K and Roger PP (2010) Rb inactivation in cell cycle and cancer: the puzzle of highly regulated activating phosphorylation of CDK4 versus constitutively active CDK-activating kinase. Cell Cycle 9, 689-699 https://doi.org/10.4161/cc.9.4.10611
  25. Bartkova J, Horejsi Z, Koed K et al (2005) DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864-870 https://doi.org/10.1038/nature03482
  26. Tsai LH, Harlow E and Meyerson M (1991) Isolation of the human cdk2 gene that encodes the cyclin A- and adenovirus E1A-associated p33 kinase. Nature 353, 174-177 https://doi.org/10.1038/353174a0
  27. Hunt T (1989) Under arrest in the cell cycle. Nature 342, 483-484 https://doi.org/10.1038/342483a0
  28. Nurse P (1990) Universal control mechanism regulating onset of M-phase. Nature 344, 503-508 https://doi.org/10.1038/344503a0
  29. Li J and Yuan J (2008) Caspase in apoptosis and beyond. Oncogene 276, 194-6206
  30. Slee EA, Harte MT, Kluck RM et al (1999) Ordering the Cytochrome c-initiated Caspase Cascade: Hierarchical Activation of Caspases-2, -3, -6, -7, -8, and -10 in a Caspase-9-dependent Manner. J Cell Biol 144, 281-292 https://doi.org/10.1083/jcb.144.2.281
  31. Meyer C, Pries R and Wollenberg B (2011) Established and novel $NF-{\kappa}B$ inhibitors lead to downregulation of TLR3 and the proliferation and cytokine secretion in HNSCC. Oral Oncol 47, 818-826 https://doi.org/10.1016/j.oraloncology.2011.06.010
  32. Liu L, Cao Y, Chen C et al (2006) Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 66, 11851-11858 https://doi.org/10.1158/0008-5472.CAN-06-1377