Primary study of the effects of ursolic acid on colorectal tumor and tumor microenvironment in mice

doi:10.3760/cma.j.issn.1673422X.2017.11.002

Abstract

Abstract: ObjectiveTo investigate the effect of ursolic acid (UA) on the colorectal tumor and microenvironment in mice, and to provide a theoretical basis for the clinical application of UA. MethodsThe models of subcutaneous transplanted tumor of mouse CT26 cells was established. The models were divided into four groups: control group, tumor bearing group, tumor bearing dimethyl sulfoxide (DMSO) group and tumor bearing UA group. The serum levels of interleukin6 (IL6) were detected by enzyme linked immunosorbent assay (ELISA). The number and percentage of myeloidderived suppressor cell (MDSC) in the spleen of mice were analyzed by flow cytometry. The mRNA levels of IL6 and signal transducer and activator of transcription 3 (STAT3) in tumor were examined by realtime quantitative polymerase chain reaction (RTPCR). The protein levels of STAT3 and pSTAT3 in tumor were detected by Western blotting. ResultsThe results showed that UA could significantly decrease the number of spleen MDSC. The accounts of spleen MDSC of tumor bearing UA group (249.60±17.12) was lower than that of tumor bearing DMSO group (366.40±34.08), and the difference was statistically significant (P=0.021). The serum level of IL6 in tumor bearing UA group ［(46.40±17.05) pg/ml］ was decreased than that in tumor bearing DMSO group ［(94.27±21.51) pg/ml］, and the difference was statistically significant (P=0.012). The expression levels of IL6 and STAT3 mRNA in tumor tissues of tumor bearing UA group (0.12±0.01, 0.21±0.08) were lower than those of tumor bearing DMSO group (0.69±0.14, 0.79±0.06), and the differences were statistically significant (P=0.008; P=0.003). The protein expression levels of STAT3 and pSTAT3 in tumor tissues of tumor bearing UA group (0.81±0.02, 0.28±0.04) were lower than those of tumor bearing DMSO group (0.98±0.02, 0.91±0.22), and the differences were statistically significant (P=0.027; P=0.029) . ConclusionUA may inhibit the activation of STAT3 signaling pathway and the amplification of MDSC in microenvironment by reducing IL6, thus to enhance the function of immunekilling tumor cells to regulate tumor immune microenvironment and inhibit the immune escape of mouse colorectal cancer cells.

Key words: Ursolic acid, Colorectal neoplasms, Tumor microenvironment, Myeloidderived suppressor cells

乐红红，郝文斌，相芬芬，倪振华，许军，吴蓉，康向东. Primary study of the effects of ursolic acid on colorectal tumor and tumor microenvironment in mice[J]. Journal of International Oncology, 2017, 44(11): 806-811.

References

［1］ Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013［J］. CA Cancer J Clin, 2013, 63(1): 11-30. DOI: 10.3322/caac.21166. ［2］ Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012［J］. Int J Cancer, 2015, 136(5): E359-386. DOI: 10.1002/ijc.29210. ［3］ Hossain F, AIKhami AA, Wyczechowska D, et al. Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloidderived suppressor cells and enhances cancer therapies［J］. Cancer Immunol Res, 2015, 3(11): 1236-1247. DOI: 10.1158/2326-6066.CIR-15-0036. ［4］ Kanterman J, SadeFeldman M, Biton M, et al. Adverse immunoregulatory effects of 5FU and CPT11 chemotherapy on myeloidderived suppressor cells and colorectal cancer outcomes［J］. Cancer Res, 2014, 74(21): 6022-6035. DOI: 10.1158/0008-5472.CAN-14-0657. ［5］ Sermeus A, Leonard W, Engels B, et al. Advances in radiotherapy and targeted therapies for rectal cancer ［J］. World J Gastroenterol, 2014, 20(1): 1-5. DOI: 10.3748/wjg.v20.i1.1. ［6］ Limagne E, Euvrard R, Thibaudin M, et al. Accumulation of MDSC and Th17 cells in patients with metastatic colorectal cancer predicts the efficacy of a FOLFOXbevacizumab drug treatment regimen［J］. Cancer Res, 2016, 76(18): 5241-5252. DOI: 10.1158/0008-5472.CAN-15-3164. ［7］ Oliphant R, Nicholson GA, Horgan PG, et al. Deprivation and colorectal cancer surgery: longerterm survival inequalities are due to differential postoperative mortality between socioeconomic groups［J］. Ann Surg Oncol, 2013, 20(7): 2132-2139. DOI: 10.1245/s10434-013-2959-9. ［8］ Gabrilovich DI, Nagaraj S. Myeloidderived suppressor cells as regulators of the immune system［J］. Nat Rev Immunol, 2009, 9(3): 162-174. DOI: 10.1038/nri2506. ［9］ Prasad S, Yadav VR, Sung B, et al. Ursolic acid inhibits the growth of human pancreatic cancer and enhances the antitumor potential of gemcitabine in an orthotopic mouse model through suppression of the inflammatory microenvironment［J］. Oncotarget, 2016, 7(11): 13182-13196. DOI: 10.18632/oncotarget.7537. ［10］ Shanmugam MK, Ong TH, Kumar AP, et al. Ursolic acid inhibits the initiation, progression of prostate cancer and prolongs the survival of TRAMP mice by modulating proinflammatory pathways［J］. PLoS One, 2012, 7(3): e32476. DOI: 10.1371/journal.pone.0032476. ［11］ Ma JQ, Ding J, Xiao ZH, et al. Ursolic acid ameliorates carbon tetrachlorideinduced oxidative DNA damage and inflammation in mouse kidney by inhibiting the STAT3 and NF-κB activities［J］. Int Immunopharmacol, 2014, 21(2): 389395. DOI: 10.1016/j.intimp.2014.05.022. ［12］ Stiff A, Trikha P, Wesolowski R, et al. Myeloidderived suppressor cells express Bruton′s tyrosine kinase and can be depleted in tumor bearing hosts by ibrutinib treatment［J］. Cancer Res, 2016, 76(8): 2125-2036. DOI: 10.1158/00085472.CAN151490. ［13］ Xu Y, Zhao W, Xu J, et al. Activated hepatic stellate cells promote liver cancer by induction of myeloidderived suppressor cells through cyclooxygenase2［J］. Oncotarget, 2016, 7(8): 8866-8878. DOI: 10.18632/oncotarget.6839. ［14］ Meirow Y, Kanterman J, Baniyash M. Paving the road to tumor development and spreading: myeloidderived suppressor cells are ruling the fate［J］. Front Immunol, 2015, 6: 523. DOI: 10.3389/fimmu.2015.00523. ［15］ Tu S, Bhagat G, Cui G, et al. Overexpression of interleukin1beta induces gastric inflammation and cancer and mobilizes myeloidderived suppressor cells in mice［J］. Cancer Cell, 2008, 14(5): 408-419. DOI: 10.1016/j.ccr.2008.10.011. ［16］ He D, Li H, Yusuf N, et al. IL-17 promotes tumor development through the induction of tumor promoting microenvironments at tumor sites and myeloidderived suppressor cells［J］. J Immunol, 2010, 184(5): 2281-2288. DOI: 10.4049/jimmunol.0902574. ［17］ Obermajer N, Kalinski P. Key role of the positive feedback between PGE(2) and COX2 in the biology of myeloidderived suppressor cells［J］. Oncoimmunol, 2012, 1(5): 762-764. DOI: 10.4161/onci.19681.

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