Onco Targets Ther 13: 6987-6996

Effect of <em>Malus asiatica</em> Nakai Leaf Flavonoids on the Prevention of Esophageal Cancer in C57BL/6J Mice by Regulating the IL-17 Signaling Pathway

^{Department of Thoracic Surgery, Zhengzhou Key Laboratory of Surgical Treatment for End-Stage Lung Diseases, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, 450003, Henan, People’s Republic of China}

^{Contributed equally.}

Correspondence: Li Wei Email 270065823@qq.com

^{These authors contributed equally to this work}

Received 2020 May 3; Accepted 2020 Jun 26.

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Abstract

Background

The aim of this study was to observe the preventive effect of flavonoids extracted from Malus asiatica Nakai leaves (FMANL) on esophageal cancer in mice, especially the ability of FMANL to regulate the interleukin 17 (IL-17) signaling pathway during this process.

Materials and Methods

The C57BL/6J mice were treated with 4-nitroquinoline N-oxide (4NQO) to induce esophageal cancer, and the visceral tissue index and the serum and esophageal tissue indexes of mice were used to verify the effect of FMANL.

Results

The experimental results showed that FMANL can effectively control the changes in visceral tissue caused by esophageal cancer. FMANL could increase the cytokine levels of interleukin 10 (IL-10), monocyte chemotactic protein 1 (MCP-1) and decrease the cytokine levels of tumor necrosis factor alpha (TNF-α), interferon-γ (IFN-γ), interleukin 6 (IL-6), and interleukin 12p70 (IL-12p70) in serum of mice with esophageal cancer. FMANL could also reduce CD3^{, CD4}^{, and CD8}^{and enhance CD19}^{mouse peripheral blood lymphocytes. The results of qPCR and Western blot analysis showed that FMANL could down-regulate the mRNA and protein expression levels of IL-17, interleukin 23 (IL-23), interleukin 1 beta (IL-1β), chemokine (C-X-C) ligand 1 (CXCL1), chemokine (C-X-C) ligand 2 (CXCL2), S100 calcium-binding protein A8 (S100A8), S100 calcium-binding protein A9 (S100A9), matrix metalloprotein 9 (MMP-9), and matrix metalloprotein 13 (MMP-1) in mice with esophageal cancer. High-performance liquid chromatography (HPLC) detection showed that FMANL contained 10 chemicals, including rutin, hyperoside, isoquercitrin, dihydroquercetin, quercitrin, hesperidin, myricetin, baicalin, neohesperidin dihydrochalcone, and quercetin.}

Conclusion

It could be concluded that FMANL can effectively prevent experimentally induced esophageal cancer in mice, and its effects might be obtained from 10 compounds present in FMANL.

Keywords: Malus asiatica Nakai leaves, flavonoid, esophageal cancer, C57BL/6J mice, mRNA IL-17 signaling pathway

Abstract

Notes:^{Mean values with different letters in the same row are significantly different (}p < 0.05) according to Duncan’s multiple-range test. FMANL-L group: 50 mg/kg flavonoids of Malus asiatica Nakai leaves dose; FMANL-H group: 100 mg/kg flavonoids of Malus asiatica Nakai leaves dose.

References

1. Zhu K, Huang G, Xie J, et al. Preventive effect of flavonoids from Wushan Shencha (Malus doumeri leaves) on CCl₄‐induced liver injury. Food Sci Nutr. 2019;7(11):3808–3818. doi:10.1002/fsn3.1243 ] [
2. Lee YH, Jung MG, Kang HB, et al. Effect of anti-histone acetyltransferase activity from Rosa rugosa Thunb. (Rosaceae) extracts on androgen receptor-mediated transcriptional regulation. J Ethnopharmacol. 2008;118(3):412–417. doi:10.1016/j.jep.2008.05.006 [] [[PubMed]
3. Bilia AR, Nieri E, Braca A, et al. Screening of Mediterranean Rosaceae plants for their molluscicidal and piscicidal activities. Phytother Res. 2000;14(2):126–129. doi:10.1002/(SICI)1099-1573(200003)14:2<126::AID-PTR553>3.0.CO;2-V [] [[PubMed]
4. Tonin TD, Thiesen LC, de Oliveira Nunes ML, et al. Rubus imperialis (Rosaceae) extract and pure compound niga-ichigoside F1: wound healing and anti-inflammatory effects. Naunyn Schmiedebergs Arch Pharmacol. 2016;389:1235–1244. doi:10.1007/s00210-016-1285-8 [] [[PubMed]
5. Riaz M, Zia-Ul-Haq M, Ur-Rahman N, et al. Neuropharmacological effects of methanolic extracts of Rubus fruticosus L. Turk J Med Sci. 2014;44(3):454–460. doi:10.3906/sag-1211-1 [] [[PubMed]
6. Li C, Liu C, Zhang J, et al. Evaluation of in vitro bio-activities effects of WST (Wushanshencha). Appl Sci. 2019;9(7):1325. doi:10.3390/app9071325 [[PubMed]
7. Mu X, Zhao X, Li GJ, et al. Preventive effect of Wushan shencha on gastric injury in SD-rats. J ZhongKai Univ Agri Technol. 2014;2014(2):57–59. doi:10.3969/j.issn.1674-5663.2014.02.014 [[PubMed]
8. Zhao X, Zhu K, Yi R, et al. Total flavonoid from Ba lotus leaf protected the reserpine-induced gastric ulcer in mice. Biomed Res. 2017;28(1):345–352. [PubMed]
9. Hu Y, Hou Z, Yi R, et al. Tartary buckwheat flavonoids ameliorate high fructose-induced insulin resistance and oxidative stress associated with the insulin signaling and Nrf2/HO-1 pathways in mice. Food Funct. 2017;8(8):2803–2816. doi:10.1039/C7FO00359E [] [[PubMed]
10. Liu B, Feng X, Zhang J, et al. Preventive effect of Anji White tea flavonoids on alcohol-induced gastric injury through their antioxidant effects in kunming mice. Biomolecules. 2019;9(4):137. doi:10.3390/biom9040137 ] [
11. Liu B, Zhang C, Zhang J, et al. Wu Shan Shen Cha (Malus asiatica Nakai. leaves)-derived flavonoids alleviate alcohol-induced gastric injury in mice via an anti-oxidative mechanism. Biomolecules. 2019;9(5):169. doi:10.3390/biom9050169 ] [
12. Huang F-L, Yu S-J. Esophageal cancer: risk factors, genetic association, and treatment. Asian J Surg. 2018;41(3):210–215. doi:10.1016/j.asjsur.2016.10.005 [] [[PubMed]
13. Zhao J, Liu J, Denney J, et al. TLR2 involved in naive CD4+ T cells rescues stress-induced immune suppression by regulating Th1/Th2 and Th17. Neuroimmunomodulation. 2015;22(5):328–336. doi:10.1159/000371468 [] [[PubMed]
14. Song Y, Yang JM. Role of interleukin (IL)-17 and T-helper (Th)17 cells in cancer. Biochem Biophys Res Commun. 2017;493(1):1–8. doi:10.1016/j.bbrc.2017.08.109 [] [[PubMed]
15. Tanaka T, Kawabata K, Sugie S. 4-nitroquinoline 1-oxide-induced tongue and esophagus carcinogenesis in obese and diabetic TSOD mice. World J Oncol. 2017;8(4):97–104. doi:10.14740/wjon1038w ] [
16. Yin J, Wang L, Shi Y, et al. Interleukin 17A rs4711998 A>G polymorphism was associated with a decreased risk of esophageal cancer in a Chinese population. Dis Esophagus. 2014;27(1):87–92. doi:10.1111/dote.12045 [] [[PubMed]
17. Guo MX, Zheng YJ, Tang B, et al. Expressions of IL-17 signaling pathway-related factors mRNA in esophageal tissue of mouse with esophageal cancer. J Zhengzhou Univ (Med Sci). 2019;54(4):492–495. doi:10.13705/j.issn.1671-6825.2019.02.046 [[PubMed]
18. Lyu CT, Dong ZB, Chen YL. Effects of Liujunzi decoction on quality of life and immune regulation of mice with esophageal carcinoma induced by 4NQO. China J Trad Chin Med Pharm. 2016;31(7):2831–2834. [PubMed]
19. Zhou Y, Tan F, Li C, et al. White Peony (fermented Camellia sinensis) polyphenols help prevent alcoholic liver injury via antioxidation. Antioxidants. 2019;8(11):524. doi:10.3390/antiox8110524 ] [
20. Liu L, Tan T, Liu L, et al. Exploring the antioxidant effects and periodic regulation of cancer cells by polyphenols produced by the fermentation of grape skin by Lactobacillus plantarum KFY02. Biomolecules. 2019;9(10):575. doi:10.3390/biom9100575 ] [
21. Bruggeman AR, Kamal AH, LeBlanc TW, et al. Cancer cachexia: beyond weight loss. J Oncol Pract. 2016;12(11):1163–1171. doi:10.1200/JOP.2016.016832 [] [[PubMed]
22. Ferraù F, Spagnolo F, Cotta OR, et al. Visceral adiposity index as an indicator of cardiometabolic risk in patients treated for craniopharyngioma. Endocrine. 2017;58(2):295–302. doi:10.1007/s12020-016-1196-y [] [[PubMed]
23. Zhu K, Tan F, Mu J, et al. Anti-obesity effects of Lactobacillus fermentum CQPC05 isolated from Sichuan pickle in high-fat diet-induced obese mice through PPAR-α signaling pathway. Microorganisms. 2019;7(7):194. doi:10.3390/microorganisms7070194 ] [
24. Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat Rev Lmmunol. 2003;3(3):199–210. doi:10.1038/nri1027 [] [[PubMed]
25. Zheng L, Wang W, Ni J, et al. Role of autophagy in tumor necrosis factor-α-induced apoptosis of osteoblast cells. J Investig Med. 2017;65(6):1014–1020. doi:10.1136/jim-2017-000426 ] [
26. Xia H-L, Li C-J, Hou X-F, et al. Interferon-γ affects leukemia cell apoptosis through regulating Fas/FasL signaling pathway. Eur Rev Med Pharmacol Sci. 2017;21(9):2244–2248. [[PubMed]
27. Hultgren EM, Patrick ME, Evans RL, et al. SUSD2 promotes tumor-associated macrophage recruitment by increasing levels of MCP-1 in breast cancer. PLoS One. 2017;12(5):e0177089. doi:10.1371/journal.pone.0177089 ] [
28. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014;6(10):a016295. doi:10.1101/cshperspect.a016295 ] [
29. Huang Z-Q, Wang J-L, Pan -G-G, et al. Association of single nucleotide polymorphisms in IL-12 and IL-27 genes with colorectal cancer risk. Clin Biochem. 2012;45(1–2):54–59. doi:10.1016/j.clinbiochem.2011.10.004 [] [[PubMed]
30. Al Omar SY, Marshall E, Middleton D, et al. Increased numbers but functional defects of CD56+CD3+ cells in lung cancer. Int Immunol. 2012;24(7):409–415. doi:10.1093/intimm/dxr122 [] [[PubMed]
31. Sato S, Steeber DA, Tedder TF. The CD19 signal transduction molecule is a response regulator of B-lymphocyte differentiation. Proc Natl Acad Sci USA. 1995;92(25):11558–11562. doi:10.1073/pnas.92.25.11558 ] [
32. Wakabayashi O, Yamazaki K, Oizumi S, et al. CD4+ T cells in cancer stroma, not CD8+ T cells in cancer cell nests, are associated with favorable prognosis in human non-small cell lung cancers. Cancer Sci. 2003;94(11):1003–1009. doi:10.1111/j.1349-7006.2003.tb01392.x [] [[PubMed]
33. Naito Y, Saito K, Shiiba K, et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 1998;58(16):3491–3494. [[PubMed]
34. Blaeschke F, Stenger D, Kaeuferle T, et al. Induction of a central memory and stem cell memory phenotype in functionally active CD4+ and CD8+ CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19+ acute lymphoblastic leukemia. Cancer Immunol Immunother. 2018;67(9967):1053–1066. doi:10.1007/s00262-018-2155-7 [] [[PubMed]
35. Wang R, Yang L, Zhang C, et al. Th17 cell-derived IL-17A promoted tumor progression via STAT3/NF-κB/Notch1 signaling in non-small cell lung cancer. Oncoimmunology. 2018;7(11):e1461303. doi:10.1080/2162402X.2018.1461303 ] [
36. Numasaki M, Fukushi J, Ono M, et al. Interleukin-17 promotes angiogenesis and tumor growth. Blood. 2003;101(7):2620–2627. doi:10.1182/blood-2002-05-1461 [] [[PubMed]
37. Hurtado CG, Wan F, Housseau F, et al. Roles for interleukin 17 and adaptive immunity in pathogenesis of colorectal cancer. Gastroenterology. 2018;155(6):1706–1715. doi:10.1053/j.gastro.2018.08.056 ] [
38. Barrie A, Khare A, Henkel M, et al. Prostaglandin E2 and IL-23 plus IL-1β differentially regulate the Th1/Th17 immune response of human CD161(+) CD4(+) memory T cells. Clin Transl Sci. 2011;4(4):268–273. doi:10.1111/j.1752-8062.2011.00300.x ] [
39. Guéry L, Hugues S. Th17 cell plasticity and functions in cancer immunity. Biomed Res Int. 2015;2015:314620. doi:10.1155/2015/314620 ] [
40. Lukanidin E, Sleeman JP. Building the niche: the role of the S100 proteins in metastatic growth. Semin Cancer Biol. 2012;22(3):216–225. doi:10.1016/j.semcancer.2012.02.006 [] [[PubMed]
41. Huang H. Matrix metalloproteinase-9 (MMP-9) as a cancer biomarker and MMP-9 biosensors: recent advances. Sensors. 2018;18(10):E3249. doi:10.3390/s18103249 ] [
42. Gautam R, Singh M, Gautam S, et al. Rutin attenuates intestinal toxicity induced by methotrexate linked with anti-oxidative and anti-inflammatory effects. BMC Complement Altern Med. 2016;16(1):99. doi:10.1186/s12906-016-1069-1 ] [
43. Jin XN, Yan EZ, Wang HM, et al. Hyperoside exerts anti-inflammatory and anti-arthritic effects in LPS-stimulated human fibroblast-like synoviocytes in vitro and in mice with collagen-induced arthritis. Acta Pharmacol Sin. 2016;37(5):674–686. doi:10.1038/aps.2016.7 ] [
44. Huang G, Tang B, Tang K, et al. Isoquercitrin inhibits the progression of liver cancer in vivo and in vitro via the MAPK signalling pathway. Oncol Rep. 2014;31(5):2377–2384. doi:10.3892/or.2014.3099 [] [[PubMed]
45. Rogovskiĭ VS, Matiushin AI, Shimanovskiĭ NL, et al. Antiproliferative and antioxidant activity of new dihydroquercetin derivatives. Eksp Klin Farmakol. 2010;73(9):39–42. [[PubMed]
46. Cincin ZB, Unlu M, Kiran B, et al. Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014;45(6):445–454. doi:10.1016/j.arcmed.2014.08.002 [] [[PubMed]
47. Ahmadi A, Shadboorestan A. Oxidative stress and cancer; the role of hesperidin, a citrus natural bioflavonoid, as a cancer chemoprotective agent. Nutr Cancer. 2016;68(1):29–39. doi:10.1080/01635581.2015.1078822 [] [[PubMed]
48. Jung SK, Lee KW, Byun S, et al. Myricetin suppresses UVB-induced skin cancer by targeting Fyn. Cancer Res. 2008;68(14):6021–6029. doi:10.1158/0008-5472.CAN-08-0899 [] [[PubMed]
49. Wang XF, Zhou QM, Du J, et al. Baicalin suppresses migration, invasion and metastasis of breast cancer via p38MAPK signaling pathway. Anticancer Agents Med Chem. 2013;13(6):923–931. doi:10.2174/18715206113139990143 [] [[PubMed]
50. Su C, Xia X, Shi Q, et al. Neohesperidin dihydrochalcone versus CCl₄-induced hepatic injury through different mechanisms: the implication of free radical scavenging and Nrf2 activation. J Agric Food Chem. 2015;63(22):5468–5475. doi:10.1021/acs.jafc.5b01750 [] [[PubMed]
51. Jeong J-H, An JY, Kwon YT, et al. Effects of low dose quercetin: cancer cell-specific inhibition of cell cycle progression. J Cell Biochem. 2009;106(1):3–82. doi:10.1002/jcb.21977 ] [