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Vitexin Inhibits Gastric Cancer Growth and Metastasis through HMGB1-mediated Inactivation of the PI3K/AKT/mTOR/HIF-1α Signaling Pathway

  • Zhou, Peng (Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University) ;
  • Zheng, Zi-Han (Department of Gastrointestinal Surgery, Jiangxi Provincial People's Hospital) ;
  • Wan, Tao (Department of Gastrointestinal Surgery, Jiangxi Provincial People's Hospital) ;
  • Wu, Jie (Department of Gastrointestinal Surgery, Jiangxi Provincial People's Hospital) ;
  • Liao, Chuan-Wen (Department of Gastrointestinal Surgery, Jiangxi Provincial People's Hospital) ;
  • Sun, Xue-Jun (Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University)
  • Received : 2021.07.21
  • Accepted : 2021.12.14
  • Published : 2021.12.31

Abstract

Purpose: Gastric cancer (GC) has high morbidity and mortality and is a serious threat to public health. The flavonoid compound vitexin is known to exhibit anti-tumor activity. In this study, we explored the therapeutic potential of vitexin in GC and its underlying mechanism. Materials and Methods: The viability, migration, and invasion of GC cells were determined using MTT, scratch wound healing, and transwell assays, respectively. Target molecule expression was determined by western blotting. Tumor growth and liver metastasis were evaluated in vivo using nude mice. Protein expression in the tumor tissues was examined by immunohistochemistry. Results: Vitexin inhibited GC cell viability, migration, invasion, and epithelial-mesenchymal transition (EMT) in a dose-dependent manner. Vitexin treatment led to the inactivation of phosphatidylinositol-3-kinase (PI3K)/AKT/hypoxia-inducible factor-1α (HIF-1α) pathway by repressing HMGB1 expression. Vitexin-mediated inhibition in proliferation, migration, invasion and EMT of GC cells were counteracted by hyper-activation of PI3K/AKT/HIF-1α pathway or HMGB1 overexpression. Finally, vitexin inhibited the xenograft tumor growth and liver metastasis in vivo by suppressing HMGB1 expression. Conclusions: Vitexin inhibited the malignant progression of GC in vitro and in vivo by suppressing HMGB1-mediated activation of PI3K/Akt/HIF-1α signaling pathway. Thus, vitexin may serve as a promising therapeutic agent for the treatment of GC.

Keywords

Acknowledgement

We would like to give our sincere gratitude to the reviewers for their constructive comments.

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90. https://doi.org/10.3322/caac.20107
  2. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 2013;49:1374-1403. https://doi.org/10.1016/j.ejca.2012.12.027
  3. Hong S, Won YJ, Lee JJ, Jung KW, Kong HJ, Im JS, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2018. Cancer Res Treat 2021;53:301-315. https://doi.org/10.4143/crt.2021.291
  4. Guideline Committee of the Korean Gastric Cancer Association (KGCA), Development Working Group & Review Panel. Korean practice guideline for gastric cancer 2018: an evidence-based, multi-disciplinary approach. J Gastric Cancer 2019;19:1-48. https://doi.org/10.5230/jgc.2019.19.e8
  5. Wang J, Wang L, Li S, Bai F, Xie H, Shan H, et al. Risk factors of lymph node metastasis and its prognostic significance in early gastric cancer: a multicenter study. Front Oncol 2021;11:649035. https://doi.org/10.3389/fonc.2021.649035
  6. Information Committee of the Korean Gastric Cancer Association. Korean Gastric Cancer Association-led nationwide survey on surgically treated gastric cancers in 2019. J Gastric Cancer 2021;21:221-235. https://doi.org/10.5230/jgc.2021.21.e27
  7. Okugawa Y, Mohri Y, Tanaka K, Kawamura M, Saigusa S, Toiyama Y, et al. Metastasis-associated protein is a predictive biomarker for metastasis and recurrence in gastric cancer. Oncol Rep 2016;36:1893-1900. https://doi.org/10.3892/or.2016.5054
  8. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell 2009;139:871-890. https://doi.org/10.1016/j.cell.2009.11.007
  9. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009;119:1420-1428. https://doi.org/10.1172/JCI39104
  10. Pastushenko I, Blanpain C. EMT transition states during tumor progression and metastasis. Trends Cell Biol 2019;29:212-226. https://doi.org/10.1016/j.tcb.2018.12.001
  11. Chiu HC, Li CJ, Yiang GT, Tsai AP, Wu MY. Epithelial to mesenchymal transition and cell biology of molecular regulation in endometrial carcinogenesis. J Clin Med 2019;8:439. https://doi.org/10.3390/jcm8040439
  12. Zhang Y, Qu X, Hu X, Yang X, Hou K, Teng Y, et al. Reversal of P-glycoprotein-mediated multi-drug resistance by the E3 ubiquitin ligase Cbl-b in human gastric adenocarcinoma cells. J Pathol 2009;218:248-255. https://doi.org/10.1002/path.2533
  13. Tan X, Chen S, Wu J, Lin J, Pan C, Ying X, et al. PI3K/AKT-mediated upregulation of WDR5 promotes colorectal cancer metastasis by directly targeting ZNF407. Cell Death Dis 2017;8:e2686. https://doi.org/10.1038/cddis.2017.111
  14. Boffa DJ, Luan F, Thomas D, Yang H, Sharma VK, Lagman M, et al. Rapamycin inhibits the growth and metastatic progression of non-small cell lung cancer. Clin Cancer Res 2004;10:293-300. https://doi.org/10.1158/1078-0432.ccr-0629-3
  15. Hill EE, Kim JK, Jung Y, Neeley CK, Pienta KJ, Taichman RS, et al. Integrin alpha V beta 3 targeted dendrimer-rapamycin conjugate reduces fibroblast-mediated prostate tumor progression and metastasis. J Cell Biochem 2018;119:8074-8083. https://doi.org/10.1002/jcb.26727
  16. Ganesan K, Xu B. Molecular targets of vitexin and isovitexin in cancer therapy: a critical review. Ann N Y Acad Sci 2017;1401:102-113. https://doi.org/10.1111/nyas.13446
  17. Zhang G, Li D, Chen H, Zhang J, Jin X. Vitexin induces G2/M-phase arrest and apoptosis via Akt/mTOR signaling pathway in human glioblastoma cells. Mol Med Rep 2018;17:4599-4604.
  18. Liu X, Jiang Q, Liu H, Luo S. Vitexin induces apoptosis through mitochondrial pathway and PI3K/Akt/mTOR signaling in human non-small cell lung cancer A549 cells. Biol Res 2019;52:7. https://doi.org/10.1186/s40659-019-0214-y
  19. Pan B, Chen D, Huang J, Wang R, Feng B, Song H, et al. HMGB1-mediated autophagy promotes docetaxel resistance in human lung adenocarcinoma. Mol Cancer 2014;13:165. https://doi.org/10.1186/1476-4598-13-165
  20. Al-Ostoot FH, Sherapura A, V V, Basappa G, H K V, B T P, et al. Targeting HIF-1α by newly synthesized Indolephenoxyacetamide (IPA) analogs to induce anti-angiogenesis-mediated solid tumor suppression. Pharmacol Rep 2021;73:1328-1343. https://doi.org/10.1007/s43440-021-00266-8
  21. Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest 2007;117:3810-3820. https://doi.org/10.1172/JCI30487
  22. Zuo J, Wen J, Lei M, Wen M, Li S, Lv X, et al. Hypoxia promotes the invasion and metastasis of laryngeal cancer cells via EMT. Med Oncol 2016;33:15. https://doi.org/10.1007/s12032-015-0716-6
  23. Srivastava C, Irshad K, Dikshit B, Chattopadhyay P, Sarkar C, Gupta DK, et al. FAT1 modulates EMT and stemness genes expression in hypoxic glioblastoma. Int J Cancer 2018;142:805-812. https://doi.org/10.1002/ijc.31092
  24. Park SJ, Kim JG, Kim ND, Yang K, Shim JW, Heo K. Estradiol, TGF-β1 and hypoxia promote breast cancer stemness and EMT-mediated breast cancer migration. Oncol Lett 2016;11:1895-1902. https://doi.org/10.3892/ol.2016.4115
  25. Liu Z, Sun T, Piao C, Zhang Z, Kong C. METTL13 inhibits progression of clear cell renal cell carcinoma with repression on PI3K/AKT/mTOR/HIF-1α pathway and c-Myc expression. J Transl Med 2021;19:209. https://doi.org/10.1186/s12967-021-02879-2
  26. He H, Wang X, Chen J, Sun L, Sun H, Xie K. High-mobility group box 1 (HMGB1) promotes angiogenesis and tumor migration by regulating hypoxia-inducible factor 1 (HIF-1α) expression via the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway in breast cancer cells. Med Sci Monit 2019;25:2352-2360. https://doi.org/10.12659/msm.915690
  27. Yao HC, Zhou M, Zhou YH, Wang LH, Zhang DY, Han QF, et al. Intravenous high mobility group box 1 upregulates the expression of HIF-1α in the myocardium via a protein kinase B-dependent pathway in rats following acute myocardial ischemia. Mol Med Rep 2016;13:1211-1219. https://doi.org/10.3892/mmr.2015.4648
  28. Min JW, Hu JJ, He M, Sanchez RM, Huang WX, Liu YQ, et al. Vitexin reduces hypoxia-ischemia neonatal brain injury by the inhibition of HIF-1alpha in a rat pup model. Neuropharmacology 2015;99:38-50. https://doi.org/10.1016/j.neuropharm.2015.07.007
  29. Liu J, Wang G, Zhao J, Liu X, Zhang K, Gong G, et al. LncRNA H19 promoted the epithelial to mesenchymal transition and metastasis in gastric cancer via activating Wnt/β-catenin signaling. Dig Dis. Forthcoming 2021.
  30. Zhou H, Hu X, Li N, Li G, Sun X, Ge F, et al. Loganetin and 5-fluorouracil synergistically inhibit the carcinogenesis of gastric cancer cells via down-regulation of the Wnt/β-catenin pathway. J Cell Mol Med 2020;24:13715-13726. https://doi.org/10.1111/jcmm.15932
  31. Hundahl SA, Phillips JL, Menck HR. The National Cancer Data Base Report on poor survival of U.S. gastric carcinoma patients treated with gastrectomy: Fifth Edition American Joint Committee on Cancer staging, proximal disease, and the "different disease" hypothesis. Cancer 2000;88:921-932. https://doi.org/10.1002/(SICI)1097-0142(20000215)88:4<921::AID-CNCR24>3.0.CO;2-S
  32. Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725-730. https://doi.org/10.1056/NEJMoa010187
  33. He JD, Wang Z, Li SP, Xu YJ, Yu Y, Ding YJ, et al. Vitexin suppresses autophagy to induce apoptosis in hepatocellular carcinoma via activation of the JNK signaling pathway. Oncotarget 2016;7:84520-84532. https://doi.org/10.18632/oncotarget.11731
  34. Lee CY, Chien YS, Chiu TH, Huang WW, Lu CC, Chiang JH, et al. Apoptosis triggered by vitexin in U937 human leukemia cells via a mitochondrial signaling pathway. Oncol Rep 2012;28:1883-1888. https://doi.org/10.3892/or.2012.2000
  35. Long-Bao W, Bo-Wen Q, Yan-Xing X. Establishment of human gastric cancer cell line (SGC-7901) intraperitoneally transplantable in nude mice. In: Takahashi T, ed. Recent Advances in Management of Digestive Cancers. Tokyo: Springer, 1993:416-418.
  36. Barranco SC, Townsend CM Jr, Casartelli C, Macik BG, Burger NL, Boerwinkle WR, et al. Establishment and characterization of an in vitro model system for human adenocarcinoma of the stomach. Cancer Res 1983;43:1703-1709.
  37. Tan Z, Zhang Y, Deng J, Zeng G, Zhang Y. Purified vitexin compound 1 suppresses tumor growth and induces cell apoptosis in a mouse model of human choriocarcinoma. Int J Gynecol Cancer 2012;22:360-366. https://doi.org/10.1097/IGC.0b013e31823de844
  38. Yang SH, Liao PH, Pan YF, Chen SL, Chou SS, Chou MY. The novel p53-dependent metastatic and apoptotic pathway induced by vitexin in human oral cancer OC2 cells. Phytother Res 2013;27:1154-1161. https://doi.org/10.1002/ptr.4841
  39. Li X, Wang M, Li S, Chen Y, Wang M, Wu Z, et al. HIF-1-induced mitochondrial ribosome protein L52: a mechanism for breast cancer cellular adaptation and metastatic initiation in response to hypoxia. Theranostics 2021;11:7337-7359. https://doi.org/10.7150/thno.57804
  40. Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell 2012;148:399-408. https://doi.org/10.1016/j.cell.2012.01.021
  41. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003;3:721-732. https://doi.org/10.1038/nrc1187
  42. O'Donnell JL, Joyce MR, Shannon AM, Harmey J, Geraghty J, Bouchier-Hayes D. Oncological implications of hypoxia inducible factor-1alpha (HIF-1alpha) expression. Cancer Treat Rev 2006;32:407-416. https://doi.org/10.1016/j.ctrv.2006.05.003
  43. Lee TJ, Sartor O, Luftig RB, Koochekpour S. Saposin C promotes survival and prevents apoptosis via PI3K/Akt-dependent pathway in prostate cancer cells. Mol Cancer 2004;3:31. https://doi.org/10.1186/1476-4598-3-31
  44. Baghery Saghchy Khorasani A, Pourbagheri-Sigaroodi A, Pirsalehi A, Safaroghli-Azar A, Zali MR, Bashash D. The PI3K/Akt/mTOR signaling pathway in gastric cancer; from oncogenic variations to the possibilities for pharmacologic interventions. Eur J Pharmacol 2021;898:173983. https://doi.org/10.1016/j.ejphar.2021.173983
  45. Zhu J, Wang FL, Wang HB, Dong N, Zhu XM, Wu Y, et al. TNF-α mRNA is negatively regulated by microRNA-181a-5p in maturation of dendritic cells induced by high mobility group box-1 protein. Sci Rep 2017;7:12239. https://doi.org/10.1038/s41598-017-12492-3
  46. Suren D, Arda Gokay A, Sayiner A. High Mobility Group Box 1 (HMGB1) expression in gastric adenocarcinomas. J BUON 2018;23:422-427.
  47. Tian L, Wang ZY, Hao J, Zhang XY. miR-505 acts as a tumor suppressor in gastric cancer progression through targeting HMGB1. J Cell Biochem 2019;120:8044-8052. https://doi.org/10.1002/jcb.28082
  48. Zhang Y, Ren H, Li J, Xue R, Liu H, Zhu Z, et al. Elevated HMGB1 expression induced by hepatitis B virus X protein promotes epithelial-mesenchymal transition and angiogenesis through STAT3/miR-34a/NF-κB in primary liver cancer. Am J Cancer Res 2021;11:479-494.
  49. Ma J, Xu Y, Li W, Zhou Y, Wang D, Yang M, et al. High-mobility group box 1 promotes epithelial-to-mesenchymal transition in crystalline silica induced pulmonary inflammation and fibrosis. Toxicol Lett 2020;330:134-143. https://doi.org/10.1016/j.toxlet.2020.05.016
  50. Li R, Zou X, Huang H, Yu Y, Zhang H, Liu P, et al. HMGB1/PI3K/Akt/mTOR signaling participates in the pathological process of acute lung injury by regulating the maturation and function of dendritic cells. Front Immunol 2020;11:1104. https://doi.org/10.3389/fimmu.2020.01104
  51. Zhou YH, Han QF, Gao L, Sun Y, Tang ZW, Wang M, et al. HMGB1 protects the heart against ischemiareperfusion injury via PI3K/AkT pathway-mediated upregulation of VEGF expression. Front Physiol 2020;10:1595. https://doi.org/10.3389/fphys.2019.01595