Anti-proliferation Effects of Interferon-gamma on Gastric Cancer Cells

  • Zhao, Ying-Hui (Institute of Aetiology, Department of Aetiology, Taishan Medical University) ;
  • Wang, Tao (Institution of Biochemistry, Basic Medical School, Taishan Medical University) ;
  • Yu, Guang-Fu (Institute of Aetiology, Department of Aetiology, Taishan Medical University) ;
  • Zhuang, Dong-Ming (Institute of Aetiology, Department of Aetiology, Taishan Medical University) ;
  • Zhang, Zhong (Institute of Aetiology, Department of Aetiology, Taishan Medical University) ;
  • Zhang, Hong-Xin (Institute of Aetiology, Department of Aetiology, Taishan Medical University) ;
  • Zhao, Da-Peng (Institute of Aetiology, Department of Aetiology, Taishan Medical University) ;
  • Yu, Ai-Lian (Institute of Aetiology, Department of Aetiology, Taishan Medical University)
  • Published : 2013.09.30


IFN-${\gamma}$ plays an indirect anti-cancer role through the immune system but may have direct negative effects on cancer cells. It regulates the viability of gastric cancer cells, so we examined whether it affects their proliferation and how that might be brought about. We exposed AGS, HGC-27 and GES-1 gastric cancer cell lines to IFN-${\gamma}$ and found significantly reduced colony formation ability. Flow cytometry revealed no effect of IFN-${\gamma}$ on apoptosis of cell lines and no effect on cell aging as assessed by ${\beta}$-gal staining. Microarray assay revealed that IFN-${\gamma}$ changed the mRNA expression of genes related to the cell cycle and cell proliferation and migration, as well as chemokines and chemokine receptors, and immunity-related genes. Finally, flow cytometry revealed that IFN-${\gamma}$ arrested the cells in the G1/S phase. IFN-${\gamma}$ may slow proliferation of some gastric cancer cells by affecting the cell cycle to play a negative role in the development of gastric cancer.


  1. Blumenthal RD, Leon E, Hansen HJ, et al (2007). Expression patterns of CEACAM5 and CEACAM6 in primary and metastatic cancers. BMC Cancer, 7, 2.
  2. Cazzalini O, Scovassi AI, Savio M, et al (2010). Multiple roles of the cell cycle inhibitor p21 (CDKN1A) in the DNA damage response. Mutat Res, 704, 12-20.
  3. Chen LZ, Shi HR (2008). Expression of Cyclin B1 and CDC25B in uterine cervix cancer Tissue. Shandong Med, 48, 93-4.
  4. Chen QF, Wang DJ (2009). Expression of cyclinB1-CDK1 and 14-3-3 protein in human gliomas and their significance. Shichuan Med J, 30, 315-7.
  5. Duxbury MS, Ito H, Benoit E, et al (2004). CEACAM6 is a determinant of pancreatic adenocarcinoma cellular invasiveness. Br J Cancer, 91, 1384-90.
  6. Feng QL, Shi HR, Wang L, et al (2009). Expression of cyclinB1, p27 and ubiquitin in epithelial overian tumor tissue. J Zhenzhou University ( Med Sic), 44, 295-7.
  7. Frank SL, Liugi T, Ilaria C, et al (2002). In situ correlation of cytokine secretion and apoptosis in H. pylori-associated gastritis. Am J Physiol Gastrointest Liver Physiol, 283, 481-8.
  8. Gao FH, Hu XH, Li W, et al (2010). Oridonin induces apoptosis and senescence in colorectal cancer cells by increasing histone hyperacetylation and regulation of p16, p21, p27 and c-myc. BMC Cancer, 10, 610.
  9. Gerber SA, Sedlacek AL, Cron KR, et al (2013). IFN-$\gamma$ mediates the antitumor effects of radiation therapy in a murine colon tumor. Am J Pathol, 182, 2345-54.
  10. Huang SH, Ma XL, Qiu C, et al (2004). The over expression of cyclinB1 and CDK1 in lung carcinoma and its clinical significance. J Shandong Uni, 39, 122-4.
  11. Huang YP, Yan JY, Liu NX, et al (2010). Expression of CDC25B and CyclinB1 in human gastric adenocarcinoma significance. J Wenzhou Med Col, 40, 346-50.
  12. Hou SW, Zhi HY, Pohl N, et al (2010). PTPH1 dephosphorylates and cooperates with p38gamma MAPK to increase ras oncogenesis through PDZ-mediated interaction. Cancer Res, 70, 2901-10.
  13. Jin SZ, Wu N, Liu LB, et al (2010). Experimental studies on relation-induced expression changes of genes related to cell cycle control and DNA damage response. Radi Pro, 30, 70-9.
  14. Karttunen R, Karttunen T, Ekre HP, et al (1995). Interferon gamma and interleukin 4 secreting cells in the gastric antrum in H. pylori positive and negative gastritis. Gut, 36, 341-5.
  15. Kim KS, Kang KW, Seu YB, et al (2009). Interferon-gamma induces cellular senescence through p53-dependent DNA damage signaling in human endothelial cells. Mech Ageing Dev, 130, 179-88.
  16. Kuga H, Morisaki T, Nakamura K, et al (2003). Interferon-$\gamma$ suppresses transforming growth factor-$\beta$-induced invasion of gastric carcinoma cells through cross-talk of Smad pathway in a three-dimensional culture model. Oncogene, 22, 7838-47.
  17. Lasa A, Serrano E, Carricondo M, et al (2008). High expression of CEACAM6 and CEACAM8 mRNA in acute lymphoblastic leukemias. Ann Hematol, 87, 205-11.
  18. Lee SH, Kim JW, Oh SH, et al (2005). IFN-$\gamma$/IRF-1-induced p27 down-regulates telomerase activity and human telomerase reverse transcriptase expression in human cervical cancer. FEBS Letters, 579, 1027-33.
  19. Li J, Chen P, Hu HZ (2009). Construction of recombinant adenovirus containing Full-length sense and antisense cyclinB1 cDNA and their impact on proliferation and apoptosis of Hela cells. J Sichuan Uni (Med Sci Edi), 40, 765-9.
  20. Li XK, Motwani M, Tong W, et al (2000). Huanglian, A chinese herbal extract, inhibits cell growth by suppressing the expression of cyclin B1 and inhibiting CDC2 kinase activity in human cancer cells. Mol Pharmacol, 58, 1287-93.
  21. Lindkvist A, Ivarsson K, Jernberg-Wiklund H, et al (2006). Interferon-induced sensitization to apoptosis is associated with repressed transcriptional activity of the hTERT promoter in multiple myeloma. Biochem and Biophys Res Commun, 341, 1141-8.
  22. Liu K, Wang G, Ding H, et al (2010). Downregulation of metastasis suppressor 1 (MTSS1) is associated with nodal metastasis and poor outcome in Chinese patients with gastric cancer. BMC Cancer, 10, 428.
  23. Liu X, Ma R, Chen W, et al (2005). Inhibition of Allicin on G2/M phase of human gastric cell line SGC-7901 and BGC-823. World Chin Digestol, 13, 2409-12.
  24. Mahata P (2006). Biomarkers for epithelial ovarian cancers. Genome Inform, 17, 184-93.
  25. Marinissen MJ, Chiariello M, Gutkind JS (2001). Regulation of gene expression by the small GTPase Rho through the ERK6 ($p38\gamma$) MAP kinase pathway. Genes Dev, 15, 535-53.
  26. Mitchell DJ, Huynh HQ, Ceponis PJ, et al (2004). Helicobacter pylori disrupts STAT1-mediated gamma interferon-induced signal transduction in epithelial cells. Infect Immun, 1, 537-45.
  27. Ni C, Wu P, Zhu X, et al (2013). IFN-$\gamma$ selectively exerts proapoptotic effects on tumor-initiating label-retaining colon cancer cells. Cancer Lett, 336, 174-84.
  28. Pan Y, Li YW, Feng JB, et al (2009). Changes of p53 related gene mRNA induced by 60co $\gamma$-RAY in lymphoblastoid cells. Radi Pro, 29, 8-12.
  29. Parkin DM, Bay F, Ferlay J, et al (2005). Global cancer statistics, 2002. CA Cancer J Clin, 55, 74-108.
  30. Poola I, Shokrani B, Bhatnagar R, et al (2006). Expression of carcinoembryonic antigen cell adhesion molecule 6 oncoprotein in atypical ductal hyperplastic tissues is associated with the development of invasive breast cancer. Clin Cancer Res, 12, 4773-83.
  31. Rajiv J, Naren LB, Swapan KR(2008). N- (4-Hydroxyphenyl) retinamide induced differentiation with repression of telomerase and cell cycle to increase interferon-$\gamma$ sensitivity for apoptosis in human glioblastoma cells. Cancer Letters, 261, 26-36.
  32. Rushing EJ, Sandberg GD, Horkayne-Szakaly I (2010). Highgrade astrocytomas show increased Nestin and Wilms's tumor gene (WT1) protein expression. Int J Surg Pathol, 18, 255-9.
  33. Sakamoto Y, Mariya Y, Sasaki S, et al (2009). WT1 mRNA level in peripheral blood is a sensitive biomarker for monitoring minimal residual disease in acute myeloid leukemia. Tohoku J Exp Med, 219, 169-76.
  34. Shimako F, Hidemi G, Yasumasa N, et al (2002). Interferon-$\gamma$ regulates apoptosis by releasing soluble tumor necrosis factor receptors in a gastric epithelial cell line. J Gastroenterol Hepatol, 17, 1283-90.
  35. Tagawa T, Wu L, Anraku M, et al (2013). Antitumor impact of interferon-$\gamma$ producing CD1d-restricted NKT cells in murine malignant mesothelioma. J Immunother, 36, 391-9.
  36. Takeuchi S, Takahashi A, Motoi N, et al (2010). Intrinsic cooperation between p16INK4a and p21Waf1/Cip1 in the onset of cellular senescence and tumor suppression in vivo. Cancer Res, 70, 9381-90.
  37. Tortorella LL, Lin CB, Pilch PF (2003). ERK6 is expressed in a developmentally regulated manner in rodent skeletal muscle. Biochem Biophys Res Commun, 306, 163-8.
  38. Tu SP, Quante M, Bhagat G, et al (2011). IFN-$\gamma$ inhibits gastric carcinogenesis by inducing epithelial cell autophagy and T-cell apoptosis. Cancer Res, 71, 4247-59.
  39. Wagner S, Beil W, Westermann J, et al (1997). Regulation of gastric epithelial cell growth by H. pylori: evidence for a major role of apoptosis. Gastroenterol, 113, 1836-47.
  40. Wei J, Zhao J, Long M, et al (2010). p21WAF1/CIP1 gene transcriptional activation exerts cell growth inhibition and enhances chemosensitivity to cisplatin in lung carcinoma cell. BMC Cancer, 10, 632.
  41. Xia Y, Xu H, Sun Y, et al (2010). Relationship between Helicobacter pylori infection and expression of CDK1 in gastric carcinoma. Chin J Prac Inter Med, 30, 266-7.
  42. Xiao H, Gong WJ, Chao JP, et al (2009). Influence of CDK1 and CDK2 siRNA interference on tumor cell cycle and cell apoptosis. Chin-Ger J of Clin Onco, 8, 371-4.
  43. Xinfang Li, Anthony WO, Jeffrey SB (2003). IFN-$\gamma$ Induction of Osteopontin Expression in Human. J Interferon Cytokine Res, 23, 259-65.
  44. Yamada A, Suzuki D, Miyazono A, et al (2009). IFN-$\gamma$ downregulates Secretoglobin 3A1 gene expression. Biochem Biophys Res Commun, 379, 964-8.
  45. Yang Y, Gao H, Chen GL (2008). Expression of cyclinB1and surviving in Hepatic carcinoma. J Hei Long Jiang Med, 32, 500-3.
  46. Yeruva S, Ramadori G, Raddatz D (2008). NF-${\kappa}B$-dependent synergistic regulation of CXCL10 gene expression by IL- 1$\beta$ and IFN-$\gamma$ in human intestinal epithelial cell lines. Int J Colorectal Dis, 23, 305-17.
  47. Yuan J, Yan R, Kramer A, et al (2004). Cyclin B1 depletion inhibits proliferation and induces apoptosis in human tumor cells. Oncogene, 23, 5843-52.
  48. Yuan J, Kramer A, Matthess Y, et al (2006). Stable gene silencing of cyclin B1 in tumor cells increases susceptibility to taxol and leads to growth arrest in vivo. Oncogene, 25, 1753-62.
  49. Zeng RX, Shu YH (2005). Progress in the signal transduction and biological function of p38$\gamma$/SAPK3. Life Sci Chin Bull, 17, 419-23.
  50. Zhang RT, Hui R, Liu HB, et al (2009). Expression of p21WAF1 and CDK1 protein in epithelial ovarian cancer tissue. J Zhengzhou Univ (Med Sci), 44, 334-6.
  51. Zhao CL, Chen LM, Gao ZQ, et al (2009). Clinacal significance of cyclinB1 and cyclin-dependent kinase 1 expression in human esophageal squamous cell carcinoma. World Chin Digestol, 17, 2374-8.

Cited by

  1. Local Cervical Immunity in Women with Low-grade Squamous Intraepithelial Lesions and Immune Responses After Abrasion vol.15, pp.10, 2014,
  2. Influence of Propofol, Isoflurane and Enflurance on Levels of Serum Interleukin-8 and Interleukin-10 in Cancer Patients vol.15, pp.16, 2014,
  3. Induction of Indoleamine 2,3-dioxygenase (IDO) Enzymatic Activity Contributes to Interferon-Gamma Induced Apoptosis and Death Receptor 5 Expression in Human Non-small Cell Lung Cancer Cells vol.15, pp.18, 2014,
  4. Interferon Apha 2b for Treating Patients with JAK2V617F Positive Polycythemia Vera and Essential Thrombocytosis vol.15, pp.4, 2014,
  5. pathway is associated with Advanced Ovarian Cancer in Saudi Patients vol.16, pp.14, 2015,
  6. Interferon gamma-induced apoptosis of head and neck squamous cell carcinoma is connected to indoleamine-2,3-dioxygenase via mitochondrial and ER stress-associated pathways vol.11, pp.1, 2016,
  7. The cellular character of liquefaction degeneration in oral lichen planus and the role of interferon gamma pp.09042512, 2017,
  8. EHHM, a novel phenolic natural product from Livistona chinensis, induces autophagy-related apoptosis in hepatocellular carcinoma cells vol.12, pp.5, 2016,
  9. Stage-specific IFN-induced and IFN gene expression reveal convergence of type I and type II IFN and highlight their role in both acute and chronic stage of pathogenic SIV infection vol.13, pp.1, 2018,
  10. Interferon Gamma Inhibits CXCL8-Induced Proliferation and Migration of Pancreatic Cancer BxPC-3 Cell Line via a RhoGDI2/Rac1/NF-κB Signaling Pathway vol.38, pp.9, 2018,
  11. CD74 a Potential Therapeutic Target for Breast Cancer Therapy: Interferon Gamma Up-regulates its Expression in CAMA-1 and MDA-MB-231 Cancer Cells vol.14, pp.2, 2018,