DOI QR코드

DOI QR Code

RASAL1 Attenuates Gastric Carcinogenesis in Nude Mice by Blocking RAS/ERK Signaling

  • Chen, Hong (Department of Gastroenterology, Affiliated Zhongda Hospital, Southeast University) ;
  • Zhao, Ji-Yi (Department of Gastroenterology, Affiliated Zhongda Hospital, Southeast University) ;
  • Qian, Xu-Chen (Department of Gastroenterology, Affiliated Zhongda Hospital, Southeast University) ;
  • Cheng, Zheng-Yuan (Department of Gastroenterology, Jiangbei Hospital) ;
  • Liu, Yang (Department of Gastroenterology, Affiliated Zhongda Hospital, Southeast University) ;
  • Wang, Zhi (Department of Gastroenterology, Affiliated Zhongda Hospital, Southeast University)
  • Published : 2015.03.04

Abstract

Recent studies have suggested that the RAS protein activator like-1 (RASAL1) functions as a tumor suppressor in vitro and may play an important role in the development of gastric cancer. However, whether or not RASAL1 suppresses tumor growth in vivo remains to be determined. In the present study, we investigated the role of RASAL1 in gastric carcinogenesis using an in vivo xenograft model. A lentiviral RASAL1 expression vector was constructed and utilized to transfect the human poorly differentiated gastric adenocarcinoma cell line, BGC-823. RASAL1 expression levels were verified by quantitative real-time RT-PCR and Western blotting analysis. Then, we established the nude mice xenograft model using BGC-823 cells either over-expressing RASAL1 or normal. After three weeks, the results showed that the over-expression of RASAL1 led to a significant reduction in both tumor volume and weight compared with the other two control groups. Furthermore, in xenograft tissues the increased expression of RASAL1 in BGC-823 cells caused decreased expression of p-ERK1/2, a downstream moleculein the RAS/RAF/MEK/ERK signal pathway. These findings demonstrated that the over-expression of RASAL1 could inhibit the growth of gastric cancer by inactivation of the RAS/RAF/MEK/ERK pathway in vivo. This study indicates that RASAL1 may attenuate gastric carcinogenesis.

Keywords

Gastric cancer;RASAL1 gene;BGC-823 cells;xenograft tumor

Acknowledgement

Supported by : National Health and Family Planning Commission of China, Natural Science Foundation

References

  1. Calvisi D F, Ladu S, Conner E A, et al (2011). Inactivation of Ras GTPase-activating proteins promotes unrestrained activity of wild-type Ras in human liver cancer. J Hepatol, 54, 311-9. https://doi.org/10.1016/j.jhep.2010.06.036
  2. Chen H, Cheng Z Y, Pan Y, et al (2014). RASAL1 influences the proliferation and invasion of gastric cancer cells by regulating the RAS/ERK signaling pathway. Human cell, 27, 1-8. https://doi.org/10.1007/s13577-013-0081-8
  3. Chen H, Pan Y, Cheng ZY, et al (2013). Hypermethylation and clinicopathological significance of RASAL1 gene in gastric cancer. Asian Pac J Cancer Prev, 14, 6261-5. https://doi.org/10.7314/APJCP.2013.14.11.6261
  4. Chen H, Yang XW, Zhang H, et al (2012). In vivo and In vitro expression of the RASAL1 gene in human gastric adenocarcinoma and its clinicopathological significance. Oncology letters, 3, 535-40.
  5. Cherfils J, Zeghouf M, (2013). Regulation of small GTPases by GEFs, GAPs, and GDIs. Physiological reviews, 93, 269-309. https://doi.org/10.1152/physrev.00003.2012
  6. Dote H, Toyooka S, Tsukuda K, et al (2005). Aberrant promoter methylation in human DAB2 interactive protein (hDAB2IP) gene in gastrointestinal tumour. Br J Cancer, 92, 1117-25. https://doi.org/10.1038/sj.bjc.6602458
  7. Downward J (2003). Targeting RAS signalling pathways in cancer therapy. Nature Reviews Cancer, 3, 11-22. https://doi.org/10.1038/nrc969
  8. Jin SH, Akiyama Y, Fukamachi H, et al (2008). IQGAP2 inactivation through aberrant promoter methylation and promotion of invasion in gastric cancer cells. Int J Cancer, 122, 1040-6.
  9. Karnoub A E, Weinberg R A (2008). Ras oncogenes: split personalities. Nature Rev Molec Cell Biol, 9, 517-31. https://doi.org/10.1038/nrm2438
  10. Liu D, Yang C, Bojdani E, et al (2013). Identification of RASAL1 as a major tumor suppressor gene in thyroid cancer. J Natl Cancer Inst, 105, 1617-27. https://doi.org/10.1093/jnci/djt249
  11. Liu J, Huang XE, Feng JF (2014).Further study on pemetrexed based chemotherapy in treating patients with advanced gastric cancer (AGC). Asian Pac J Cancer Prev, 15, 6587-90. https://doi.org/10.7314/APJCP.2014.15.16.6587
  12. Lu Q, Nassar N, Wang J. A mechanism of catalyzed GTP hydrolysis by Ras protein through magnesiumion. Chemical Physics Letters, 516, 233-8.
  13. Maertens O, Cichowski K (2014). An expanding role for RAS GTPase activating proteins (RAS GAPs) in cancer. Adv Biological Regulation, 55, 1-14. https://doi.org/10.1016/j.jbior.2014.04.002
  14. Malumbres M, Barbacid M (2003). RAS oncogenes: the first 30 years. Nature Reviews Cancer, 3, 459-65. https://doi.org/10.1038/nrc1097
  15. McLaughlin S K, Olsen S N, Dake B, et al (2013). The RasGAP Gene,RASAL2, is a tumor and metastasis suppressor. Cancer Cell, 24, 365-78. https://doi.org/10.1016/j.ccr.2013.08.004
  16. Qiao F, Su X, Qiu X, et al (2012). Enforced expression of RASAL1 suppresses cell proliferation and the transformation ability of gastric cancer cells. Oncology Reports, 28, 1475-81.
  17. Seto M, Ohta M, Ikenoue T, et al (2011). Reduced expression of RAS protein activator like-1 in gastric cancer. Int J Cancer, 128, 1293-302. https://doi.org/10.1002/ijc.25459
  18. Stephen A G, Esposito D, Bagni R K, et al (2014). Dragging Ras back in the ring. Cancer Cell, 25, 272-81. https://doi.org/10.1016/j.ccr.2014.02.017
  19. Sugimoto N, Imoto I, Fukuda Y, et al (2001). IQGAP1, a negative regulator of cell-cell adhesion, is upregulated by gene amplification at 15q26 in gastric cancer cell lines HSC39 and 40A. J Human Genetics, 46, 21-5. https://doi.org/10.1007/s100380170119
  20. Takemoto H, Doki Y, Shiozaki H, et al (2001). Localization of IQGAP1 is inversely correlated with intercellular adhesion mediated by E-cadherin in gastric cancers. Int J Cancer, 91, 783-8. https://doi.org/10.1002/1097-0215(200002)9999:9999<::AID-IJC1121>3.0.CO;2-Z
  21. Walch A, Seidl S, Hermannstädter C, et al (2008). Combined analysis of Rac1, IQGAP1, Tiam1 and E-cadherin expression in gastric cancer. Modern Pathology, 21, 544-52. https://doi.org/10.1038/modpathol.2008.3
  22. Wei GL, Huang XE, Huo JG, et al (2014).Phase II study on pemetrexed-based chemotherapy in treating patients with metastatic gastric cancer not responding to prior palliative chemotherapy. Asian Pac J Cancer Prev, 14, 2703-6.
  23. Xu S, Zhou Y, Du WD, et al (2013). Association of the variant rs2243421 of human DOC-2/DAB2 interactive protein gene (hDAB2IP) with gastric cancer in the Chinese Han population. Gene, 515, 200-4. https://doi.org/10.1016/j.gene.2012.11.043

Cited by

  1. Targeting CD133+ laryngeal carcinoma cells with chemotherapeutic drugs and siRNA against ABCG2 mediated by thermo/pH-sensitive mesoporous silica nanoparticles vol.37, pp.2, 2016, https://doi.org/10.1007/s13277-015-4007-9
  2. ABCG2 is required for self-renewal and chemoresistance of CD133-positive human colorectal cancer cells vol.37, pp.9, 2016, https://doi.org/10.1007/s13277-016-5209-5
  3. Downregulation of RASAL2 promotes the proliferation, epithelial-mesenchymal transition and metastasis of colorectal cancer cells vol.13, pp.3, 2017, https://doi.org/10.3892/ol.2017.5581