Effect of MUC1 siRNA on Drug Resistance of Gastric Cancer Cells to Trastuzumab

  • Deng, Min (Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiao Tong University) ;
  • Jing, Da-Dao (Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiao Tong University) ;
  • Meng, Xiang-Jun (Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiao Tong University)
  • Published : 2013.01.31


Trastuzumab is the first molecular targeting drug to increase the overall survival rate in advanced gastric cancer. However, it has also been found that a high intrinsic or primary trastuzumab resistance exists in some proportion of gastric cancer patients. In order to explore the mechanism of resistance to trastuzumab, firstly we investigated the expression of MUC1 (membrane-type mucin 1) in gastric cancer cells and its relationship with drug-resistance. Then using gene-silencing, we transfected a siRNA of MUC1 into drug-resistant cells. The results showed the MKN45 gastric cell line to be resistant to trastuzumab, mRNA and protein expression of MUC1 being significantly upregulated. After transfection of MUC1 siRNA, protein expression of MUC1 in MKN45cells was significantly reduced. Compared with the junk transfection and blank control groups, the sensitivity to trastuzumab under MUC1 siRNA conditions was significantly increased. These results imply that HER2-positive gastric cancer cell MKN45 is resistant to trastuzumab and this resistance can be cancelled by silencing expression of the MUC1 gene.


  1. Bang Y, Van Cutsem E, Feyereislova A, et al (2010). ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet, 376, 687-97.
  2. Citri A, Kochupurakkal BS, Yarden Y (2004). The achilles heel of ErbB-2/HER2: regulation by the Hsp90 chaperone machine and potential for pharmacological intervention. Cell Cycle, 3, 51-60.
  3. Fessler SP, Wotkowicz MT, Mahanta SK, et al (2009). MUC1* is a determinant of trastuzumab (Herceptin) resistance in breast cancer cells. Breast Cancer Res Treat, 118, 113-24.
  4. Gerlinger M, Rowan AJ, Horswell S, et al (2012). Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med, 366, 883-92.
  5. Hikita ST, Kosik KS, Clegg DO, et al (2008). MUC1* mediates the growth of human pluripotent stem cells. PLoS One, 3, e3312.
  6. Lang SA, Klein D, Moser C, et al (2007). Inhibition of heat shock protein 90 impairs epidermal growth factor-mediated signaling in gastric cancer cells and reduces tumor growth and vascularization in vivo. Mol Cancer Ther, 6, 1123-32.
  7. Lapointe J, Li C, Higgins JP, et al (2004). Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc Natl Acad Sci U S A, 101, 811.
  8. L'Esperance S, Popa I, Bachvarova M, et al (2006). Gene expression profiling of paired ovarian tumors obtained prior to and following adjuvant chemotherapy: molecular signatures of chemoresistant tumors. Int J Oncol, 29, 5-24.
  9. Mahanta S, Fessler SP, Park J, et al (2008). A minimal fragment of MUC1 mediates growth of cancer cells. PLoS One, 3, e2054.
  10. Nahta R, Esteva FJ (2007). Trastuzumab: triumphs and tribulations. Oncogene, 26, 3637-43.
  11. Price, Schiavi SA, Jepson S, Li P, et al (2002). Rat Muc4 (sialomucin complex) reduces binding of anti. ErbB2 antibodies to tumor cell surfaces, a potential mechanism for herceptin resistance. Int J Cancer, 99, 783-791.
  12. Raina D, Kharbanda S, Kufe D (2004). The MUC1 oncoprotein activates the anti-apoptotic phosphoinositide 3-kinase/Akt and Bcl-xL pathways in rat 3Y1 fibroblasts. J Biol Chem, 279, 20607-12.
  13. Ren J, Agata N, Chen D, et al (2004). Human MUC1 carcinomaassociated protein confers resistance to genotoxic anticancer agents. Cancer Cell, 5, 163-75.
  14. Siragusa M, Zerilli M, Iovino F, et al (2007). MUC1 oncoprotein promotes refractoriness to chemotherapy in thyroid cancer cells. Cancer Res, 67, 5522.
  15. Valabrega G, Montemurro F, Aglietta M (2007). Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Ann Oncol, 18, 977-84.
  16. Velho S, Oliveira C, Ferreira A, et al (2005). The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer, 41, 1649-54.
  17. Vogel CL, Cobleigh MA, Tripathy D, et al (2001). Firstline Herceptin monotherapy in metastatic breast cancer. Oncology, 2, 37-42.
  18. Yang J, Luo H, Li Y, et al (2012). Intratumoral heterogeneity determines discordant results of diagnostic tests for human epidermal growth factor receptor (HER) 2 in gastric cancer specimens. Cell Biochem Biophys, 62, 221-28.
  19. Yin L, Li Y, Ren J, et al (2003). Human MUC1 carcinoma antigen regulates intracellular oxidant levels and the apoptotic response to oxidative stress. J Biol Chem, 278, 35458-64.

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