Downregulation of liver–intestine cadherin enhances cisplatin-induced apoptosis in human gastric cancer BGC823 cells

Abstract

Gastric cancer is the fourth most common type of cancer. Liver–intestine cadherin (CDH17) has been found to be involved in the proliferation and apoptosis of gastric cancer cells. Cisplatin is one of the most widely used antineoplastic agents in the treatment of solid tumor and hematological malignancies. However, the mechanism of enhancing cisplatin-inducing effects on human gastric cancer BGC823 cells by blocking CDH17 gene, both in vitro and in vivo, remains to be clarified. In this study, we investigated the signaling pathway by which cisplatin induces apoptosis by blocking CDH17 gene in gastric cancer BGC823 cells. Our results indicate that down-expression of CDH17 gene can enhance apoptosis-inducing effects of cisplatin on human gastric cancer BGC823 cells. The expression levels of Bax and Cyt-c proteins were upregulated, but the expression levels of Bcl-2 and Bcl-xL proteins were downregulated by blocking CDH17 gene in gastric cancer BGC823 cells after treatment with cisplatin. Moreover, down-expression of CDH17 enhanced the efficacy of cisplatin-induced inhibition of tumor growth in nude mice via apoptosis induction. Down-expression of CDH17 gene can significantly improve apoptosis-inducing effects of cisplatin in vitro and in vivo, which is a new strategy to improve chemotherapeutic effects on gastric cancer.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig.1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. 1.

    Sugano K. Screening of gastric cancer in Asia. Best Pract Res Clin Gastroenterol. 2015;29:895–905.

  2. 2.

    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics. 2002. CA Cancer J Clin. 2005;55:74–108.

  3. 3.

    Winer E, Gralow J, Diller L, Karlan B, Loehrer P, Pierce L, et al. Clinical cancer advances 2008: major research advances in cancer treatment, prevention, and screening—a report from the American Society of Clinical Oncology. J Clin Oncol. 2009;27:812–26.

  4. 4.

    Bozzetti F, Marubini E, Bonfanti G, Miceli R, Piano C, Gennari L. Subtotal versus total gastrectomy for gastric cancer: five-year survival rates in a multicenter randomized Italian trial. Ann Surg. 1999;230:170–8.

  5. 5.

    Uña E. Gastric cancer: predictors of recurrence when lymph-node dissection is inadequate. World J Surg Oncol. 2009;7:69.

  6. 6.

    Gessner R, Tauber R. Intestinal cell adhesion molecules. Liver–intestine cadherin. Ann N Y Acad Sci. 2000;915:136–43.

  7. 7.

    Grötzinger C, Kneifel J, Patschan D, Schnoy N, Anagnostopoulos I, Faiss S, et al. LI-cadherin: a marker of gastric metaplasia and neoplasia. Gut 2001;49:73–81.

  8. 8.

    Dong WG, Yu QF, Xu Y, Fan LF. Li-cadherin is inversely correlated with galectin-3 expression ingastric cancer. Dig Dis Sci. 2008;53:1811–7.

  9. 9.

    Dong W, Yu Q, Xu Y. Altered expression of a Li-cadherin in gastric cancer and intestinal metaplasia. Dig Dis Sci. 2007;52:536–42.

  10. 10.

    Berndorff D, Gessner R, Kreft B, Schnoy N, Lajous-Petter AM, Loch N, et al. Liver-intestine cadherin: molecular cloning and characterization of a novel Ca(2+)-dependent cell adhesion molecule expressed in liver and intestine. J Cell Biol. 1994;125:1353–69.

  11. 11.

    Hinoi T, Lucas PC, Kuick R, Hanash S, Cho KR, Fearon ER. CDX2 regulates liver intestine-cadherin expression in normal and malignant colon epithelium and intestinal metaplasia. Gastroenterology 2002;123:1565–77.

  12. 12.

    Takamura M, Ichida T, Matsuda Y, Kobayashi M, Yamagiwa S, Genda T, et al. Reduced expression of liver-intestine cadherin is associated with progression and lymph node metastasis of human colorectal carcinoma. Cancer Lett. 2004;212:253–9.

  13. 13.

    Kwak JM, Min BW, Lee JH, Choi JS, Lee SI, Park SS, et al. The prognostic significance of E-cadherin and liver intestine-cadherin expression in colorectal cancer. Dis Colon Rectum 2007;50:1873–80.

  14. 14.

    Boo YJ, Park JM, Kim J, Chae YS, Min BW, Um JW, et al. L1 expression as a marker for poor prognosis, tumor progression, and short survival in patients with colorectal cancer. Ann Surg Oncol. 2007;14:1703–11.

  15. 15.

    Kim BR, Shim JW, Sung DK, Kim SS, Jeon GW, Kim MJ, et al. Granulocyte stimulating factor attenuates hypoxic-ischemic brain injury by inhibiting apoptosis in neonatal rats. Yonsei Med J. 2008;49:836–42.

  16. 16.

    Liu M, Luo XJ, Liao F, Lei XF, Dong WG. Noscapine induces mitochondria-mediated apoptosis in gastric cancer cells in vitro and in vivo. Cancer Chemoth Pharm. 2011;67:605–12.

  17. 17.

    Suzuki H, Iwasaki E, Hibi T. Helicobacter pylori and gastric cancer. Gastric Cancer 2009;12:79–87.

  18. 18.

    Digklia A, Wagner AD. Advanced gastric cancer: current treatment landscape and future perspectives. World J Gastroenterol. 2016;22:2403.

  19. 19.

    Boller K, Vestweber D, Kemler R. Cell-adhesion molecule uvomorulin is localized in the intermediate junctions of adult intestinal epithelial cells. J Cell Biol. 1985;100:327–32.

  20. 20.

    Gumbiner B, Simons K. A functional assay for proteins involved in establishing an epithelial occluding barrier: identification of a uvomorulin-like polypeptide. J Cell Biol. 1986;102:457–68.

  21. 21.

    Gumbiner B, Simons K. The role of uvomorulin in the formation of epithelial occluding junctions. Ciba Found Symp. 1987;125:168–86.

  22. 22.

    Takamura M, Sakamoto M, Ino Y, Shimamura T, Ichida T, Asakura H, et al. Expression of liver intestine cadherin and its possible interaction with galectin-3 in ductal adenocarcinoma of the pancreas. Cancer Sci. 2003;94:425–30.

  23. 23.

    Hinoi T, Lucas PC, Kuick R, Hanash S, Cho KR, Fearon ER. CDX2 regulates liver–intestine cadherin expression in normal and malignant colon epithelium and intestinal metaplasia. Gastroenterology 2002;123:1565–77.

  24. 24.

    Takamura M, Ichida T, Matsuda Y, Kobayashi M, Yamagiwa S, Genda T, et al. Reduced expression of liver intestine cadherin is associated with progression and lymph node metastasis of human colorectal carcinoma. Cancer Lett. 2004;212:253–59.

  25. 25.

    Krysko DV, Berghe TV, D’Herde K, e Vandenabeele P. Apoptosis and necrosis: detection, discrimination and phagocytosis. Methods 2008;44:205–21.

  26. 26.

    Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM. Cloning of the chromosome breakpoint of neoplastic B cells with the t (14;18) chromosome translocation. Science 1984;226:1097–99.

  27. 27.

    Jourdain A, Martinou JC. Mitochondrial outer-membrane permeabilization and remodeling in apoptosis. Int J Biochem Cell Biol. 2009;41:1884–9.

Download references

Acknowledgements

This work was supported by Wuhan Science and Technology Bureau of applied basic research projects (2015060101010064), Hubei Province Natural Science Foundation of China (2013CFB358), and Project of Health and Family Planning Commission of Wuhan Municipality (WX15C09 and WX14C18). We sincerely thank Dr. Wei Guo Dong and Mr. Hong Xia from the Institute of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University.

Author information

Correspondence to Xia Tian or Xiaodong Huang.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Meng Liu and Zheng Han contributed equally to this work.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark