All Title Author
Keywords Abstract

Overexpression of FOXO3, MYD88, and GAPDH Identified by Suppression Subtractive Hybridization in Esophageal Cancer Is Associated with Autophagy

DOI: 10.1155/2014/185035

Full-Text   Cite this paper   Add to My Lib


To find genes involved in tumorigenesis and the development of esophageal cancer, the suppression subtractive hybridization (SSH) method was used to identify genes that are overexpressed in esophageal cancer tissues compared to normal esophageal tissues. In our SSH library, the forkhead box O3 (FOXO3), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and myeloid differentiation primary response 88 (MYD88) genes were the most highly upregulated genes, and they were selected for further studies because of their potential role in the induction of autophagy. Upregulation of these genes was also observed in clinical samples using qRT-PCR. In addition, coexpression analysis of the autophagy-related genes Beclin1, ATG12, Gabarapl, PIK3C3, and LC3 demonstrated a significant correlation between the differentially overexpressed genes and autophagy. Autophagy is an important mechanism in tumorigenesis and the development of chemoresistance in cancer cells. The upregulation of FOXO3, GAPDH, and MYD88 variants in esophageal cancer suggests a role for autophagy and provides new insight into the biology of esophageal cancer. We propose that FOXO3, GAPDH, and MYD88 are novel targets for combating autophagy in esophageal cancer. 1. Introduction Esophageal cancer is one of the most aggressive and life-threatening types of carcinoma in developing countries, and it has a high incidence rate in some geographical regions, particularly in the “Asian esophageal cancer belt,” which extends from the Caspian Littoral in Iran, Turkmenistan, Uzbekistan, and Kazakhstan to the northern provinces of China [1]. Esophageal cancer is among the top 10 causes of cancer-related deaths worldwide [2]. Although some altered oncogenes and tumor suppressor genes have been identified in esophageal cancer (e.g., p53 deletion, p21 alteration, and amplification of CCND1 and c-myc), the fundamental molecular mechanisms leading to esophageal cancer remain unknown [3–6]. The identification of genes that are differentially expressed in esophageal cancer cells allows for the identification of new biomarkers and therapeutic target genes. In addition, this strategy could lead to an improved understanding of the molecular biology and mechanisms of carcinogenesis in esophageal cancer. In contrast to apoptosis, autophagy is primarily a cell survival process; thus, autophagy has been considered an important mechanism in chemoresistance and is known as a survival factor for tumor cells in the early stages of tumorigenesis [7–10]. In this study, suppression subtractive hybridization (SSH) was used to identify


[1]  J. Kmet and E. Mahboubi, “Esophageal cancer in the Caspian littoral of Iran: initial studies,” Science, vol. 175, no. 4024, pp. 846–853, 1972.
[2]  F. Bray, J.-S. Ren, E. Masuyer, and J. Ferlay, “Global estimates of cancer prevalence for 27 sites in the adult population in 2008,” International Journal of Cancer, vol. 132, pp. 1133–1145, 2013.
[3]  T. Anayama, M. Furihata, T. Takeuchi et al., “Insufficient effect of p27(KIP1) to inhibit cyclin D1 in human esophageal cancer in vitro,” International Journal of Oncology, vol. 18, no. 1, pp. 151–155, 2001.
[4]  U. Ribeiro, S. D. Finkelstein, A. V. Safatle-Ribeiro et al., “p53 sequence analysis predicts treatment response and outcome of patients with esophageal carcinoma,” Cancer, vol. 83, pp. 7–18, 1998.
[5]  R. Ralhan, S. Arora, T. K. Chattopadhyay, N. K. Shukla, and M. Mathur, “Circulating p53 antibodies, p53 gene mutational profile and product accumulation in esophageal squamous-cell carcinoma in India,” International Journal of Cancer, vol. 85, pp. 791–795, 2000.
[6]  M. E. Nita, H. Nagawa, O. Tominaga et al., “p21Waf1/Cip1 expression is a prognostic marker in curatively resected esophageal squamous cell carcinoma, but not p27Kip1, p53, or Rb,” Annals of Surgical Oncology, vol. 6, no. 5, pp. 481–488, 1999.
[7]  P. Maycotte and A. Thorburn, “Autophagy and cancer therapy,” Cancer Biology and Therapy, vol. 11, no. 2, pp. 127–137, 2011.
[8]  L. Moretti, E. S. Yang, K. W. Kim, and B. Lu, “Autophagy signaling in cancer and its potential as novel target to improve anticancer therapy,” Drug Resistance Updates, vol. 10, no. 4-5, pp. 135–143, 2007.
[9]  N. Chen and J. Debnath, “Autophagy and tumorigenesis,” FEBS Letters, vol. 584, no. 7, pp. 1427–1435, 2010.
[10]  L. Yang, Y. Yu, R. Kang et al., “Up-regulated autophagy by endogenous high mobility group box-1 promotes chemoresistance in leukemia cells,” Leukemia and Lymphoma, vol. 53, no. 2, pp. 315–322, 2012.
[11]  D. J. Klionsky and S. D. Emr, “Autophagy as a regulated pathway of cellular degradation,” Science, vol. 290, no. 5497, pp. 1717–1721, 2000.
[12]  D. Glick, S. Barth, and K. F. Macleod, “Autophagy: cellular and molecular mechanisms,” Journal of Pathology, vol. 221, no. 1, pp. 3–12, 2010.
[13]  Y. Kondo, T. Kanzawa, R. Sawaya, and S. Kondo, “The role of autophagy in cancer development and response to therapy,” Nature Reviews Cancer, vol. 5, no. 9, pp. 726–734, 2005.
[14]  Y. Kondo and S. Kondo, “Autophagy and cancer therapy,” Autophagy, vol. 2, no. 2, pp. 85–90, 2006.
[15]  C. Mammucari, G. Milan, V. Romanello et al., “FoxO3 controls autophagy in skeletal muscle in vivo,” Cell Metabolism, vol. 6, no. 6, pp. 458–471, 2007.
[16]  J. Zhao, J. J. Brault, A. Schild et al., “FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells,” Cell Metabolism, vol. 6, no. 6, pp. 472–483, 2007.
[17]  J. Zhou, W. Liao, J. Yang et al., “FOXO3 induces FOXO1-dependent autophagy by activating the AKT1 signaling pathway,” Autophagy, vol. 8, pp. 1712–1723, 2012.
[18]  R. Medzhitov, P. Preston-Hurlburt, E. Kopp et al., “MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways,” Molecular Cell, vol. 2, no. 2, pp. 253–258, 1998.
[19]  E. L. Wang, Z. R. Qian, M. Nakasono et al., “High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer,” British Journal of Cancer, vol. 102, no. 5, pp. 908–915, 2010.
[20]  J. H. Wang, B. J. Manning, Q. D. Wu, S. Blankson, D. Bouchier-Hayes, and H. P. Redmond, “Endotoxin/lipopolysaccharide activates NF-κb and enhances tumor cell adhesion and invasion through a β1 integrin-dependent mechanism,” Journal of Immunology, vol. 170, no. 2, pp. 795–804, 2003.
[21]  C.-S. Shi and J. H. Kehrl, “MyD88 and Trif target Beclin 1 to trigger autophagy in macrophages,” Journal of Biological Chemistry, vol. 283, no. 48, pp. 33175–33182, 2008.
[22]  A. Colell, J.-E. Ricci, S. Tait et al., “GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation,” Cell, vol. 129, no. 5, pp. 983–997, 2007.
[23]  S. Jin and E. White, “Role of autophagy in cancer: management of metabolic stress,” Autophagy, vol. 3, no. 1, pp. 28–31, 2007.
[24]  T. R. O'Donovan, G. C. O'Sullivan, and S. L. McKenna, “Induction of autophagy by drug-resistant esophageal cancer cells promotes their survival and recovery following treatment with chemotherapeutics,” Autophagy, vol. 7, no. 5, pp. 509–524, 2011.


comments powered by Disqus