DLC-1 is a candidate biomarker methylated and down-regulated in pancreatic ductal adenocarcinoma
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Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive malignancies in humans, and its prognosis is generally poor even after surgery. Many advances have been made to understand the pathogenesis of PDA; however, the molecular mechanisms that lead to pancreatic carcinogenesis are still not clearly understood. The aims of this study were to investigate the relationship between DLC-1 methylation status and clinicopathological characteristics of PDA patients and evaluate the role of DLC-1 methylation status in PDA. The expression of DLC-1 mRNA in PDA tissues was analyzed by real-time PCR. The methylation status of DLC-1 was analyzed by methylation-specific polymerase chain reaction (MSP). Furthermore, we determined the prognostic importance of DLC-1 methylation status in PDA patients. Our results showed that the expression level of DLC-1 mRNA in PDA tissues was lower than that in non-cancerous tissues. The rate of DLC-1 promoter methylation was significantly higher in PDA tissues than in adjacent non-cancerous tissues (p < 0.001). Downregulation of DLC-1 was strongly correlated with promoter methylation (P = 0.003). The presence of DLC-1 methylation in PDA tissue samples was significantly correlated with clinical stage (P = 0.005), histological differentiation (P = 0.05), and lymph node metastasis (P = 0.006). Kaplan–Meier survival analysis showed that DLC-1 methylation status was inversely correlated with overall survival of the PDA patients. Further, Cox multivariate analysis indicated that DLC-1 methylation status was an independent prognostic factor for the overall survival rate of PDA patients. In conclusion, our data suggest that downregulation of DLC-1 may be explained by DNA methylation; DLC-1 may be a biomarker for PDA.
- Malik NK, May KS, Chandrasekhar R, Wee W, Flaherty L, Iyer R, et al. Treatment of locally advanced unresectable pancreatic cancer: a 10-year experience. J Gastrointest Oncol. 2012;3:326–34. doi:10.3978/j.issn.2078-6891.2012.029.
- Kaur S, Baine MJ, Jain M, Sasson AR, Batra SK. Early diagnosis of pancreatic cancer: challenges and new developments. Biomark Med. 2012;6:597–612. doi:10.2217/bmm.12.69. CrossRef
- McCleary-Wheeler AL, Lomberk GA, Weiss FU, Schneider G, Fabbri M, Poshusta TL, et al. Insights into the epigenetic mechanisms controlling pancreatic carcinogenesis. Cancer Lett. 2013;328:212–21. doi:10.1016/j.canlet.2012.10.005. CrossRef
- Sun C, Ansari D, Andersson R, Wu DQ. Does gemcitabine-based combination therapy improve the prognosis of unresectable pancreatic cancer? World J Gastroenterol. 2012;18:4944–58. doi:10.3748/wjg.v18.i35.4944. CrossRef
- Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683–92. CrossRef
- Bird AP. CpG-rich islands and the function of DNA methylation. Nature. 1986;321:209–13. CrossRef
- Goelz SE, Vogelstein B, Hamilton SR, Feinberg AP. Hypomethylation of DNA from benign and malignant human colon neoplasms. Science. 1985;228:187–90. doi:10.1126/science.2579435. CrossRef
- Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349:2042–54. doi:10.1056/NEJMra023075. CrossRef
- Peng D, Ren CP, Yi HM, Zhou L, Yang XY, Li H, et al. Genetic and epigenetic alterations of DLC-1, a candidate tumor suppressor gene, in nasopharyngeal carcinoma. Acta Biochim Biophys Sin (Shanghai). 2006;38:349–55. doi:10.1111/j.1745-7270.2006.00164.x. CrossRef
- Ullmannova V, Popescu NC. Expression profile of the tumor suppressor genes DLC-1 and DLC-2 in solid tumors. Int J Oncol. 2006;29:1127–32.
- Guan M, Zhou X, Soulitzis N, Spandidos DA, Popescu NC. Aberrant methylation and deacetylation of deleted in liver cancer-1 gene in prostate cancer: potential clinical applications. Clin Cancer Res. 2006;12:1412–9. doi:10.1158/1078-0432.CCR-05-1906. CrossRef
- Song YF, Xu R, Zhang XH, Chen BB, Chen Q, Chen YM, et al. High-frequency promoter hypermethylation of the deleted in liver cancer-1 gene in multiple myeloma. J Clin Pathol. 2006;59:947–51. doi:10.1136/jcp.2005.031377. CrossRef
- Feng X, Li C, Liu W, Chen H, Zhou W, Wang L, et al. DLC-1, a candidate tumor suppressor gene, inhibits the proliferation, migration and tumorigenicity of human nasopharyngeal carcinoma cells. Int J Oncol. 2013;42:1973–84. doi:10.3892/ijo.2013.1885.
- Liu H, Shi H, Hao Y, Zhao G, Yang X, Wang Y, et al. Effect of FAK, DLC-1 gene expression on OVCAR-3 proliferation. Mol Biol Rep. 2012;39:10665–70. doi:10.1007/s11033-012-1956-6. CrossRef
- Chen WT, Yang CH, Wu CC, Huang YC, Chai CY. Aberrant deleted in liver cancer-1 expression is associated with tumor metastasis and poor prognosis in urothelial carcinoma. APMIS. 2013. doi:10.1111/apm.12060.
- Peng H, Long F, Wu Z, Chu Y, Li J, Kuai R, Zhang J, Kang Z, Zhang X, Guan M. Downregulation of DLC-1 gene by promoter methylation during primary colorectal cancer progression. Biomed Res Int. 2013; 2013: 181384. doi:10.1155/2013/181384.
- Guan CN, Zhang PW, Lou HQ, Liao XH, Chen BY. DLC-1 expression levels in breast cancer assessed by qRT- PCR are negatively associated with malignancy. Asian Pac J Cancer Prev. 2012;13:1231–3. CrossRef
- Liu JB, Zhang YX, Zhou SH, Shi MX, Cai J, Liu Y, et al. CpG island methylator phenotype in plasma is associated with hepatocellular carcinoma prognosis. World J Gastroenterol. 2011;17:4718–24. doi:10.3748/wjg.v17.i42.4718. CrossRef
- Feng M, Huang B, Du Z, Xu X, Chen Z. DLC-1 as a modulator of proliferation, apoptosis and migration in Burkitt's lymphoma cells. Mol Biol Rep. 2011;38(3):1915–20. doi:10.1007/s11033-010-0311-z. CrossRef
- Zhang T, Zheng J, Jiang N, Wang G, Shi Q, Liu C, et al. Overexpression of DLC-1 induces cell apoptosis and proliferation inhibition in the renal cell carcinoma. Cancer Lett. 2009;283:59–67. doi:10.1016/j.canlet.2009.03.025. CrossRef
- Zhang T, Zheng J, Liu C, Lu Y. Expression of DLC-1 in clear cell renal cell carcinoma: prognostic significance for progression and metastasis. Urol Int. 2009;82:380–7. doi:10.1159/000218524. CrossRef
- Jin Z, Mori Y, Yang J, Sato F, Ito T, Cheng Y, et al. Hypermethylation of the nel-like 1 gene is a common and early event and is associated with poor prognosis in early-stage esophageal adenocarcinoma. Oncogene. 2007;26:6332–40. doi:10.1038/sj.onc.1210461. CrossRef
- Sun D, Zhang Z, Van do N, Huang G, Ernberg I, Hu L. Aberrant methylation of CDH13 gene in nasopharyngeal carcinoma could serve as a potential diagnostic biomarker. Oral Oncol. 2007;43:82–7. CrossRef
- Brock MV, Gou M, Akiyama Y, Muller A, Wu TT, Montgomery E, et al. Prognostic importance of promoter hypermethylation of multiple genes in esophageal adenocarcinoma. Clin Cancer Res. 2003;9:2912–9.
- DLC-1 is a candidate biomarker methylated and down-regulated in pancreatic ductal adenocarcinoma
Volume 34, Issue 5 , pp 2857-2861
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- 1. Department of Gastroenterology, The Third Hospital Affiliated to Nantong University, No. 585, Xingyuan North Rd., Wuxi, 214041, Jiangsu, China
- 2. Department of Gastroenterology, Changhai Hospital of Second Military Medical University, No. 168, Changhai Rd., Shanghai, 200001, China