Hypermethylation in promoter region of spalt-like transcription factor 3 (SALL3)gene is associated with poor prognosis in patients with hepatocellular carcinoma
Abstract：Objective To study the relationship between hypermethylation in SALL3 promoter and clinicopathological features in patients with primary hepatocellular carcinoma (HCC). Methods Methylation statuses of SALL3 promoter in 283 pairs of HCC and its adjacent non-tumor tissues were analyzed by methylation specific PCR (MSP) technique, and the correlation between SALL3 promoter methylation and clinical characteristics was evaluated.Results The methylation rate of SALL3 promoter region was higher in HCC than in adjacent paracancerous tissues (38.87% vs. 9.89%), showing a statistically significant difference (χ2=64.43, P<0.000,1). Univariate analysis revealed that the methylation rate of SALL3 gene showed no statistically significant difference among HCC patients with different ages, genders, hepatitis B virus infectious statuses and tumor sizes (P>0.05), but showed statistically significant differences among HCC patients with different conditions of differentiation of HCC cells (χ2=3.046,P=0.018,9), clinical stages (χ2=4.684, P=0.030,4) and portal vein thrombosis (χ2=14.930, P=0.000,1). Univariate COX regression analysis indicated that SALL3 gene methylation (OR=1.73, 95%CI:1.28-2.33, P=0.002,6), cirrhosis (OR=1.56, 95%CI:1.11-2.18, P=0.009,6) and clinical stage (OR=1.63, 95%CI: 1.36-1.94, P=0.000,0) were the factors influencing the patients’ 5-year survival. Multivariate COX regression analysis confirmed that SALL3 gene methylation (OR=1.41, 95%CI:1.02-1.94, P=0.035,7) and clinical stage (OR=1.73, 95%CI:1.39-2.01, P=0.000,0) were the independent risk factors affecting the HCC patients’ postoperative survival time. The postoperative survival time was significantly shorter in HCC patients with methylated SALL3 promoter than those with unmethylated SALL3 promoter ((20.37±3.5) months vs. (30.77±5.5) months, P=0.002,4). Conclusions The methylation status of promoter region of SALL3 gene is a potential biomarker for detecting primary HCC and poor prognosis.
[1] Kanwal F, El-Serag HB, Ross D. Surveillance for hepatocellular carcinoma:can we focus on the mission[J]. Clin Gastroenterol Hepatol, 2015,13:805-807. [2] Folkman J, Hahnfeldt P, Hlatky L. Cancer: looking outside the genome[J]. Nat Rev Mol Cell Biol, 2000,1(1):76-79. [3] Rakyan VK, Hildmann T, Novik KL, et al. DNA methylation profiling of the human major histocompatibility complex:a pilot study for the human epigenome project[J]. PLoS Biol, 2004, 2(12):e405. [4] Gaudet F, Hodgson JG, Eden A, et al. Induction of tumors in mice by genomic hypomethylation[J]. Science, 2003, 300(5618):489-492. [5] Kohlhase J, Hausmann S, Stojmenovic G, et al. SALL3, A new member of the human spalt-like gene family, maps to 18q23[J]. Genomics, 1999, 62(2):216-222. [6] Yang XX, Sun JZ, Li FX, et al. Aberrant methylation and downregulation of SALL3 in human hepatocellular carcinoma[J]. World J Gastroenterol, 2012,18(21):2719-2726. [7] Shikauchi Y, Saiura A, Kubo T, et al. SALL3 interacts with DNMT3A and shows the ability to inhibit CpG island methylation in hepatocellular carcinoma[J].Mol Cell Biol, 2009, 29(7):1944-1958. [8] 夏卫,倪唯益,费琦,等.肝癌中SALL3基因甲基化的研究[J].诊断学理论与实践,2010, 9(5):491-494. [9] Edmondson HA, Steiner PE. Primary carcinoma of the liver:a study of 100 cases among 48,900 necropsies[J]. Cancer, 1954, 7:462-503. [10] Sobin LH, Wittekind Ch. TNM classification of malignant tumors[M]. 6th ed. New York:Wiley-Liss, Inc, 2002:51-54. [11] Yu J, Zhu T, Wang Z, et al. A novel set of DNA methylation markers in urine sediments for sensitive/specific detection of bladder cancer[J].Clin Cancer Res, 2007, 13(24):7296-7304 . [12] Ting AH, McGarvey KM, Baylin SB. The cancer epigenome-components and functional correlates [J].Genes Dev, 2006, 20(23):3215-3231. [13] Yang J, Gao C, Chai L, et al. A novel SALL4/OCT4 transcriptional feedback network for pluripotency of embryonic stem cells [J]. PLoS One, 2010, 5(5):e10766. [14] de Melo J, Peng GH, Chen S, et al. The Spalt family transcription factor SALL3 regulates the development of cone photoreceptors and retinal horizontal interneurons[J]. Development, 2011, 138(11):2325-2336. [15] Love C1, Sun Z, Jima D, et al. The genetic landscape of mutations in Burkitt lymphom[J].Nat Genet, 2012, 44(12):1321-1325.
2018, Vol. 25 
