DKK-1和NNMT与肝癌患者临床病理指标及预后的相关性

doi:10.3969/j.issn.1004-616x.2024.06.005

摘要/Abstract

摘要： 目的： 探讨Dickkopf相关蛋白1(DKK-1)、尼克酰胺-N-甲基转移酶(NNMT) mRNA和蛋白表达与肝癌患者临床病理指标和预后的关系。方法： 通过GEPIA2数据库分析NNMT和DKK-1 mRNA在正常肝组织和肝癌中的表达水平，分析两者对肝癌患者总生存期(OS)和无疾病生存期(DFS)的影响。采用免疫组织化学方法检测NNMT和DKK-1蛋白在肝癌、肝良性病变及正常组织中的表达情况，分析其与肝癌发生发展及临床病理指标间的关系。结果： GEPIA2数据库的分析结果显示，在肝癌组织中NNMT mRNA的表达水平明显低于正常肝组织(P<0.05)，NNMT和DKK-1 mRNA在肝癌中的表达呈负相关关系(r=-0.13，P<0.05)，两者对肝癌患者的10年OS及DFS均无明显影响。NNMT mRNA高表达的肝癌患者5年生存率比低表达者高(P<0.05)。免疫组织化学法检测结果发现与正常肝组织比较，DKK-1与NNMT蛋白在肝癌组织中的表达明显降低(P<0.01)，DKK-1蛋白在肝细胞癌中的表达明显高于胆管细胞癌，两者的表达与肿瘤大小、分期及组织分级等无明显相关(P>0.05)。结论： DKK-1和NNMT蛋白在肝癌组织中的表达水平较正常肝组织下降，DKK-1蛋白的表达水平与肝癌的组织类型有关，NNMT mRNA的表达水平可能影响肝癌患者的5年生存率。

关键词: 肝癌, Dickkopf相关蛋白1, 尼克酰胺-N-甲基转移酶, 临床病理指标, 生存率

Abstract: OBJECTIVE： To investigate the involvement of Dickkopf-related protein-1 (DKK-1) and nicotinamide N-methyltransferase (NNMT) in clinicopathology and prognosis among liver cancer patients. METHODS： Expression levels of NNMT and DKK-1 mRNA in normal liver tissues and liver cancer cells were analyzed by GEPIA2 database.，Effects of the two on the overall survival (OS) and disease-free survival (DFS) of patients with liver cancer were analyzed. Immunohistochemistry was used to detect the protein expression of NNMT and DKK-1 in liver tumor group，benign lesion group and normal group，and the relationship between them and the occurrence and development of liver cancer and clinicopathological features was analyzed. RESULTS： The GEPIA2 database showed that expression levels of NNMT mRNA in liver cancer tissues were significantly lower than that in normal liver tissues (P<0.05). Expressions of NNMT and DKK-1 mRNA in liver cancers were negatively correlated (r=-0.13，P<0.05). Both had no significant effect on the 10-year OS and DFS of liver cancer patients. The 5-year survival rate of liver cancer patients with high expression of NNMT mRNA was higher than that of those with low expression (P<0.05). The results of immunohistochemistry showed that compared with normal liver tissues，the expressions of DKK-1 and NNMT proteins in liver cancer tissues were significantly reduced (P<0.01). Expression of DKK-1 protein in hepatocellular carcinoma was significantly higher than that in cholangiocarcinoma. The expression of both proteins was not significantly correlated with tumor size，stage and tissue grade (P>0.05). CONCLUSION： The expression levels of DKK-1 and NNMT proteins in liver cancer tissues are lower than those in normal liver tissues. The expression levels of DKK-1 protein were related to the tissue types of liver cancers，and the expression levels of NNMT mRNA affected the 5-year survival rate of patients with liver cancer.

Key words: liver cancer, NNMT, DKK-1, clinicopathological features, survival rate

中图分类号:

R735.7

吴秀浅, 梁泰榕, 庄学龙, 王星星, 黄海花. DKK-1和NNMT与肝癌患者临床病理指标及预后的相关性[J]. 癌变·畸变·突变, 2024, 36(6): 452-456,462.

WU Xiuqian, LIANG Tairong, ZHUANG Xuelong, WANG Xingxing, HUANG Haihua. Involvement of DKK-1 and NNMT in clinicopathology and prognosis among liver cancer patients[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2024, 36(6): 452-456,462.

参考文献

[1] 胡博文, 徐聪, 王欣, 等. DKK1蛋白在肿瘤中的研究与相关治疗策略的进展[J]. 现代肿瘤医学, 2024, 32(21): 4173-4177.
[2] TANG Z F, KANG B X, LI C W, et al. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis[J]. Nucleic Acids Res, 2019, 47(W1): 556-560.
[3] CONSORTIUM G. The genotype-tissue expression (GTEx) project[J]. Nat Genet, 2013, 45(6): 580-585.
[4] SHEN Q J, FAN J, YANG X R, et al. Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study[J]. Lancet Oncol, 2012, 13(8): 817-826.
[5] YU B, YANG X R, XU Y, et al. Elevated expression of DKK1 is associated with cytoplasmic/nuclear beta-catenin accumulation and poor prognosis in hepatocellular carcinomas[J]. J Hepatol, 2009, 50(5): 948-957.
[6] LI J P, GONG W L, LI X X, et al. Recent progress of Wnt pathway inhibitor dickkopf-1 in liver cancer[J]. J Nanosci Nanotechnol, 2018, 18(8): 5192-5206.
[7] 许镒洧, 郭竑, 郭海鹏, 等. DKK1在食管胃结合部腺癌患者血清中的水平及其临床诊断价值[J]. 癌变·畸变·突变, 2017, 29(2): 139-142.
[8] LIANG T R, WU X Q, WANG L, et al. Correlation of NNMT and DKK1 protein expression with clinicopathological characteristics and prognosis of breast cancer[J]. Clin Med Insights Oncol, 2023, 17. doi: 10.1177/11795549231168073.
[9] WU M W, HU W L, WANG G S, et al. Nicotinamide N-methyltransferase is a prognostic biomarker and correlated with immune infiltrates in gastric cancer[J]. Front Genet, 2020, 11: 580299.
[10] SONG M M, LI Y, MIAO M Y, et al. High stromal nicotinamide N-methyltransferase (NNMT) indicates poor prognosis in colorectal cancer[J]. Cancer Med, 2020, 9(6): 2030-2038.
[11] HOLSTEIN S, VENZ S, JUNKER H, et al. Nicotinamide N-methyltransferase and its precursor substrate methionine directly and indirectly control malignant metabolism during progression of renal cell carcinoma[J]. Anticancer Res, 2019, 39(10): 5427-5436.
[12] WU Y, SIADATY M S, BERENS M E, et al. Overlapping gene expression profiles of cell migration and tumor invasion in human bladder cancer identify metallothionein 1E and nicotinamide N-methyltransferase as novel regulators of cell migration[J]. Oncogene, 2008, 27(52): 6679-6689.
[13] POMPEI V, SALVOLINI E, RUBINI C, et al. Nicotinamide N-methyltransferase in nonmelanoma skin cancers[J]. Eur J Clin Invest, 2019, 49(12): e13175.
[14] MASCITTI M, SANTARELLI A, SARTINI D, et al. Analysis of nicotinamide N-methyltransferase in oral malignant melanoma and potential prognostic significance[J]. Melanoma Res, 2019, 29(2): 151-156.
[15] LI S M, QIAO L, YANG Z W, et al. Prognostic value of nicotinamide N-methyltransferase expression in patients with solid tumors: a systematic review and meta-analysis[J]. Front Physiol, 2018, 9: 1407.
[16] ZHANG J, WANG Y Z, LI G L, et al. Down-regulation of nicotinamide N-methyltransferase induces apoptosis in human breast cancer cells via the mitochondria-mediated pathway[J]. PLoS One, 2014, 9(2): e89202.
[17] XIE X Y, YU H T, WANG Y Z, et al. Nicotinamide N-methyltransferase enhances the capacity of tumorigenesis associated with the promotion of cell cycle progression in human colorectal cancer cells[J]. Arch Biochem Biophys, 2014, 564: 52-66.