Moya Leire, Lai John, Hoffman Andrea, Srinivasan Srilakshmi, Panchadsaram Janaththani, Chambers Suzanne, Clements Judith A, Batra Jyotsna
Australian Prostate Cancer Research Centre - Queensland, Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia.
Cancer Program, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.
Front Genet. 2018 Oct 4;9:428. doi: 10.3389/fgene.2018.00428. eCollection 2018.
With an estimated 1.1 million men worldwide diagnosed with prostate cancer yearly, effective and more specific biomarkers for early diagnosis could lead to better patient outcome. As such, novel genetic markers are sought for this purpose. The tribbles homologue 1 gene () has recently shown to have a role in prostate tumorigenesis and data-mining of prostate cancer expression data confirmed clinical significance of in prostate cancer. For the first time, a polymorphic microsatellite in this gene was studied for its potential association with prostate cancer risk and aggressiveness. Genomic DNA was extracted from a cohort of 1,152 prostate cancer patients and 1,196 cancer-free controls and the TTTTG- microsatellite was genotyped. The socio-demographic and clinical characteristics were analyzed using the non-parametric -test and two-way ANOVA. Association of the TTTTG- microsatellite and prostate cancer risk and aggressiveness were analyzed by binary logistic regression and confirmed by bootstrapping. Total and prostate cancer mortality was analyzed using the Kaplan Meier test. Genotype and allele correlation with TRIB1 mRNA levels was analyzed using the non-parametric Kolmogorov-Smirnov test. To predict the effect that the TTTTG- polymorphisms had on the mRNA structure, the RNA folding predictor tool, mfold, was used. By analyzing the publicly available data, we confirmed a significant over-expression of in prostate cancer compared to other cancer types, and an over-expression in prostate cancerous tissue compared to adjacent benign. Three alleles (three-five repeats) were observed for TTTTG-. The three-repeat allele was associated with prostate cancer risk at the allele (OR = 1.16; = 0.044) and genotypic levels (OR = 1.70; = 0.006) and this association was age-independent. The four-repeat allele was inversely associated with prosatet cancer risk (OR = 0.57; < 0.0001). expression was upregulated in tumors when compared to adjacent cancer-free tissue but was not allele specific. analysis suggested that the TTTTG- alleles may alter TRIB1 mRNA structure. In summary, the three-repeat allele was significantly associated with prostate cancer risk, suggesting a biomarker potential for this microsatellite to predict prostate cancer. Further studies are needed to elucidate the functional role of this microsatellite in regulating expression, perhaps by affecting the TRIB1 mRNA structure and stability.
全球每年估计有110万男性被诊断出患有前列腺癌，因此，有效且更具特异性的早期诊断生物标志物可改善患者预后。为此，人们一直在寻找新的基因标志物。TRIB1基因最近被证明在前列腺肿瘤发生中起作用，对前列腺癌表达数据的数据挖掘证实了TRIB1在前列腺癌中的临床意义。首次对该基因中的一个多态微卫星进行研究，以探讨其与前列腺癌风险和侵袭性的潜在关联。从1152例前列腺癌患者和1196例无癌对照者中提取基因组DNA，并对TTTTG-微卫星进行基因分型。使用非参数检验和双向方差分析来分析社会人口统计学和临床特征。通过二元逻辑回归分析TTTTG-微卫星与前列腺癌风险和侵袭性的关联，并通过自抽样法进行验证。使用Kaplan Meier检验分析总死亡率和前列腺癌死亡率。使用非参数Kolmogorov-Smirnov检验分析基因型和等位基因与TRIB1 mRNA水平的相关性。为了预测TTTTG-多态性对mRNA结构的影响，使用了RNA折叠预测工具mfold。通过分析公开可用的数据，我们证实与其他癌症类型相比，TRIB1在前列腺癌中显著过表达，与相邻良性组织相比，在前列腺癌组织中也过表达。观察到TTTTG-有三个等位基因（三到五个重复）。三个重复等位基因在等位基因水平（OR = 1.16；P = 0.044）和基因型水平（OR = 1.70；P = 0.006）与前列腺癌风险相关，且这种关联与年龄无关。四个重复等位基因与前列腺癌风险呈负相关（OR = 0.57；P < 0.0001）。与相邻的无癌组织相比，肿瘤中TRIB1的表达上调，但不具有等位基因特异性。分析表明，TTTTG-等位基因可能会改变TRIB1 mRNA结构。总之，三个重复等位基因与前列腺癌风险显著相关，表明该微卫星有作为预测前列腺癌生物标志物的潜力。需要进一步研究来阐明该微卫星在调节TRIB1表达中的功能作用，或许是通过影响TRIB1 mRNA的结构和稳定性来实现。
