Duca Rocío Belén, Massillo Cintia, Farré Paula Lucía, Graña Karen Daniela, Moro Juana, Gardner Kevin, Lacunza Ezequiel, De Siervi Adriana
Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, United States.
Front Oncol. 2022 Oct 26;12:997457. doi: 10.3389/fonc.2022.997457. eCollection 2022.
The incidence and mortality of Prostate Cancer (PCa) worldwide correlate with age and bad dietary habits. Previously, we investigated the mRNA/miRNA role on PCa development and progression using high fat diet (HFD) fed mice. Here our main goal was to investigate the effect of HFD on the expression of PCa-related miRNAs and their relevance in PCa patients. We identified 6 up- and 18 down-regulated miRNAs in TRAMP-C1 mice prostate tumors under HFD conditions using miRNA microarrays. Three down-regulated miRNAs: mmu-miR-133a-3p, -1a-3p and -29c-3p were validated in TRAMP-C1 mice prostate tumor by stem-loop RT-qPCR. Hsa-miR-133a-3p/1-3p expression levels were significantly decreased in PCa compared to normal tissues while hsa-miR-133a-3p was found to be further decreased in metastatic prostate cancer tumors compared to non-metastatic PCa. We examined the promoter region of hsa-miR-133a-3p/1-3p genes and compared methylation at these loci with mature miRNA expression. We found that hsa-miR-1-2/miR-133a-1 cluster promoter hypermethylation decreased hsa-miR-133a-3p/1-3p expression in PCa. GOLPH3 and JUP, two hsa-miR-133a-3p and miR-1-3p predicted target genes, were up-regulated in PCa. ROC analysis showed that the combination of hsa-miR-133a-3p, miR-1-3p, GOLPH3 and JUP is a promising panel biomarker to distinguish between PCa and normal adjacent tissue (NAT). These results link PCa aggressiveness to the attenuation of hsa-miR-133a-3p and miR-1-3p expression by promoter hypermethylation. Hsa-miR-133a-3p and miR-1-3p down-regulation may enhance PCa aggressiveness in part by targeting GOLPH3 and JUP.
全球前列腺癌（PCa）的发病率和死亡率与年龄及不良饮食习惯相关。此前，我们利用高脂饮食（HFD）喂养的小鼠研究了mRNA/miRNA在PCa发生发展中的作用。在此，我们的主要目标是研究HFD对PCa相关miRNA表达的影响及其在PCa患者中的相关性。我们使用miRNA芯片在HFD条件下的TRAMP-C1小鼠前列腺肿瘤中鉴定出6个上调和18个下调的miRNA。通过茎环RT-qPCR在TRAMP-C1小鼠前列腺肿瘤中验证了3个下调的miRNA：mmu-miR-133a-3p、-1a-3p和-29c-3p。与正常组织相比，PCa中hsa-miR-133a-3p/1-3p的表达水平显著降低，而与非转移性PCa相比，转移性前列腺癌肿瘤中hsa-miR-133a-3p进一步降低。我们检测了hsa-miR-133a-3p/1-3p基因的启动子区域，并将这些位点的甲基化与成熟miRNA的表达进行比较。我们发现hsa-miR-1-2/miR-133a-1簇启动子高甲基化降低了PCa中hsa-miR-133a-3p/1-3p的表达。GOLPH3和JUP是hsa-miR-133a-3p和miR-1-3p的两个预测靶基因，在PCa中上调。ROC分析表明，hsa-miR-133a-3p、miR-1-3p、GOLPH3和JUP的组合是区分PCa和正常相邻组织（NAT）的有前景的生物标志物组合。这些结果将PCa的侵袭性与启动子高甲基化导致的hsa-miR-133a-3p和miR-1-3p表达减弱联系起来。hsa-miR-133a-3p和miR-1-3p的下调可能部分通过靶向GOLPH3和JUP增强PCa的侵袭性。
