Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
J Cell Mol Med. 2020 Dec;24(24):14160-14170. doi: 10.1111/jcmm.16026. Epub 2020 Oct 28.
Fatty acids are involved in the development and progression of colorectal cancer (CRC). However, genetic effects of fatty acid biosynthesis pathway on CRC outcome are unclear. Cox regression model was used to evaluate genetic effects on CRC overall survival (OS) and progression-free survival (PFS), accompanied by calculating hazard ratios (HRs) and confidence intervals (CIs). Differential expression analysis, expression quantitative trait loci analysis, dual-luciferase reporter assay and chromatin immunoprecipitation assay were performed to explore the genetically biological mechanism. The rs10838164 C>T in HSD17B12 was significantly associated with an increased risk of death and progression of CRC (OS, HR = 2.12, 95% CI = 1.40-3.22, P = 4.03 × 10 ; PFS, HR = 1.64, 95% CI = 1.11-2.44, P = 1.35 × 10 ), of which T allele could increase HSD17B12 expression (P = 1.78 × 10 ). Subsequently, the functional experiments indicated that rs10838164 T allele could not only enhance the binding affinity of transcription factor YY1 to HSD17B12 region harbouring rs10838164 but also promote the transcriptional activity of HSD17B12, which was significantly up-regulated in colorectal tumour tissues. Our findings suggest that genetic variants in fatty acid biosynthesis pathway play an important role in CRC outcome.
脂肪酸参与结直肠癌（CRC）的发生和发展。然而，脂肪酸生物合成途径的遗传效应对 CRC 结局的影响尚不清楚。Cox 回归模型用于评估遗传效应对 CRC 总生存（OS）和无进展生存（PFS）的影响，并计算风险比（HR）和置信区间（CI）。进行差异表达分析、表达数量性状基因座分析、双荧光素酶报告基因检测和染色质免疫沉淀分析，以探讨遗传生物学机制。HSD17B12 中的 rs10838164C>T 与 CRC 死亡和进展风险增加显著相关（OS，HR=2.12，95%CI=1.40-3.22，P=4.03×10-4；PFS，HR=1.64，95%CI=1.11-2.44，P=1.35×10-4），其中 T 等位基因可增加 HSD17B12 的表达（P=1.78×10-4）。随后，功能实验表明，rs10838164T 等位基因不仅可以增强转录因子 YY1 与含有 rs10838164 的 HSD17B12 区域的结合亲和力，还可以促进 HSD17B12 的转录活性，其在结直肠肿瘤组织中显著上调。我们的研究结果表明，脂肪酸生物合成途径中的遗传变异在 CRC 结局中起重要作用。
