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Abstract：
The identification of novel screening tools is imperative to empower the early detection of colorectal cancer (CRC). The influence of the long non-coding RNA maternally expressed gene 3 (MEG3) rs941576 single nucleotide polymorphism on CRC susceptibility remains uninvestigated. This research appraised MEG3 rs941576 association with the risk and clinical features of CRC and obesity-related CRC and its impact on serum MEG3 expression and its targets miR-27a/insulin-like growth factor 1 (IGF1)/IGF binding protein 3 (IGFBP3) and miR-181a/sirtuin 1 (SIRT1), along with the potential of these markers in obesity-related CRC diagnosis. 130 CRC patients (60 non-obese and 70 obese) and 120 cancer-free controls (64 non-obese and 56 obese) were enrolled. MEG3 targets were selected using bioinformatics analysis. MEG3 rs941576 was associated with magnified CRC risk in overall (OR (95% CI) 4.69(1.51-14.57), P = 0.0018) and stratified age and gender groups, but not with obesity-related CRC risk or MEG3/downstream targets\' expression. Escalated miR-27a and IGFBP3 and reduced IGF1 serum levels were concomitant with MEG3 downregulation in overall CRC patients versus controls and obese versus non-obese CRC patients. Serum miR-181a and SIRT1 were upregulated in CRC patients versus controls but weren\'t altered in the obese versus non-obese comparison. Serum miR-181a and miR-27a were superior in overall and obesity-related CRC diagnosis, respectively; meanwhile, IGF1 was superior in distinguishing obese from non-obese CRC patients. Only serum miR-27a was associated with obesity-related CRC risk in multivariate logistic analysis. Among overall CRC patients, MEG3 rs941576 was associated with lymph node (LN) metastasis and tumor stage, serum MEG3 was negatively correlated with tumor stage, while SIRT1 was correlated with the anatomical site. Significant correlations were recorded between MEG3 and anatomical site, SIRT1 and tumor stage, and miR-27a/IGFBP3 and LN metastasis among obese CRC patients, while IGF1 was correlated with tumor stage and LN metastasis among non-obese CRC patients. Conclusively, this study advocates MEG3 rs941576 as a novel genetic marker of CRC susceptibility and prognosis. Our findings accentuate circulating MEG3/miR-27a/IGF1/IGFBP3, especially miR-27a as valuable markers for the early detection of obesity-related CRC. This axis along with SIRT1 could benefit obesity-related CRC prognosis.
摘要：
鉴定新的筛查工具对于增强结直肠癌（CRC）的早期检测至关重要。长非编码RNA母体表达基因3（MEG3）rs941576单核苷酸多态性对CRC易感性的影响仍未研究。本研究评估了MEG3rs941576与CRC和肥胖相关CRC的风险和临床特征的相关性，及其对血清MEG3表达及其靶基因miR-27a/胰岛素样生长因子1（IGF1）/IGF结合蛋白3（IGFBP3）和miR-181a/sirtuin1（SIRT1）的影响。以及这些标志物在肥胖相关CRC诊断中的潜力。纳入130例CRC患者（60例非肥胖和70例肥胖）和120例无癌对照（64例非肥胖和56例肥胖）。使用生物信息学分析选择MEG3靶标。MEG3rs941576与总体CRC风险放大相关（OR（95％CI）4.69（1.51-14.57），P=0.0018）和分层的年龄和性别组，但与肥胖相关的CRC风险或MEG3/下游靶标表达无关。升级的miR-27a和IGFBP3以及降低的IGF1血清水平在总体CRC患者与对照和肥胖与非肥胖CRC患者中伴随MEG3下调。血清miR-181a和SIRT1在CRC患者与对照组中上调，但在肥胖与非肥胖比较中没有改变。血清miR-181a和miR-27a在总体和肥胖相关的CRC诊断中具有优势，分别；同时，IGF1在区分肥胖和非肥胖CRC患者方面具有优势。在多因素logistic分析中，只有血清miR-27a与肥胖相关的CRC风险相关。在所有CRC患者中，MEG3rs941576与淋巴结（LN）转移和肿瘤分期有关，血清MEG3与肿瘤分期呈负相关,而SIRT1与解剖部位相关。在MEG3和解剖部位之间记录了显着的相关性，SIRT1和肿瘤分期，肥胖CRC患者中miR-27a/IGFBP3和LN转移，IGF1与非肥胖CRC患者的肿瘤分期和LN转移相关。最后，本研究提倡MEG3rs941576作为CRC易感性和预后的新遗传标记。我们的发现强调了循环MEG3/miR-27a/IGF1/IGFBP3，特别是miR-27a作为早期检测肥胖相关CRC的有价值的标志物。该轴与SIRT1一起可能有益于肥胖相关的CRC预后。
