Downregulation of acetyl-CoA synthetase 2 is a metabolic hallmark of tumor progression and aggressiveness in colorectal carcinoma
Downregulation of acetyl-CoA synthetase 2 is a metabolic hallmark of tumor progression and aggressiveness in colorectal carcinoma
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DOI：
10.1038/modpathol.2016.172
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发表时间：
2017-02-01
期刊：
影响因子：
7.5
通讯作者：
Kang, Gyeong Hoon
中科院分区：
文献类型：
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作者：
Bae, Jeong Mo;Kim, Jung Ho;Kang, Gyeong Hoon
乙酰辅酶A合成酶2是一种新兴的癌症代谢关键酶，它在应激条件下通过捕获乙酸作为碳源为肿瘤细胞提供乙酰辅酶A。然而，乙酰辅酶A合成酶2在结直肠癌中的影响可能与其他恶性肿瘤不同，因为正常结肠细胞使用短链脂肪酸作为能量来源，而短链脂肪酸是由肠道菌群发酵提供的。在这里，我们通过逆转录定量PCR分析了12例结直肠癌配对正常粘膜和肿瘤组织中乙酰辅酶A合成酶2 mRNA的表达，随后通过免疫组织化学评估了157例结直肠癌前病变中乙酰辅酶A合成酶2蛋白的表达，其中包括60例常规腺瘤和97例锯齿状息肉、1,106例手术切除的原发性结直肠癌和23例转移性结直肠癌。肝脏结直肠癌。逆转录定量PCR分析显示，与相应的正常粘膜组织相比，肿瘤组织中乙酰辅酶A合成酶2 mRNA的表达显着降低。在乙酰辅酶A合成酶2免疫组织化学分析中，所有157个结直肠息肉均显示乙酰辅酶A合成酶2中度至强表达。然而，在 1,106 例结直肠癌中的 771 例（69.7%）和 23 例转移病灶中的 21 例（91.3%）中，细胞质乙酰辅酶A合成酶 2 表达下调（乙酰辅酶A合成酶 2 低表达）。乙酰辅酶A合成酶2低表达的结直肠癌与TNM分期晚期、分化差和肿瘤出芽频繁显着相关。在分子方面，乙酰辅酶A合成酶2低表达表现出KRT7表达频繁、KRT20和CDX2表达减少的趋势。在生存分析中，乙酰辅酶A合成酶2低表达是5年无进展生存率较差的独立预后因素（风险比，1.39；95%置信区间，1.08-1.79；P = 0.01）。总之，这些发现表明乙酰辅酶A合成酶2表达的下调是结直肠癌肿瘤进展和侵袭行为的代谢标志。
Acetyl-CoA synthetase-2 is an emerging key enzyme for cancer metabolism, which supplies acetyl-CoA for tumor cells by capturing acetate as a carbon source under stressed conditions. However, implications of acetyl-CoA synthetase-2 in colorectal carcinoma may differ from other malignancies, because normal colonocytes use short chain fatty acids as an energy source, which are supplied by fermentation of the intestinal flora. Here we analyzed acetyl-CoA synthetase-2 mRNA expression by reverse-transcription quantitative PCR in paired normal mucosa and tumor tissues of 12 colorectal carcinomas, and subsequently evaluated acetyl-CoA synthetase-2 protein expression by immunohistochemistry in 157 premalignant colorectal lesions, including 60 conventional adenomas and 97 serrated polyps, 1,106 surgically resected primary colorectal carcinomas, and 23 metastatic colorectal carcinomas in the liver. In reverse-transcription quantitative PCR analysis, acetyl-CoA synthetase-2 mRNA expression was significantly decreased in tumor tissues compared with corresponding normal mucosa tissues. In acetyl-CoA synthetase-2 immunohistochemistry analysis, all 157 colorectal polyps showed moderate to -strong expression of acetyl-CoA synthetase-2. However, cytoplasmic acetyl-CoA synthetase-2 expression was downregulated (acetyl-CoA synthetase-2 low expression) in 771 (69.7%) of 1,106 colorectal carcinomas and 21 (91.3%) of 23 metastatic lesions. The colorectal carcinomas with acetyl-CoA synthetase-2-low expression were significantly associated with advanced TNM stage, poor differentiation, and frequent tumor budding. Regarding the molecular aspect, acetyl-CoA synthetase-2-low expression exhibited a tendency of frequent KRT7 expression and decreased KRT20 and CDX2 expression. In survival analysis, acetyl-CoA synthetase-2-low expression was an independent prognostic factor for poor 5-year progression-free survival (hazard ratio, 1.39; 95% confidence interval, 1.08-1.79; P = 0.01). In conclusion, these findings suggest that downregulation of acetyl-CoA synthetase-2 expression is a metabolic hallmark of tumor progression and aggressive behavior in colorectal carcinoma.