Fang Wenzhang, Cui Hongmei, Yu Danyang, Chen Ying, Wang Jiejun, Yu Guanzhen
Department of Medical Oncology, Changzheng Hospital, Hetian Road 64, Shanghai, 200070, People's Republic of China.
Med Oncol. 2014 Jul;31(7):15. doi: 10.1007/s12032-014-0015-7. Epub 2014 Jun 13.
Upregulation of acetyl-CoA carboxylase (ACC), as a rate-limiting enzyme of fatty acid synthesis,has been recognized in multiple human cancers, implicating a critical role in cancer development and progression; yet, its role in gastric cancer still remains unclear. In the present study, we detected ACC and phosphorylated form of ACC (pACC) expression in gastric cancers and explored its clinical significance. Tissue microarray blocks containing primary gastric cancer and adjacent normal mucosa specimens obtained from 1,072 Chinese patients were used for the detection of ACC and pACC expression by immunohistochemistry. Gastric cancer cell lines were treated by metformin, and pACC was measured by Western blotting. ACC overexpression was observed in all the tumor specimens. High expression of pACC was found in 630 (58.8 %) of the 1,072 primary tumors and in 237 (66.6 %) of the 356 primary tumors without lymph node metastasis. Absent/low expression of pACC significantly correlated with advanced T stage (P < 0.001), tumor size (P = 0.010), lymph node metastasis (P < 0.001), advanced disease stage (P < 0.001), and poor histological differentiation (P = 0.014) in 1,072 primary tumors, and with advanced T stage (P = 0.015), tumor size (P = 0.017), and poor histological differentiation (P = 0.001) in 356 tumors without lymph node metastasis. Kaplan-Meier analysis showed that high expression of pACC is strongly related to better survival rates in all gastric cancer patients (P = 0.006). Cox regression analysis revealed that pACC is an independent prognostic factor only in patients without lymph node metastasis (P = 0.016). Metformin treatment leaded to increased expression of pACC, which, in turn, resulted in the reduction of cell proliferation and colony formation of gastric cancer cells (P < 0.05). Increased activation of ACC is frequent in human gastric cancer, and downregulation of pACC is an important prognostic factor, suggesting that ACC/pACC might be a potential target for cancer intervention.
乙酰辅酶A羧化酶（ACC）作为脂肪酸合成的限速酶，其上调在多种人类癌症中已得到确认，这表明它在癌症发生和发展中起关键作用；然而，其在胃癌中的作用仍不清楚。在本研究中，我们检测了胃癌中ACC及其磷酸化形式（pACC）的表达，并探讨了其临床意义。采用免疫组织化学方法，对1072例中国患者的原发性胃癌及癌旁正常黏膜标本制成的组织芯片进行ACC和pACC表达检测。用二甲双胍处理胃癌细胞系，通过蛋白质免疫印迹法检测pACC。在所有肿瘤标本中均观察到ACC过表达。在1072例原发性肿瘤中，630例（58.8%）pACC高表达；在356例无淋巴结转移的原发性肿瘤中，237例（66.6%）pACC高表达。在1072例原发性肿瘤中，pACC缺失/低表达与T分期进展（P<0.001）、肿瘤大小（P=0.010）、淋巴结转移（P<0.001）、疾病分期进展（P<0.001）及组织学分化差（P=0.014）显著相关；在356例无淋巴结转移的肿瘤中，pACC缺失/低表达与T分期进展（P=0.015）、肿瘤大小（P=0.017）及组织学分化差（P=0.001）显著相关。Kaplan-Meier分析显示，pACC高表达与所有胃癌患者的较好生存率密切相关（P=0.006）。Cox回归分析显示，pACC仅在无淋巴结转移的患者中是独立的预后因素（P=0.016）。二甲双胍处理导致pACC表达增加，进而导致胃癌细胞增殖和集落形成减少（P<0.05）。ACC激活增加在人类胃癌中常见，pACC下调是一个重要的预后因素，提示ACC/pACC可能是癌症干预的潜在靶点。
