Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital/Institute, Beijing 100142, China.
Mol Cancer. 2013 Sep 25;12(1):110. doi: 10.1186/1476-4598-12-110.
Increasing evidence suggests that cancer is a metabolic disease. Here, we investigated the potential role of fructose-1,6-bisphosphatase-2 (FBP2), the enzyme that catalyses the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate and inorganic phosphate in glucose metabolism, in gastric cancer (GC) development.
Our data indicated that FBP2 was downregulated in GC tissues (86.2%, 100/116), and absent or low FBP2 expression in GC tissues was correlated with poor survival of GC patients (P = 0.019). Conversely, ectopic expression of FBP2 in GC cells activated AMP-activated protein kinase (AMPK) signalling, inhibited the Akt-mTOR pathway, suppressed glucose metabolism, enhanced apoptosis, and reduced cell proliferation. Bisulphite genomic sequencing (BGS) in gastric cancer cell lines revealed that the FBP2 promoter region was densely methylated, and treatment of GC cells with the demethylation reagent, 5-aza-2-deoxycytidine (5-Aza), led to an increase in FBP2 expression. Importantly, forced expression of FBP2 abrogated tumour formation of these GC cells in nude mice.
Our results indicate that FBP2 does negatively regulate cell growth, and reduced expression of FBP2 may contribute to carcinogenesis for GC. These findings suggest that restoration of FBP2 expression can be a promising strategy for the target therapy of GC.
越来越多的证据表明，癌症是一种代谢疾病。在这里，我们研究了果糖-1,6-二磷酸酶-2（FBP2）在胃癌（GC）发展中的潜在作用。FBP2 是催化果糖-1,6-二磷酸水解为果糖-6-磷酸和无机磷酸的酶，参与葡萄糖代谢。
我们的数据表明，FBP2 在 GC 组织中下调（86.2%，100/116），GC 组织中 FBP2 的缺失或低表达与 GC 患者的不良生存相关（P = 0.019）。相反，FBP2 在 GC 细胞中的异位表达激活了 AMP 激活的蛋白激酶（AMPK）信号通路，抑制了 Akt-mTOR 通路，抑制了葡萄糖代谢，增强了细胞凋亡，减少了细胞增殖。胃癌细胞系中的亚硫酸氢盐基因组测序（BGS）显示，FBP2 启动子区域高度甲基化，用去甲基化试剂 5-氮杂-2-脱氧胞苷（5-Aza）处理 GC 细胞可导致 FBP2 表达增加。重要的是，FBP2 的强制表达可消除这些 GC 细胞在裸鼠中的肿瘤形成。
我们的结果表明，FBP2 确实负调控细胞生长，FBP2 的表达降低可能有助于 GC 的癌变。这些发现表明，恢复 FBP2 的表达可能是 GC 靶向治疗的一种有前途的策略。
