Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Mol Carcinog. 2018 Jun;57(6):772-783. doi: 10.1002/mc.22799. Epub 2018 Mar 23.
Gallbladder cancer (GBC) is the most general biliary tract malignancy, with poor prognosis due to rapid tumor progression and lack of specific symptoms. Lactate dehydrogenase-A (LDHA) can promote Warburg effect to produce lactate and Adenosine Triphosphate (ATP) in aerobic condition, which contributes to oncogenesis metastasis and drug resistance in various cancers. However, the expression and functional role of LDHA in GBC are largely unknown. We determined that LDHA was over-expressed in GBC tumor tissues compared with normal tissues, which was also an independent prognostic factor for the overall survival of GBC patients by tissue microarrays analysis. In addition, RNAi-mediated LDHA silencing could suppress the GBC cell proliferation, invasion, colony formation and glycolysis while promoting cell apoptosis in vitro. Similar results were observed in GBC cells treated with LDHA specific inhibitor FX11. Moreover, we confirmed that knockdown of LDHA could inhibit tumor growth in vivo. Additionally, we found that the 3'-untranslated region (3'-UTR) of LDHA mRNA was the direct target of microRNA-30d-5p (miR-30d-5p), which was low expressed in GBC tissues and associated with poor prognosis of GBC patients. Our findings disclose a novel role for miR-30d-5p/LDHA axis contribute to aggressive progression by reprogramming the metabolic process in GBC cells, and suggest a potential application of miR-30d-5p/LDHA axis in prognosis prediction and GBC treatment.
胆囊癌（GBC）是最常见的胆道恶性肿瘤，由于肿瘤进展迅速且缺乏特异性症状，预后较差。乳酸脱氢酶 A（LDHA）可在有氧条件下促进瓦博格效应产生乳酸和三磷酸腺苷（ATP），有助于各种癌症的发生、转移和耐药。然而，LDHA 在 GBC 中的表达和功能作用在很大程度上是未知的。我们通过组织微阵列分析确定，LDHA 在 GBC 肿瘤组织中的表达高于正常组织，这也是 GBC 患者总生存的独立预后因素。此外，RNAi 介导的 LDHA 沉默可抑制 GBC 细胞的增殖、侵袭、集落形成和糖酵解，同时促进细胞凋亡。在 LDHA 特异性抑制剂 FX11 处理的 GBC 细胞中也观察到类似的结果。此外，我们证实敲低 LDHA 可抑制体内肿瘤生长。此外，我们发现 LDHA mRNA 的 3'非翻译区（3'-UTR）是微小 RNA-30d-5p（miR-30d-5p）的直接靶标，miR-30d-5p 在 GBC 组织中低表达，与 GBC 患者的预后不良相关。我们的研究结果揭示了 miR-30d-5p/LDHA 轴通过重编程 GBC 细胞的代谢过程促进侵袭性进展的新作用，并表明 miR-30d-5p/LDHA 轴在预后预测和 GBC 治疗中有潜在的应用。
