Metabolic alterations caused by HNF1β expression in ovarian clear cell carcinoma contribute to cell survival.
Metabolic alterations caused by HNF1β expression in ovarian clear cell carcinoma contribute to cell survival.
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DOI：
10.18632/oncotarget.4692
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发表时间：
2015-09-22
期刊：
影响因子：
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通讯作者：
Konishi I
中科院分区：
文献类型：
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作者：
Amano Y;Mandai M;Yamaguchi K;Matsumura N;Kharma B;Baba T;Abiko K;Hamanishi J;Yoshioka Y;Konishi I
HNF1β仅在卵巢透明细胞癌（OCCC）中表达，而在其他卵巢癌中不表达，这被认为是这种肿瘤的标志。这意味着它在OCCC的独特特征中起着核心作用，包括对化疗的耐药性，但它在癌症生物学中的确切作用和影响或其功能的分子基础在很大程度上是未知的。通过对HNF1β - shrna稳定细胞系的综合代谢组分析，我们发现HNF1β显著改变细胞内代谢，特别是在增强有氧糖酵解的方向上，即所谓的“Warburg效应”。只有当葡萄糖供应充足时，代谢变化的结果才能促进细胞在缺氧和化学试剂等压力下的存活。细胞存活的增强是基于代谢改变（如从氧化磷酸化到糖酵解的转变）引起的ROS活性降低和细胞内抗氧化剂谷胱甘肽（GSH）的增加。rBAT是胱氨酸转运体之一，可能在GSH增加中起主要作用。这些数据表明，HNF1β可能是由子宫内膜异位症囊肿中的应激微环境诱导的，赋予上皮细胞生存优势，从而导致OCCC的发生，OCCC是卵巢癌的一种耐药表型。
HNF1β is expressed exclusively in ovarian clear cell carcinoma (OCCC) and not in other ovarian cancers, regarded as a hallmark of this tumor. This implies its central role in the unique character of OCCC, including resistance to chemotherapy, but its exact role and influence in cancer biology or the molecular bases of its function are largely unknown. Using comprehensive metabolome analysis of HNF1β_shRNA-stable cell lines, we show here that HNF1β drastically alters intracellular metabolism, especially in direction to enhance aerobic glycolysis, so called the “Warburg effect”. The consequence of the metabolic change contributed cell survival under stresses such as hypoxia and chemo-reagent, only when sufficient glucose supply was available. Augmented cell survival was based on the reduced ROS activity derived from metabolic alteration such as shift from oxidative phosphorylation to glycolysis and increased intracellular anti-oxidant, glutathione (GSH). One of the cystine transporters, rBAT is likely to play a major role in this GSH increase. These data suggest that HNF1β, possibly induced by stressful microenvironment in the endometriotic cyst, confers survival advantage to the epithelial cells, which leads to the occurrence of OCCC, a chemo-resistant phenotype of ovarian cancer.