【作者】 陈伟；

【导师】 欧阳高亮；

【作者基本信息】 厦门大学 ， 生物学， 2019， 硕士

【摘要】 乳腺癌是女性中最常见的恶性肿瘤,也是世界上三大最常见的恶性肿瘤之一,由于针对乳腺癌不同的分子分型有着不同的治疗策略,一些靶向药物的应用也使得患者存活时间延长,但是转移性乳腺癌依然难以治愈。之前的研究已经表明Periostin(POSTN)可以通过影响肿瘤干细胞和肿瘤微环境进而促进乳腺癌的发生发展,但是对于POSTN是否会影响乳腺癌代谢并不清楚。在本研究中,我们利用了MMTV-PyMT这一自发性Luminal B型乳腺癌的小鼠模型,通过18F-FDG-PET-CT实验和乳酸测定实验发现,Postn敲除后自发性乳腺癌的原位肿瘤糖酵解降低;我们进一步分离出了自发性乳腺癌的原位肿瘤细胞,发现Postn敲除的肿瘤细胞的糖酵解也降低。在组织和细胞水平上检测了糖酵解相关酶之后,我们发现Postn敲除可降低肿瘤细胞的己糖激酶-2(HK2)表达,这可能是POSTN对糖酵解水平产生影响的主要原因。我们接着通过抑制剂实验证明了POSTN主要通过FAK对HK2起促进作用,而磷酸化Akt并不在其中起调控作用;但是Postn敲除后HIF1α的蛋白量降低和入核减少,这可能是HK2产生变化的重要原因。我们还发现Postn敲除后自发性乳腺癌肺转移灶的HK2表达也有所降低,说明Postn敲除也影响了肺转移灶的代谢。最后我们发现在HER2阴性的Luminal亚型的人乳腺癌样本中POSTN和HK2的表达呈正相关。本研究首次对POSTN在肿瘤代谢中的功能进行了初步研究,揭示了POSTN和HK2在乳腺癌代谢中的关系,使得我们对POSTN在肿瘤发生发展中的功能有了新的认识,为进一步阐明POS TN与肿瘤代谢的关系奠定了基础,也将有助于乳腺癌靶向药物的研发。更多还原

【Abstract】 Breast cancer is the most common malignant tumor in women and one of the three most common malignant tumors in the world.Different therapeutic strategies for distinct molecular types and the implication of some targeted drugs elevate the survival time of patients with breast cancer.However,metastatic breast cancer remains difficult to be cured.Previous studies have shown that periostin(POSTN)can promote the development of breast cancer by affecting cancer stem cells and tumor microenvironments,but it is not clear whether POSTN affects breast tumor metabolism.In this study,we used MMTV-PyMT,a mouse model of spontaneous breast cancer,to determine the relationship between POSTN and tumor metabolism.We discovered a glycolytic decrease in breast tumor after Po.stn knockout by 18F-FDG-PET-CT and lactate assays.We further isolated the tumor cells from the mice with spontaneous breast tumors and found that the Postn-/-cells also have reduced glycolysis.After detecting glycolytic-related enzymes at the tumor tissue and cellular levels,we found that Postn knockdown reduces hexokinase 2(HK2)in tumor cells,which may be the main reason for the decrease of glycolysis levels.We then demonstrate that POSTN promotes HK2 via FAK but not via Akt.We further demonstrate that Postn knockout decreases the protein level and nuclear input of HIF1α,suggesting that the change of HIF1α may influence HK2.We further found that HK2 expression is decreased in the lung metastases of Postn-knockout mice with spontaneous breast tumors,indicating that Postn knockout also affects the metabolism of lung metastases.Finally,we found a positive correlation between POSTN and HK2 expression in human breast cancer samples that are HER2-negative and hormone-positive.This study is the first one to investigate the function of POSTN in tumor metabolism and identify a relationship between POSTN and HK2 in breast tumor metabolism.It will help us to better understand the metabolic function of POSTN in tumors and to develop targeted drugs for breast cancer.更多还原