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PFKFB3在促进肝癌细胞增殖中的作用及机制
中文摘要

肝细胞癌(hepatocellular carcinoma,HCC)是原发性肝脏肿瘤中最常见的,其年发病率在全世界所有肿瘤中排第五名,并且是导致肿瘤相关死亡排名第二的恶性肿瘤。目前,尽管早期HCC患者(BCLC stage 0 and A)根治性切除术术后5年生存率可以达到50%以上,但是对于晚期HCC患者有效治疗手段的欠缺,使这部分病人的预后很差,即使使用索拉非尼作为晚期肝癌的一线治疗药物也仅仅能延长患者3个月左右的生存时间。因此寻找一种能够对HCC有效治疗的特异性靶向治疗药物就显得迫在眉睫。 有氧糖酵解作为肿瘤细胞的重要供能方式与肿瘤的发生发展密切相关,而在与肿瘤发展过程密切相关的有氧糖酵解过程中伴随着多种基因表达的改变。 PFKFB3是这些改变的基因中的一个,并且与细胞的快速增殖明显相关,同时在多种肿瘤细胞中呈现出高表达。在乳腺癌中的研究发现,PFKFB3的特异性抑制剂3PO可以抑制葡萄糖的摄取利用和肿瘤的生长。在头颈部肿瘤的研究中发现, PFKFB3被抑制以后可以通过抑制糖酵解的过程抑制肿瘤的增殖和转移。但是,在Hela、HCT116和MDA-MB-231等细胞系中的研究则发现,PFKFB3不仅定位于细胞浆(糖酵解场所)中,而且也定位在细胞核内,将PFKFB3过表达以后可以明显的增强细胞的增殖能力而对肿瘤的糖代谢过程则不产生较大的影响。进一步的研究表明,PFKFB3可以通过Cdk-1调节p27的磷酸化过程来促进细胞周期和抑制细胞的凋亡。目前,关于PFKFB3在肝癌细胞中的定位和作用尚未研究。 在我们的研究中,我们发现PFKFB3的表达与HCC的生长密切相关,并且除定位于细胞浆外在细胞核内也明显表达,PFKFB3在HCC患者中的高表达和HCC患者的肿瘤大小(p=0.04)和较差的总体生存时间(p=0.027)明显相关。将肝癌细胞中的PFKFB3敲低以后不仅可以明显减少肝癌细胞对葡萄糖的摄取也可以损坏DNA的修复功能而引起肝癌细胞的G2/M期阻滞和细胞凋亡。在体内研究中发现,PFKFB3过表达以后可以明显的促进肿瘤的生长。在相关的机制研究中,我们发现PFKFB3敲低可以减少AKT的磷酸化并进一步的减少ERCC1的表达来引起肝癌细胞DNA修复能力的损坏。同时,PFKFB3的特异性小分子抑制剂PFK15在小鼠体内也可以明显的抑制肝癌细胞的生长。

英文摘要

Primary liver cancer is the second most common cause of cancer-related death in the world, and 90% of liver cancers are hepatocellular carcinoma (HCC). Although curative treatment provides long-term survival for patients during early-stage HCC (Barcelona clinic liver cancer [BCLC] stage 0 and A), most of patients have the advanced stage; therefore, they are not amenable for curative treatment, and the survival of these patients is poor. Survival associated with systemic treatment, such as sorafenib, for advanced-stage cancer patients is approximately 3 months. Hence, it is important to find a novel treatment for HCC. Accumulating evidence suggests that the continuous activation of aerobic glycolysis (Warburg effect) plays a vital role in tumor development and the many altered gene expressions accompanied by aerobic glycolysis in tumor development. One of the altered genes is 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), which significantly accelerates the glycolysis rate and is expressed in rapidly multiplying cells and various human cancers. In a previous report, PFKFB3 was overexpressed in cancer cells and associated with cancer progression. In breast and ovarian cancer cell line models, the PFKFB3 inhibitor 3-PO suppresses glycolytic flux and tumor growth. In a study of head and neck squamous cell carcinoma, blocking PFKFB3 suppressed tumor growth and metastasis mediated by suppressing glycolysis. However, a report revealed that in some cancer cells (Hela, HCT116, and MDA-MB-231), PFKFB3 localized not only in the cytoplasm (the site of glycolysis) but also in the nucleus, and overexpressed PFKFB3 increased during cell proliferation without changes in glucose metabolism. Furthermore, PFKFB3 promoted cell-cycle progression and suppressed apoptosis via Cdk1 -mediated phosphorylation of p27, and MAPK increased the PFKFB3 transcript to accelerate cell proliferation. Nevertheless, the specific location and function of PFKFB3 in HCC cells are not known. We report that PFKFB3 was mainly located in the nucleus in tumor cells and that PFKFB3 overexpression was associated with tumor progression by directly regulating cell proliferation. Moreover, PFK15, a selective PFKFB3 inhibitor, significantly inhibited tumor growth.

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