Localisation of PGK1 determines metabolic phenotype to balance metastasis and proliferation in patients with SMAD4-negative pancreatic cancer
Localisation of PGK1 determines metabolic phenotype to balance metastasis and proliferation in patients with SMAD4-negative pancreatic cancer
复制标题
PGK1 的定位决定了 SMAD4 阴性胰腺癌患者的代谢表型，以平衡转移和增殖。
DOI：
10.1136/gutjnl-2018-317163
复制
发表时间：
2020-05-01
期刊：
影响因子：
24.5
通讯作者：
Yu, Xian-Jun
中科院分区：
文献类型：
--
作者：
Liang, Chen;Shi, Si;Yu, Xian-Jun
目的胰腺导管腺癌（PDAC）是最具侵袭性的胃肠道肿瘤，具有细胞能量失调的特点。尽管PDAC生物学的最新进展已经导致在Kras、TP 53和SMAD 4中发现了与这种疾病相关的复发性基因突变，PDAC的分子表型的临床应用仍然具有挑战性。设计（正电子发射断层扫描/CT）和免疫组化以评估最大标准化摄取值和SMAD 4表达之间的相关性，并检查SMAD 4的作用。通过体外和体内实验研究糖酵解。此外，我们通过代谢组学和葡萄糖代谢基因表达分析确定了SMAD 4对代谢重编程的影响。进行双荧光素酶报告基因测定和染色质免疫沉淀以鉴定SMAD 4是否在PDAC细胞中作为磷酸甘油酸激酶1（PGK 1）的转录因子起作用。的恶性行为的PDAC.Results我们提供了令人信服的证据表明，糖酵解酶PGK 1抑制转化生长因子-β/SMAD 4的增殖和转移试验进行检查PGK 1的效果。SMAD 4的缺失诱导PDAC中PGK 1上调，这增强了糖酵解和侵袭性肿瘤行为。值得注意的是，在SMAD 4阴性PDAC中，细胞核PGK 1优先通过线粒体氧化磷酸化诱导驱动细胞转移，而细胞质PGK 1优先通过充当糖酵解酶来支持增殖。PDAC的进展模式和不同的PGK 1定位结合联合收割机，以预测总生存期和无病survival.Conclusion PGK 1是一个决定性的癌基因在SMAD 4阴性PDAC患者，并可以为SMAD 4阴性PDAC的治疗策略的发展目标。
Objective Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive type of GI tumour, and it possesses deregulated cellular energetics. Although recent advances in PDAC biology have led to the discovery of recurrent genetic mutations in Kras, TP53 and SMAD4, which are related to this disease, clinical application of the molecular phenotype of PDAC remains challenging.Design We combined molecular imaging technology (positron emission tomography/CT) and immunohistochemistry to evaluate the correlation between the maximum standardised uptake value and SMAD4 expression and examined the effect of SMAD4 on glycolysis through in vitro and in vivo experiments. Furthermore, we identified the effect of SMAD4 on metabolic reprogramming by metabolomics and glucose metabolism gene expression analyses. Dual luciferase reporter assays and chromatin immunoprecipitation were performed to identify whether SMAD4 functioned as a transcription factor for phosphoglycerate kinase 1 (PGK1) in PDAC cells. Proliferative and metastatic assays were performed to examine the effect of PGK1 on the malignant behaviour of PDAC.Results We provide compelling evidence that the glycolytic enzyme PGK1 is repressed by transforming growth factor-beta/SMAD4. Loss of SMAD4 induces PGK1 upregulation in PDAC, which enhances glycolysis and aggressive tumour behaviour. Notably, in SMAD4-negative PDAC, nuclear PGK1 preferentially drives cell metastasis via mitochondrial oxidative phosphorylation induction, whereas cytoplasmic PGK1 preferentially supports proliferation by functioning as a glycolytic enzyme. The PDAC progression pattern and distinct PGK1 localisation combine to predict overall survival and disease-free survival.Conclusion PGK1 is a decisive oncogene in patients with SMAD4-negative PDAC and can be a target for the development of a therapeutic strategy for SMAD4-negative PDAC.