Pyruvate carboxylase promotes thyroid cancer aggressiveness through fatty acid synthesis.
Pyruvate carboxylase promotes thyroid cancer aggressiveness through fatty acid synthesis.
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丙酮酸羧化酶通过脂肪酸合成促进甲状腺癌的侵袭性
DOI：
10.1186/s12885-021-08499-9
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发表时间：
2021-06-22
期刊：
影响因子：
3.8
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Liu C;Zhou X;Pan Y;Liu Y;Zhang Y
丙酮酸羧化酶（Pyruvate carboxylase，PC）是癌细胞三羧酸循环（tricarboxylic acid cycle，TCA）中的一种重要回补酶。虽然PC过度表达已被观察到在甲状腺癌（TC），PC的致癌作用的机制仍不清楚。MethodsBioinformatics分析和临床标本被用来分析PC的表达与临床病理变量在TC的关系。通过LC/MS、尼罗红染色和甘油三酯分析监测脂肪酸合成。通过Seahorse XF Mito细胞应激试验评价线粒体耗氧量。通过qRT-PCR和IHC在38个人TC组织中评估PC与FRENTA和SREBP1c的相关性。蛋白质印迹法被用来评估PC，FRENT，和SREBP1c的蛋白质表达和TC细胞系中的AKT/mTOR和EMT通路的成员。伤口愈合，CCK-8，和Transwell试验和裸鼠异种移植瘤模型被用来验证PC和SREBP1c对甲状腺肿瘤细胞增殖，迁移和invasion.ResultsWe的调节作用表明，PC增加脂肪酸的合成，然后促进TC进展和转移。GEO数据分析表明，PC在甲状腺乳头状癌（PTC）中的过表达与PTC侵袭和脂肪酸合成途径有关。对PTC患者的临床组织标本的分析显示，PC在有淋巴结转移的PTC患者的标本中的表达高于无淋巴结转移的患者。与对照细胞相比，脂肪酸合成信号通路中的多个基因，包括Festival和SREBP1c，在PC敲低的TC细胞中下调。脂质水平也降低PC敲低TC细胞。此外，细胞生长，侵袭和转移的能力也受到抑制后，PC敲低，表明PC介导的脂肪生成激活增加TC细胞的侵略性。此外，发现PC激活AKT/mTOR通路，从而通过上调SREBP1c表达来改善TC细胞中FAS介导的从头脂肪生成。在裸鼠移植瘤模型中的研究表明，PC基因敲低可降低肿瘤重量，但这种作用可被SREBP 1c的强制表达所减弱。结论PC通过刺激脂肪酸合成而参与TC的肿瘤侵袭性。
BackgroundPyruvate carboxylase (PC) is an important anaplerotic enzyme in the tricarboxylic acid cycle (TCA) in cancer cells. Although PC overexpression has been observed in thyroid cancer (TC), the mechanisms involved in the carcinogenic effects of PC are still unclear.MethodsBioinformatics analysis and clinical specimens were used to analyze the relationship of PC expression with clinicopathological variables in TC. Fatty acid synthesis was monitored by LC/MS, Nile red staining, and triglyceride analysis. Mitochondrial oxygen consumption was evaluated by the Seahorse XF Mito Cell Stress Test. The correlation of PC with FASN and SREBP1c was assessed by qRT-PCR and IHC in 38 human TC tissues. Western blotting was used to evaluate the protein expression of PC, FASN, and SREBP1c and members of the AKT/mTOR and EMT pathways in TC cell lines. Wound-healing, CCK-8, and Transwell assays and a nude mouse xenograft model were used to verify the regulatory effects of PC and SREBP1c on thyroid tumor cell proliferation, migration and invasion.ResultsWe demonstrated that PC increased fatty acid synthesis, which then promoted TC progression and metastasis. Analysis of GEO data showed that the overexpression of PC in papillary thyroid cancer (PTC) was associated with PTC invasion and the fatty acid synthesis pathway. Analysis of clinical tissue specimens from PTC patients revealed that PC was more highly expressed in specimens from PTC patients with lymph node metastasis than in those from patients without metastasis. Multiple genes in the fatty acid synthesis signaling pathway, including FASN and SREBP1c, were downregulated in PC-knockdown TC cells compared to control cells. Lipid levels were also decreased in the PC-knockdown TC cells. Moreover, the ability of cells to grow, invade, and metastasize was also suppressed upon PC knockdown, suggesting that PC-mediated lipogenesis activation increases the aggressiveness of TC cells. In addition, PC was found to activate the AKT/mTOR pathway, thus improving FASN-mediated de novo lipogenesis in TC cells by upregulating SREBP1c expression. Studies in a nude mouse xenograft model showed that PC knockdown decreased tumor weight, but this effect was attenuated by forced expression of SREBP1c.ConclusionsOur results demonstrate that PC is strongly involved in the tumor aggressiveness of TC via its stimulation of fatty acid synthesis.
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影响因子：
2.3
作者：
De Wever, Olivier;Pauwels, Patrick;De Craene, Bram;Sabbah, Michele;Emami, Shahin;Redeuilh, Gerard;Gespach, Christian;Bracke, Marc;Berx, Geert
通讯作者：
Berx, Geert
影响因子：
2
作者：
Jouppila-Matto, Anna;Tuhkanen, Hanna;Kosma, Veli-Matti
通讯作者：
Kosma, Veli-Matti
DOI：
10.1042/bj20080709
发表时间：
2008-08-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Jitrapakdee S;St Maurice M;Rayment I;Cleland WW;Wallace JC;Attwood PV
通讯作者：
Attwood PV
影响因子：
6.1
作者：
Ezzeddini, Rana;Taghikhani, Mohammad;Rasaee, Mohammad Javad
通讯作者：
Rasaee, Mohammad Javad
影响因子：
6
作者：
He, Lina;Hou, Xiaogang;Stiles, Bangyan L.
通讯作者：
Stiles, Bangyan L.