突变型KRAS在胰腺导管腺癌代谢中的作用

陈懿; 谢黎; 吴健

doi:10.3969/j.issn.1001-5256.2022.12.043

突变型KRAS在胰腺导管腺癌代谢中的作用

DOI: 10.3969/j.issn.1001-5256.2022.12.043

陈懿^{1, 4},
谢黎¹,
吴健^{1, 2, 3, , ,}

1.
复旦大学基础医学院病原生物学系, 教育部/卫健委医学分子病毒重点实验室, 上海 200032
2.
复旦大学附属中山医院消化科, 上海 200032
3.
上海市肝病研究所上海 200032
4.
复旦大学上海医学院临床医学院, 上海 200032

基金项目:

国家自然科学基金面上项目 (81871997);

国家自然科学基金面上项目 (82170624)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：陈懿对本文的思路和撰写有关键贡献；谢黎参与起草或修改文章关键内容；吴健负责文字的修改与定稿。

详细信息

通信作者:
吴健, jian.wu@fudan.edu.cn

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出版历程
- 收稿日期: 2022-05-24
- 录用日期: 2022-08-10
- 出版日期: 2022-12-20

Role of KRAS mutation in metabolism of pancreatic ductal adenocarcinoma

Yi CHEN^{1, 4},
Li XIE¹,
Jian WU^{1, 2, 3
, ,
,}

1.
Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai 200032, China
2.
Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
3.
Shanghai Institute of Liver Diseases, Shanghai 200032, China
4.
School of Clinical Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China

Research funding:

National Science Foundation of China (81871997);

National Science Foundation of China (82170624)

More Information

Corresponding author: WU Jian, jian.wu@fudan.edu.cn (ORCID: 0000-0001-9933-7364)

摘要

摘要: 胰腺癌作为一种致死率高、预后差的恶性肿瘤，肿瘤代谢相关的基因突变被认为是其进展和预后不良的基础。胰腺导管腺癌(PDAC)是最常见的胰腺癌类型，86%的PDAC患者被检测出KRAS突变，KRAS作为多种信号通路和转录因子上游的“分子开关”，对肿瘤细胞代谢过程起着重要的调控作用。突变型KRAS可影响营养物质和能量代谢重编程、巨胞饮作用和自噬，调节肿瘤微环境中的成分相互作用，维持癌细胞的生存和增殖。目前，临床上对PDAC的KRAS靶向治疗大多停留在试验阶段，未来能否真正应用于治疗仍需进一步临床研究。
- 胰腺肿瘤 /
- 代谢 /
- 肿瘤微环境
Abstract: Pancreatic cancer is a malignant tumor with high fatality rate and poor prognosis, and gene mutations involved in tumor metabolism are considered as the basis of its progression and poor prognosis. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and it is reported that KRAS mutations are detected in 86% of PDAC patients. As a molecular switch in the upstream of various signaling pathways and transcription factors, KRAS plays an important role in the regulation of tumor cell metabolism. KRAS mutations may affect the metabolic reprogramming of nutrients and energy, macropinocytosis, and autophagy, regulate the interaction between components in tumor microenvironment, and maintain the survival and proliferation of cancer cells. At present, KRAS-targeting therapies for PDAC still remain in an experimental stage, and further clinical studies are needed to determine whether they can be safely applied in treatment.
- Pancreatic Neoplasms /
- Metabolism /
- Tumor Microenvironment

HTML全文

图 1 KRAS信号通路及其对细胞功能的作用

注：KRAS在与GTP结合时被激活，启动下游多种信号通路，最终促进细胞存活、增殖、转化、侵袭、胞吞/胞吐功能。KRAS的突变破坏RAS的内在GTP酶活性，使GAP失去对GTP的失活作用，促进GTP向GDP转化，导致KRAS及其下游信号通路的持续激活。GEF：鸟苷酸交换因子；RALGEF：鸟嘌呤核苷酸交换因子；RALA：Ras样蛋白A；RALB：Ras样蛋白B；PLC：磷酯酶C；NK-κB：核因子κB；MEKK1/2/3/4：MAPK激酶1/2/3/4；JNK：c-Jun氨基末端激酶。

Figure 1. KRAS signaling pathway and its effects on cell function

下载: 全尺寸图片幻灯片

图 2 KRAS突变影响胰腺导管腺癌代谢重编程

注：葡萄糖在胞液中可裂解为丙酮酸，是葡萄糖无氧氧化和有氧氧化的共同起始途径。在正常细胞中，氧供充足，丙酮酸主要进入线粒体，经历三羧酸循环，遵循糖的有氧氧化途径(黑色箭头路线所示)。(1)KRAS突变，致使葡萄糖转运体、糖酵解限速酶、糖代谢分支途径的关键酶(棕色)上调，糖代谢以无氧氧化为主(棕色箭头路线所示)，从而促进葡萄糖摄取，增加糖酵解通量。(2)KRAS突变，刺激磷酸甘油酸激酶1向线粒体易位，致使癌细胞中丙酮酸脱氢酶激酶1磷酸化，抑制丙酮酸脱氢酶(蓝色箭头路线所示)，从而抑制胰腺癌细胞中线粒体氧化磷酸化，产能减少。GFPT1：谷氨酰胺6-磷酸果糖转移酶；RPE：5-磷酸核丁糖-3-差向异构酶；RPIA：5-磷酸核丁糖异构酶。

Figure 2. KRAS mutation affects metabolic reprogramming in pancreatic ductal adenocarcinoma

下载: 全尺寸图片幻灯片

表 1 KRAS突变对PDAC代谢的影响

Table 1. Effects of KRAS mutations on PDAC metabolism

影响类型	涉及机制	分子水平改变	最终效应
肿瘤细胞代谢重编程	糖代谢	上调：葡萄糖转运体、己糖激酶、磷酸果糖激酶1、乳酸脱氢酶、谷氨酰胺6-磷酸果糖转移酶、5-磷酸核丁糖-3-差向异构酶、5-磷酸核丁糖异构酶	葡萄糖摄取↑乳酸产量↑糖酵解通量↑
		磷酸甘油酸激酶1线粒体易位	氧化磷酸化↓能量产生↓
	脂代谢	以细胞外脂质供应占主导	避免损耗，限制细胞死亡
		过度表达酰基辅酶A合成酶长链3	抑制细胞自噬
	氨基酸代谢	诱导：磷酸戊糖途径的代谢重组、天冬氨酸转氨酶的表达	谷氨酰胺代谢↑
		抑制：苹果酸脱氢酶1精氨酸甲基化、谷氨酸脱氢酶的表达、线粒体解耦连蛋白2的表达	维持肿瘤细胞活力
巨胞饮与自噬作用	巨胞饮	突变型KRAS与肿瘤细胞表面的αvβ3和半乳糖凝集素3形成复合物	癌细胞巨胞饮作用↑
		促进关键效应因子V-ATPase向质膜易位	维持癌细胞的氧化还原平衡
	自噬	激活YAP-TAZ途径及其下游JAK-STAT3信号转导	诱导细胞自噬相关的MHC-I降解

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