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浙江大学学报（医学版）
浙江大学学报（医学版）  2021, Vol. 50 Issue (1): 17-22    DOI: 10.3724/zdxbyxb-2021-0054
专题报道     
RAS基因与脂代谢在恶性肿瘤中的相互调控
张明佺(),潘俊辰,黄蓬()
中山大学肿瘤防治中心，广东 广州 510060
Interaction between RAS gene and lipid metabolism in cancer
ZHANG Mingquan(),PAN Junchen,HUANG Peng()
Cancer Center，Sun Yat-Sen University，Guangzhou 510060，China
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摘要：

RAS基因是恶性肿瘤中常见的驱动基因，在多种恶性肿瘤中高频率突变并异常活化，是驱动肿瘤发生发展的重要因素。代谢重编程作为恶性肿瘤重要特征之一，是抗肿瘤治疗的关键靶点。 RAS基因可通过蛋白激酶B/哺乳动物雷帕霉素靶蛋白复合物1信号轴或其他多条信号通路调控脂代谢，如脂质合成途径和降解途径等。同样，脂代谢也能修饰并激活RAS蛋白及其下游信号通路。因此，本文概述了现阶段脂代谢与 RAS之间相互调控的研究，旨在为靶向脂代谢在 RAS驱动型肿瘤的临床应用提供思路。

关键词： RAS基因;  脂代谢;  肿瘤;  治疗;  综述    
Abstract:

The RAS gene is frequently mutated and abnormally activated in many cancers，and plays an important role in cancer development. Metabolic reprogramming occurs in malignant tumors，which can be one of the key targets for anti-tumor therapy. RAS gene can regulate lipid metabolism through AKT-mTORC1 single axis or multiple pathways，such as lipid synthesis pathways and degradation pathways. Similarly，lipid metabolism can also modify and activate RAS protein and its downstream signaling pathways. This article overviews the current research progress on the interaction between lipid metabolism and RAS，to provide insight in therapeutic strategies of lipid metabolism for RAS-driven tumors.

Key words: RAS gene    Lipid metabolism    Tumor    Therapy    Review
收稿日期: 2020-12-14 出版日期: 2021-05-14
CLC:  R730.23  
基金资助: 中山大学国家自然科学基金重大项目培育专项
通讯作者: 黄蓬     E-mail: zhangmq@sysucc.org.cn;huangpeng@sysucc.org.cn
作者简介: 张明佺，博士研究生，主要从事肿瘤代谢及干预研究；E-mail：zhangmq@sysucc.org.cn；https://orcid.org/0000-0002-1853-935X
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引用本文:

张明佺,潘俊辰,黄蓬. RAS基因与脂代谢在恶性肿瘤中的相互调控[J]. 浙江大学学报（医学版）, 2021, 50(1): 17-22.

ZHANG Mingquan,PAN Junchen,HUANG Peng. Interaction between RAS gene and lipid metabolism in cancer. J Zhejiang Univ (Med Sci), 2021, 50(1): 17-22.

链接本文:

http://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2021-0054    或    http://www.zjujournals.com/med/CN/Y2021/V50/I1/17

图 1  RAS的分子开关功能 RAS具有分子开关的作用：其与鸟苷三磷酸（GTP）结合时被激活，呈“开启”状态；当GTP被水解时RAS失活，呈“关闭”状态. 该过程受鸟嘌呤核苷酸交换因子（GEF）或GTP酶激活蛋白（GAP）的调控：GEF刺激鸟苷二磷酸（GDP）与GTP交换，而GAP促进GTP水解. 磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B（AKT）信号轴和RAF/丝裂原激活的蛋白激酶激酶（MEK）/胞外信号调节激酶（ERK）信号轴是RAS的主要下游信号通路，调控多种代谢过程，包括糖酵解、三羧酸循环及脂代谢等. PIP3：3，4，5-三磷酸磷脂酰肌醇；mTOR：哺乳动物雷帕霉素靶蛋白.
图 2  RAS调控脂代谢的主要途径 激活状态的RAS主要通过其下游信号通路磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B（AKT）和RAF/丝裂原激活的蛋白激酶激酶（MEK）/胞外信号调节激酶（ERK）调控细胞代谢. 被激活的哺乳动物雷帕霉素靶蛋白复合物（mTORC）1能够促进成熟的固醇调节元件结合蛋白（mSREBP）在细胞核中累积从而引导脂质合成. P：磷酸化；PIP2：4，5-二磷酸磷脂酰肌醇；PIP3：3，4，5-三磷酸磷脂酰肌醇；PTEN：10号染色体缺失磷酸酶及张力蛋白同源物；PDK：丙酮酸脱氢酶激酶；TSC：结节性硬化症蛋白；Rheb：RAS蛋白脑组织同源类似物；GF：生长因子；ACAT：乙酰辅酶A乙酰转移酶；HMGCR：3-羟基-3-甲基戊二酰辅酶A还原酶；FASN：脂肪酸合酶；SCD：硬脂酰辅酶A去饱和酶；OMe：甲氧基.
图 3  脂质对RAS活性的调控及干预策略 法尼基转移酶（FTase）催化法尼基类异戊二烯与RAS蛋白羧基端的CAAX基序的半胱氨酸结合，随后RAS转换酶1（RCE1）切去AAX氨基酸，而异戊二烯半胱氨酸羧基甲基转移酶（ICMT）将羧基端法尼基化半胱氨酸的羧基甲基化，最终生成具有疏水性的尾巴. 该疏水区域使RAS蛋白易于锚定在细胞膜从而促使RAS活化. 法尼基转移酶抑制剂（FTI）通过阻断RAS蛋白的法尼基类异戊二烯修饰而抑制RAS的活性. OMe：甲氧基.
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