Glutamate from nerve cells promotes perineural invasion in pancreatic cancer by regulating tumor glycolysis through HK2 mRNA-m6A modification
Glutamate from nerve cells promotes perineural invasion in pancreatic cancer by regulating tumor glycolysis through HK2 mRNA-m6A modification
复制标题
神经细胞中的谷氨酸通过 HK2 mRNA-m6A 修饰调节肿瘤糖酵解，促进胰腺癌神经周围侵袭
DOI：
10.1016/j.phrs.2022.106555
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发表时间：
2022-12-06
影响因子：
9.3
通讯作者：
Chen, Shangxiang
中科院分区：
文献类型：
--
作者：
Li, Fengjiao;He, Chong;Chen, Shangxiang
背景：胰腺导管腺癌（PDAC）中神经周围浸润（PNI）发生率高，预后差。方法：采用Matrigel/背根神经节（dorsal root ganglia，DRG）模型和小鼠坐骨神经侵袭模型，观察PNI的体内外变化。磁共振（MR）成像和正电子发射断层扫描/计算机断层扫描（PET-CT）成像也用于评估肿瘤生长。结果：神经细胞中的谷氨酸可通过N甲基-D-天冬氨酸受体（NMDAR）引起PDAC细胞内钙内流，进而激活下游钙依赖性蛋白激酶CaMKII/ERK-MAPK通路，促进胃L3基因mRNA的转录。接下来，胃L3通过mRNA中的N6-甲基腺苷（m6 A）修饰上调己糖激酶2（HK 2）的表达，增强PDAC细胞的糖酵解，并促进PNI。此外，合成了双靶向PDAC细胞上的CD 44变体同种型6（CD 44 v6）和t NMDAR亚基2B（NMDAR 2B）的IONPs-PEG-scFvCD 44 v6-scAbNMDAR 2B纳米颗粒，并验证了其对PNI显示出令人满意的阻断效果。在这里，我们首次提供证据表明，来自神经细胞的谷氨酸可以通过NMDAR 2B和下游Ca 2+通过mRNA m6 A修饰上调HK 2的表达依赖于CaMKII/ ERK-MAPK通路，增强PDAC细胞中的糖酵解，并最终促进PNI。此外，我们合成的双靶向纳米粒子被证实可以有效地阻断PDAC中的PNI。
Background: Perineural invasion (PNI) has a high incidence and poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Our study aimed to identify the underlying molecular mechanism of PNI and propose effective intervention strategies.Methods: To observe PNI in vitro and in vivo, a Matrigel/ dorsal root ganglia (DRG) model and a murine sciatic nerve invasion model were respectively used. Magnetic resonance (MR) imaging and positron emission tomography/computed tomography (PET-CT) imaging were also used to evaluate tumor growth. Publicly available datasets and PDAC tissues were used to verify how the nerve cells regulate PDAC cells' PNI.Results: Our results showed that glutamate from nerve cells could cause calcium influx in PDAC cells via the Nmethyl-D-aspartate receptor (NMDAR), subsequently activating the downstream Ca2+ dependent protein kinase CaMKII/ERK-MAPK pathway and promoting the mRNA transcription of gene METTL3. Next, METTL3 upregulates the expression of hexokinase 2 (HK2) through N6-methyladenosine (m6A) modification in mRNA, enhances the PDAC cells' glycolysis, and promotes PNI. Furthermore, the IONPs-PEG-scFvCD44v6-scAbNMDAR2B nanoparticles dual targeting CD44 variant isoform 6 (CD44v6) and t NMDAR subunit 2B (NMDAR2B) on PDAC cells were synthesized and verified showing a satisfactory blocking effect on PNI.Conclusions: Here, we firstly provided evidence that glutamate from the nerve cells could upregulate the expression of HK2 through mRNA m6A modification via NMDAR2B and downstream Ca2+ dependent CaMKII/ ERK-MAPK pathway, enhance the glycolysis in PDAC cells, and ultimately promote PNI. In addition, the dual targeting nanoparticles we synthesized were verified to block PNI effectively in PDAC.