Shp2是一种非受体蛋白酪氨酸磷酸酶，在宫颈癌中过度表达。然而，Shp2在宫颈癌代谢和肿瘤发生调节方面的作用尚不清楚。EGFR信号通路在宫颈癌中常常发生失调。我们表明，在宫颈癌细胞中删除Shp2后，EGFR表达减少并且下游的RAS-ERK激活被调控下降。尽管在Shp2敲除细胞中，AKT被激活，但抑制AKT不一定能让细胞更加敏感死亡。Shp2去除抑制了宫颈癌细胞增殖，并在移植的小鼠模型中减小了肿瘤生长。1H NMR光谱分析表明，在Shp2敲除的细胞中，谷氨酰胺、谷氨酸、丙酸、肌酸、谷胱甘肽和UDP-GlcNAc显着改变了。Shp2敲除细胞内谷氨酰胺水平高于对照细胞。进一步的分析表明，Shp2敲除通过上调谷氨酰胺代谢相关基因（如谷氨酰胺酶（GLS））促进了谷氨酰胺代谢和谷胱甘肽产生。然而，抑制GLS并不总能让细胞对死亡更敏感，这取决于葡萄糖浓度。氧化磷酸化水平显著增加，并伴随着Shp2敲除细胞中产生的反应氧气种类的增加。Shp2缺陷增加了C-Myc和C-Jun的表达，这可能与谷氨酰胺代谢的上调有关。这些结果表明，Shp2调控宫颈癌的增殖、谷氨酰胺代谢和肿瘤发生。©2023美国实验生物学会。

Shp2 is a nonreceptor protein tyrosine phosphatase that is overexpressed in cervical cancer. However, the role of Shp2 in the regulation of cervical cancer metabolism and tumorigenesis is unclear. EGFR signaling pathways are commonly dysregulated in cervical cancer. We showed that Shp2 knockout in cervical cancer cells decreased EGFR expression and downregulated downstream RAS-ERK activation. Although AKT was activated in Shp2 knockout cells, inhibition of AKT activation could not make cells more sensitive to death. Shp2 depletion inhibited cervical cancer cell proliferation and reduced tumor growth in a xenograft mouse model. 1 H NMR spectroscopic analysis showed that glutamine, glutamate, succinate, creatine, glutathione, and UDP-GlcNAc were significantly changed in Shp2 knockout cells. The intracellular glutamine level was higher in Shp2 knockout cells than in control cells. Further analysis demonstrated that Shp2 knockout promoted glutaminolysis and glutathione production by up-regulating the glutamine metabolism-related genes such as glutaminase (GLS). However, inhibition of GLS did not always make cells sensitive to death, which was dependent on glucose concentration. The level of oxidative phosphorylation was significantly increased, accompanied by an increased generation of reactive oxygen species in Shp2 knockout cells. Shp2 deficiency increased c-Myc and c-Jun expression, which may be related to the upregulation of glutamine metabolism. These findings suggested that Shp2 regulates cervical cancer proliferation, glutamine metabolism, and tumorigenicity.© 2023 Federation of American Societies for Experimental Biology.