The Molecular Landscape and Biological Alterations Induced by PRAS40-Knockout in Head and Neck Squamous Cell Carcinoma.
The Molecular Landscape and Biological Alterations Induced by PRAS40-Knockout in Head and Neck Squamous Cell Carcinoma.
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头颈鳞状细胞癌中 PRAS40 敲除引起的分子景观和生物学改变
DOI：
10.3389/fonc.2020.565669
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发表时间：
2020
影响因子：
4.7
通讯作者：
Zhu G
中科院分区：
文献类型：
--
作者：
Chen G;Li Z;Chen C;Liu J;Zhu W;She L;Huang H;Qin Y;Liu G;Wang J;Liu Y;Huang D;Tang Q;Zhang X;Zhu G
PRAS 40（Prolin-rich Akt substrate of 40 kDa）是一种重要的蛋白质，直接连接PI 3 K/Akt和mTORC 1通路。它在各种疾病的发展中起着不可或缺的作用。然而，PRAS 40与头颈部鳞状细胞癌（HNSCC）的关系尚不清楚。在此，我们的研究通过分析498例临床和mRNA数据表明，PRAS 40 mRNA的高表达是HNSCC患者的有利预后因素。此外，我们证实CRISPR/Cas9诱导的PRAS 40敲除将促进几种HNSCC细胞系中的集落形成、细胞迁移和侵袭。采用RNA-seq研究涉及HNSCC细胞中PRAS 40的上述调节的进一步可能机制。PRAS 40基因敲除后253条差异表达mRNA的分子图谱主要集中在TGF-β、PI 3 K-Akt、P53、mTOR、NF-κB信号通路。通过qPCR或Western印迹验证这些途径内的部分分子改变。此外，我们发现HNSC患者PRAS 40高表达者比PRAS 40低表达者表达更多的CD 8 + T细胞和T辅助细胞，而Th 17细胞较少。PRAS 40在HNSCC细胞中发挥抑制作用的机制可能与PRAS 40分子通路的改变和肿瘤浸润的免疫细胞有关，PRAS 40可能成为HNSCC患者的预后预测因子和治疗靶点。
PRAS40 (Prolin-rich Akt substrate of 40 kDa) is a critical protein, which directly connects PI3K/Akt and mTORC1 pathway. It plays an indispensable role in the development of various diseases. However, the relationship between PRAS40 and head and neck squamous cell carcinoma (HNSCC) remains unclear. Here, our study indicated that high expression of PRAS40 mRNA is a favorable prognostic factor in HNSCC patients by analyzing 498 clinical and mRNA data. Moreover, we confirmed that CRISPR/Cas9 induced PRAS40-knockout would promote colony formation, cell migration, and invasion in several HNSCC cell lines. RNA-seq was employed to investigate the further possible mechanisms involving the above regulations by PRAS40 in HNSCC cells. The molecular landscape contributed by 253 differentially expressed mRNA after PRAS40-knockout was enriched in TGF-beta, PI3K-Akt, P53, mTOR, NF-κB signaling pathway. Partial molecular alternations within these pathways were validated by qPCR or Western blotting. Besides, we found that high expression of PRAS40 in HNSC patients would present more CD8+ T and T follicular helper cells, but less Th17 cells than the patients with low expression of PRAS40. The altered molecular pathways and tumor-infiltrating immune cells might associate with the mechanism of PRAS40 being a suppressor in HNSCC cells, which would provide a potential prognostic predictor and therapeutic target in HNSCC patients.
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