LHPP suppresses colorectal cancer cell migration and invasion in vitro and in vivo by inhibiting Smad3 phosphorylation in the TGF-β pathway.
LHPP suppresses colorectal cancer cell migration and invasion in vitro and in vivo by inhibiting Smad3 phosphorylation in the TGF-β pathway.
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DOI：
10.1038/s41420-021-00657-z
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发表时间：
2021-10-04
影响因子：
7
通讯作者：
Chang D
中科院分区：
文献类型：
--
作者：
Hou B;Li W;Xia P;Zhao F;Liu Z;Zeng Q;Wang S;Chang D
磷酸赖氨酸磷酸组氨酸无机焦磷酸磷酸酶（LHPP）在肿瘤发生中的作用最近已被证明在肝细胞癌（HCC），宫颈癌，胰腺癌，膀胱癌和甲状腺癌。先前的研究表明，LHPP抑制细胞增殖和生长，通过在体外和体内的磷脂酰肌醇3-激酶/AKT信号通路的失活。然而，LHPP作为一种肿瘤抑制因子在结直肠癌（CRC）转移中的作用及其可能机制尚不清楚。因此，Transwell实验和裸鼠移植瘤模型显示LHPP分别在体外和体内抑制CRC细胞的迁移和侵袭。LHPP上调后，总的和核上皮间质转化（EMT）相关蛋白的表达显著降低。应用人类基因表达阵列和IPA（InfluencityPathwayAnalysis）商业软件鉴定差异表达基因（DEG）和潜在的细胞信号通路。共观察到330个不同的基因，包括177个上调基因和153个下调基因。生物信息学分析表明，本研究中转化生长因子-β（TGF-β）信号通路高度失活。上调LHPP表达后，Smad 3磷酸化水平明显降低，而Smad 7表达明显增强。这些结果在TGF-β1刺激后再次得到证实。此外，应用Smad 3磷酸化的特异性抑制剂（SIS 3）来验证LHPP通过减弱TGF-β/Smad信号转导来抑制癌细胞的EMT。结果表明，LHPP过表达对TGF-β/Smad信号通路的抑制可被SIS 3消除。
The roles of phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) in tumorigenesis have been recently proven in hepatocellular carcinoma (HCC), cervical, pancreatic, bladder, and thyroid cancers. Previous research demonstrated that LHPP repressed cell proliferation and growth by inactivating the phosphatidylinositol 3-kinase/AKT signaling pathway in vitro and in vivo. However, the functions and potential mechanisms of LHPP as a tumor suppressor in colorectal cancer (CRC) metastasis are still unknown. Consequently, the Transwell assay and xenograft nude model showed that LHPP inhibited migration and invasion of CRC cells in vitro and in vivo, respectively. The expression of total and nuclear epithelial-to-mesenchymal transition (EMT)-related proteins were significantly reduced after LHPP upregulation. Human Gene Expression Array and IPA (Ingenuity Pathway Analysis) commercial software were applied to identify differentially expressed genes (DEGs) and potential cell signaling pathways. A total of 330 different genes were observed, including 177 upregulated genes and 153 downregulated genes. Bioinformatics analysis suggested that the transforming growth factor-β (TGF-β) signaling pathway was highly inactivated in this study. Then, Smad3 phosphorylation was apparently decreased, whereas Smad7 expression was markedly enhanced after upregulating LHPP expression. These results were proven once again after TGF-β1 stimulation. Furthermore, a specific inhibitor of Smad3 phosphorylation (SIS3) was applied to verify that LHPP repressed EMT of cancer cells by attenuating TGF-β/Smad signaling. The results suggested that suppression of the TGF-β/Smad signaling pathway by LHPP overexpression could be abolished by SIS3.
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