Abstract
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.
Highlights
Colorectal cancer (CRC) is one of the most malignant gastrointestinal cancers worldwide
LHPP gene definitely inhibits CRC cell growth To verify previous conclusions, LHPP-overexpressing LVs were transferred to Caco2 and short hair-cap LVs to Sw480, respectively
The results showed that LHPP overexpression apparently caused a reduction of p-Smad3 protein and a significant increase of Smad7 which was a negative regulator in the transforming growth factor-β (TGF-β)/Smad signaling pathway (Fig. 3d–i, all P value
Summary
Colorectal cancer (CRC) is one of the most malignant gastrointestinal cancers worldwide. The prognosis of patients with CRC has improved due to recent developments in colonoscopy, a 5-year relative survival still remains less than 50% in lowincome countries [1, 2]. The situation in China has become more serious. The estimated new CRC cases and deaths of colorectal cancer in 2015 were 376,300 and 191,000, respectively [3]. The number of patients with CRC < 45 years old was surprisingly high (25,300) [3]. It is urgent to uncover the pathological mechanism of colorectal cancer to develop new therapy
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