Abstract
High levels of the imprinted gene pleckstrin homology like domain family A member 2 (PHLDA2) correlate with tumor progression in several malignancies. Here, we investigated the effects of PHDLDA2 expression in CRC through assays of cellular proliferation, invasion, migration, and apoptosis. We also screened for possible mechanisms of action. Our results show that PHLDA2 was upregulated in CRC tissues. Knockdown of PHLDA2 inhibited cellular proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) in vitro. Knockout of PHLDA2 promoted cellular apoptosis, in part by activating autophagy. PHLDA2 knockout also inhibited tumorigenesis and expression of KI67 protein in vivo. The effects of PHLDA2 on autophagy and EMT were mediated in part via the PI3K/AKT signaling pathway. Taken together, these results suggest that downregulation of PHLDA2 inhibits tumor growth and PI3K, thereby promoting autophagy and inhibiting EMT, in part through the PI3K/AKT/mTOR and PI3K/AKT/GSK-3β signaling pathways.
Highlights
Colorectal cancer (CRC) is the most common malignancy of the human digestive system
Using western blot (WB) and PCR, we found that protein and mRNA levels of PHLDA2 were higher in HCT116 and SW480 cells than in the six other CRC cell lines (Figure 1E–1G); these cell lines were used for subsequent experiments in our study
These results indicate that PHLDA2-induced autophagy and epithelial-mesenchymal transition (EMT) partially depend on the PI3K/AKT/mTOR and PI3K/AKT/GSK3β pathways, respectively
Summary
Colorectal cancer (CRC) is the most common malignancy of the human digestive system. As a cause of cancer-related death, CRC is ranked second only to lung cancer [1]. The discovery of new biomarkers would benefit CRC patients [3]. Pleckstrin homology like domain family A member 2 (PHLDA2) is a maternal imprinting gene. The loss of this form of imprinting can result in gene overexpression [4], with tissue-specific differential imprinted gene variation due to mono-allelic expression [5]. PHLDA2 inhibits tumorigenesis and metastasis in osteosarcoma patients via the PI3K/ AKT/mTOR pathway [6]. PHLDA2 knockdown restrains invasion and proliferation of breast cancer [7]
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