Title : The phosphoinositide hydrolase phospholipase C delta1 inhibits epithelial-mesenchymal transition and is silenced in colorectal cancer
Abstract:
In this study, we found that the phospholipase C delta1 (PLCD1) protein expression is reduced in colorectal tumor tissues compared with paired surgical margin tissues. PLCD1-promoted CpG methylation was detected in 29/64 (45%) primary colorectal tumors, but not in nontumor tissues. The PLCD1 RNA expression was also reduced in three out of six cell lines, due to PLCD1 methylation. The ectopic expression of PLCD1 resulted in inhibited proliferation and attenuated migration of colorectal tumor cells, yet promoted colorectal tumor cell apoptosis in vitro. We also observed that PLCD1 suppressed proliferation and promoted apoptosis in vivo. In addition, PLCD1 induced G1/S phase cell cycle arrest. Furthermore, we found that PLCD1 led to the downregulation of several factors downstream of β-catenin, including c-Myc and cyclin D1, which are generally known to be promoters of tumorigenesis. This downregulation was caused by an upregulation of E-cadherin in colorectal tumor cells. Our findings provide insights into the role of PLCD1 as a tumor suppressor gene in colorectal cancer (CRC), and demonstrate that it plays significant roles in proliferation, migration, invasion, cell cycle progression, and epithelial-mesenchymal transition. On the basis of these results, tumor-specific methylation of PLCD1 could be used as a novel biomarker for early detection and prognostic prediction in CRC.
Audience Take Away Notes:
- Colorectal cancer (CRC), one of the top three most common cancers, has a high incidence of mortality. It is of great significance to find an effective biomarker for diagnosis of CRC. Previous studies indicate that abnormal promoter methylation is an excellent biomarker for the early diagnosis of multiple malignancies, including CRC. Recent reports indicate that the main mechanism for tumor suppressor gene (TSG) silencing through epigenetic disruption, such as prompter methylation, during cancer process results in the inhibition of TSG expression. Therefore, identification of other silencing TSGs by epigenetic modifications is urgently needed
- This study demonstrates that PLCD1 is down-regulated in colorectal cells by hypermethylation at the first time. Restoration of PLCD1 expression in CRC cells results in strong cytotoxicity due to the inhibition of proliferation and the induction of apoptosis
- We also found that PLCD1 suppressed cell proliferation, metastasis, and tumorigenicity through inhibiting the Wnt and EMT signaling pathway in CRC. We speculate that the activation of PLCD1, which ultimately inhibits cancer malignancy, could be used as a novel biomarker for CRC prognosis
