Abstract
Tumor metastasis is the major cause of poor prognosis and mortality in colorectal cancer (CRC). However, early diagnosis of highly metastatic CRC is currently difficult. In the present study, we screened for a novel biomarker, GDNF family receptor alpha 1 (GFRA1) based on the expression and methylation data in CRC patients from The Cancer Genome Altlas (TCGA), followed by further analysis of the correlation between the GFRA1 expression, methylation, and prognosis of patients. Our results show DNA hypomethylation-mediated upregulation of GFRA1 in invasive CRC, and it was found to be correlated with poor prognosis of CRC patients. Furthermore, GFRA1 methylation-modified sequences were found to have potential as methylation diagnostic markers of highly metastatic CRC. The targeted demethylation of GFRA1 by dCas9-TET1CD and gRNA promoted CRC metastasis in vivo and in vitro. Mechanistically, demethylation of GFRA1 induces epithelial-mesenchymal transition (EMT) by promoting AKT phosphorylation and increasing c-Jun expression in CRC cells. Collectively, our findings indicate that GFRA1 hypomethylation can promote CRC invasion via inducing EMT, and thus, GFRA1 methylation can be used as a biomarker for the early diagnosis of highly metastasis CRC.
Highlights
Colorectal cancer (CRC) ranks third in terms of incidence and second in terms of mortality caused by cancer; more than 1.8 million new CRC cases were diagnosed and 881,000 deaths occurred from CRC in 2018 [1]
We screened a novel biomarker gene, GDNF family receptor alpha 1 (GFRA1), which associated with the invasion and poor prognosis of CRC
Our results demonstrate the promoting effect of GFRA1 demethylation on CRC invasion and GFRA1 methylation may be a potential prognostic marker for predicting metastasis of CRC
Summary
Colorectal cancer (CRC) ranks third in terms of incidence and second in terms of mortality caused by cancer; more than 1.8 million new CRC cases were diagnosed and 881,000 deaths occurred from CRC in 2018 [1]. 25% of the CRC patients present metastases at the initial diagnosis stage and almost 50% of them developed metastases, contributing to the high mortality rates associated with CRC [2]. Cancer metastases cannot be predicted or identified by the histopathologic or imaging examinations of colonoscopy, there is still lacking effective screening methods for CRC with high metastatic potential [5, 6]. The mechanism of invasion of CRC had been investigated previously, a specific and sensitive tumor invasion biomarker capable of predicting CRC metastasis and prognosis in the clinic is lacking [10]. Developing a novel biomarker for early diagnosis of high metastatic CRC is an effective method to improve the treatment effects and survival of CRC patients
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