Exploring the Roles of Cellular Prion Protein in Lung Cancer Cell Migration and Invasion

• Main Authors: Shin-Chih Lin, 林信志
• Other Authors: Teh-Ying Chou
• Format: Others
• Language: en_US
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/2k8gqe

博士 === 國立陽明大學 === 生化暨分子生物研究所 === 106 === Metastasis is one of the major causes of treatment failure and mortality in cancer patients. We identified the PRNP gene, which encodes cellular prion protein (PrPc), from differential gene expression profiling between in situ and invasive lung adenocarcinoma tissues. High PrPc levels were found to be associated with lung cancer invasiveness. Similarly, PrPc level was higher in the more invasive CL1-5 lung adenocarcinoma cell line than in the less invasive CL1-1 cell line. Knockdown of PRNP in CL1-5 cells decreased lamellipodia formation, in vitro migration and invasion abilities, and in vivo experimental metastasis. Phosphorylation of JNKs was associated with PrPc expression. Inhibition of JNKs repressed the PrPc-induced up-regulation of lung cancer cell invasion and migration. Moreover, we identified a transcription factor, nuclear factor, interleukin 3 regulated (NFIL3), which can bind to the PRNP promoter and enhance its transcriptional activity. Accordingly, NFIL3 promotes lung cancer cell migration in a PrPc-dependent manner. In addition, high NFIL3 expression is associated with lung cancer cell invasiveness in lung cancer tissues. MicroRNAs are 21-23-nucleotide non-coding RNAs that regulate gene expression and known to be implicated in tumorigenesis. It is not yet determined if PrPc expression is regulated by microRNAs in lung adenocarcinoma cells. Bioinformatic prediction showed that 3’-UTR of PRNP mRNA may be targeted by six miRNAs. Among these miRNAs, the expression level of miR-193b-3p in CL1-1 cells is higher than that in CL1-5 cells. Overexpression of miR-193b-3p decreased the PRNP level in CL1-5 cells, while knocking down miR-193b-3p increased PRNP expression in CL1-1 cells. Furthermore, the 3’-UTR of PRNP mRNA was verified as a direct target of miR-193b-3p. We also demonstrated that miR-193b-3p downregulated migration and invasion of CL1-5 cells, and the level of miR-193b-3p was negatively correlated with PrPc expression in clinical specimens of lung cancer tissues. In summary, our findings suggest that PrPc plays a critical role in lung cancer invasiveness by mediating lung cancer cell migration via JNKs signaling, and the expression of PrPc is transcriptionally regulated by NFIL3 and post-transcriptionally regulated by miR-193b-3p.