Long non-coding RNA LINC01133 silencing exerts antioncogenic effect in pancreatic cancer through the methylation of DKK1 promoter and the activation of Wnt signaling pathway

Abstract

Recent studies have acknowledged the critical roles played by long non-coding RNAs (lncRNAs) in the development and progression of pancreatic cancer. Therefore, the present study aimed to elucidate the mechanism underlying on how LINC01133 regulates the Wnt signaling pathway in pancreatic cancer. A microarray-based gene expression analysis was performed to identify the differentially expressed lncRNAs in pancreatic cancer. In addition, ectopic expression assays, knockdown experiments and gene reporter assays were conducted to clarify the role of LINC01133 in pancreatic cancer and to understand the interaction between LINC01133 and the methylation of DKK1 promoter. The expression of LINC01133, DKK1, and other genes related to the Wnt signaling pathway was also measured. EDU staining, scratch test and Transwell assay were employed to measure the proliferation, migration and invasion of pancreatic cancer cells, respectively. GSE32676 and GSE16515 revealed that LINC01133 was upregulated in pancreatic cancer, which was also associated with increased DKK1 methylation and higher expression of genes related to the Wnt signaling pathway, although the expression of DKK1 decreased in pancreatic cancer. In addition, LINC01133 bound to the promoter region of DKK1, resulting in the trimethylation of H3K27 and decreased DKK1 expression, while the expression of Wnt-5a, MMP-7, and β-catenin increased upon LINC01133 binding. Finally, over-expressed LINC01133 enhanced the growth, proliferation, migration, metastasis, and invasion of pancreatic cancer cells. The present study clarified the distinct effect of LINC01133 on pancreatic cancer. In summary, by inducing the methylation of DKK1 promoter, LINC01133 silencing suppresses the development of pancreatic cancer cells through the Wnt signaling pathway. ARTICLE HISTORY

Wnt/β-Catenin Signaling: The Culprit in Pancreatic Carcinogenesis and Therapeutic Resistance

“…In contrast, miR-774 targets the negative regulators of the Wnt/β-catenin axis, such as SFRP1, GSK3β, and TLE3, promoting the stem cell phenotype of pancreatic cancer cells in vitro [57]. Increased expression of long noncoding RNA LINC01133 is observed in pancreatic cancer, where it decreases the expression of DKK1 and increases the expression of Wnt5a, MMP-7, and β-catenin by binding to their promoters [58]. Similarly, the expression of long noncoding RNA H19, which is shown to activate the Wnt pathway, is increased in pancreatic cancer.…”

A Role for the WNT Co-Receptor LRP6 in Pathogenesis and Therapy of Epithelial Cancers

“…On the other hand, LRP6 activity is also controlled by LINC01133, a long non-coding RNA upregulated in pancreatic cancers. Indeed, LINC01133 decreases DKK1 expression by inducing DKK1 promoter methylation (Figure 3D) [117]. Therefore, LINCO1133 overexpression in pancreatic cancer cell lines increases β-catenin transcriptional activity and promotes proliferative, tumoral and invasive properties.…”

Dipeptidyl peptidase like 6 promoter methylation is a potential prognostic biomarker for pancreatic ductal adenocarcinoma

“…Hypermethylation in gene promoters is a general epigenetic modification in cancer formation, especially for inhibition of tumor-suppressive genes such as PCDH10 [17], DKK1 [18], and KLF4 [19]. For example, PCDH10 is down-regulated in PC cells and overexpression of PCDH10 inhibits proliferation and migration of cells.…”