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Grainyhead-like 2 (GRHL2) regulates epithelial plasticity in pancreatic cancer progression.

ABSTRACT: The epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) contribute to cancer metastasis of pancreatic ductal adenocarcinoma (PDAC). We explored the role of grainyhead-like 2 (GRHL2), a suppressor of EMT, in the progression of PDAC. Expressions of GRHL2 were assessed using surgically resected PDAC tissues by immunohistochemistry analysis, and in vitro using human and mouse PDAC cells. Effects on epithelial plasticity and stemness of GRHL2 were examined in vitro using liver metastatic PDAC cells (CFPAC-1) with GRHL2 knockdown by specific siRNAs. GRHL2 has a significantly positive correlation with E-cadherin and CD133 in 155 resected human primary PDAC tissues. GRHL2 is highly expressed in liver metastatic cells than in primary invasive cells of both human and mouse PDAC, accompanied by a positive correlation with E-cadherin expression. GRHL2 knockdown CFPAC-1 cells demonstrated morphological changes into mesenchymal appearances and reduced proliferation through EMT. Notably, knockdown studies followed by flow cytometry analysis for a subpopulation of CD133+ showed that GRHL2 facilitates CFPAC-1 cells to maintain stem-like characters including self-renewal capacity and anoikis resistance. GRHL2 regulates epithelial plasticity along with stemness in PDAC, both of which are crucial for metastasis, implicating the possibility of GRHL2 as a therapeutic target for PDAC liver metastasis.

SUBMITTER: Nishino H

PROVIDER: S-EPMC5673909 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Grainyhead-like 2 (GRHL2) regulates epithelial plasticity in pancreatic cancer progression.

Nishino Hitoe H Takano Shigetsugu S Yoshitomi Hideyuki H Suzuki Kensuke K Kagawa Shingo S Shimazaki Reiri R Shimizu Hiroaki H Furukawa Katsunori K Miyazaki Masaru M Ohtsuka Masayuki M

Cancer medicine 20170929 11

The epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) contribute to cancer metastasis of pancreatic ductal adenocarcinoma (PDAC). We explored the role of grainyhead-like 2 (GRHL2), a suppressor of EMT, in the progression of PDAC. Expressions of GRHL2 were assessed using surgically resected PDAC tissues by immunohistochemistry analysis, and in vitro using human and mouse PDAC cells. Effects on epithelial plasticity and stemness of GRHL2 were examined in vitro usi ...[more]

PMID: 28960866

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Project description:ObjectiveThis study attempts to investigate whether hsa_circRNA_001859 (circ_001859) could regulate the proliferation and invasion of pancreatic cancer through the miR-21-5p/SLC38A2 pathway.MethodsGSE79634 microarray was analyzed with R package. The expression of circ_001859 in pancreatic cancer tissues and cells was verified by qRT-PCR. After the overexpression of circ_001859, cell proliferation, cell migration and invasion were verified by colony formation and transwell assay. The targeting relationship between miR-21-5p and circ_001859 was predicted by TargetScan and was verified by dual luciferase reporter assay, RNA pull down and qRT-PCR. The effect of miR-21-5p on cell proliferation, migration and invasion were investigated by colony formation and transwell assay respectively. Similarly, the targeting relationship between miR-21-5p and SLC38A2 was predicted by TargetScan and was verified by dual luciferase reporter assay, western blot and qRT-PCR. The effect of SLC38A2 on cell proliferation was investigated by colony formation.ResultsCirc_001859 was lowly expressed in pancreatic cancer tissues and cells. In vitro assays showed that overexpression of circ_001859 could inhibit the proliferation, migration and invasion of pancreatic cancer. In addition, this effect was also confirmed in xenograft transplantation model. Circ_001859 could be bind to miR-21-5p and sponge its expression in pancreatic cancer cells. Overexpression of miR-21-5p enhanced the proliferation, migration and invasion ability of pancreatic cancer cells, while the inhibition of miR-21-5p expression suppressed these abilities. Moreover, miR-21-5p directly targeted at SLC38A2 and inhibited SLC38A2 expression levels while circ_001859 up-regulated SLC38A2 levels. SLC38A2 expression knockdown enhanced cell proliferation but SLC38A2 overexpression resulted in decreased proliferation, and effects of SLC38A2 could be rescued by miR-21-5p and circ_001859. In addition, both QRT-PCR and immunofluorescence confirmed that circ_001859 could regulate tumor epithelial-mesenchymal transition (EMT) through the miR-21-5p/SLC38A2 pathway.ConclusionsThis study suggests that circ_001859 may inhibit the proliferation, invasion and EMT of pancreatic cancer through the miR-21-5p/SLC38A2 pathway.

Dataset Information

Grainyhead-like 2 (GRHL2) regulates epithelial plasticity in pancreatic cancer progression.

Publications

Grainyhead-like 2 (GRHL2) regulates epithelial plasticity in pancreatic cancer progression.

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