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

• Published in: Cancer medicine (Malden, MA) Vol. 6; no. 11; pp. 2686 - 2696
• Main Authors: Nishino, Hitoe, Takano, Shigetsugu, Yoshitomi, Hideyuki, Suzuki, Kensuke, Kagawa, Shingo, Shimazaki, Reiri, Shimizu, Hiroaki, Furukawa, Katsunori, Miyazaki, Masaru, Ohtsuka, Masayuki
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.11.2017; John Wiley and Sons Inc
• Subjects: AC133 Antigen - metabolism; Aged; Animals; Anoikis; Antimetabolites, Antineoplastic - pharmacology; Cadherins - metabolism; Cancer Biology; Cancer stem cell; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - secondary; Cell Line, Tumor; Cell Plasticity - genetics; Cell Proliferation - genetics; Cell self-renewal; Cell Survival; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Drug Resistance, Neoplasm - genetics; Epithelial Cells - physiology; epithelial plasticity; Epithelial-Mesenchymal Transition - genetics; Female; Gene Expression; Gene Silencing; GRHL2; Humans; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Male; mesenchymal‐epithelial transition (MET); Metastasis; Mice; Middle Aged; Original Research; Pancreatic cancer; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Phenotype; RNA, Messenger - metabolism; siRNA; Spheroids, Cellular; Transcription Factors - genetics; Transcription Factors - metabolism; Vimentin - metabolism; Cancer stem cell; pancreatic cancer; epithelial plasticity; GRHL2; mesenchymal-epithelial transition (MET)
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.1212

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. 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. 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.