Knockdown of Ezrin by RNA Interference Reverses Malignant Behavior of Human Pancreatic Cancer Cells in Vitro

Zhong, Zhiqiang; Song, Man; He, Ying; Cheng, Shi Yuan; Yuan, Hong-Wen

doi:10.7314/apjcp.2012.13.8.3781

Cited by 12 publications

(5 citation statements)

References 55 publications

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“…Ezrin regulates cell migration in several malignancies (18,19), and we found that the loss of Ezrin expression significantly inhibited the migration of L3.6pl cells by >99% ( Fig. 2D) consistent with other reports (22,23). We also carried out gain-of-function studies and overexpressed the constitutively active Ezrin-mutant T567D in L3.6pl cells and observed significantly increased colony formation (1.9fold) and cell migration (2.2-fold) compared with cells transduced with an empty vector ( Fig.…”

Section: Ezrin Regulates Csc Functionssupporting

confidence: 92%

“…Ezrin expression is associated with decreased OS and the development of distant metastases in osteosarcoma, soft-tissue sarcomas, as well as colorectal, breast, and hepatocellular carcinomas (15)(16)(17)(18)(19). In PDAC, Ezrin activation is associated with shorter OS (20,21) and impacts the growth and motility of PDAC cell lines (22,23). Despite these findings, the role of Ezrin in PDAC CSC biology is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Ezrin Promotes Stem Cell Properties in Pancreatic Ductal Adenocarcinoma

Penchev

Chang

Begum

et al. 2019

Molecular Cancer Research

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Self-renewal maintains the long-term clonogenic growth that is required for cancer relapse and progression, but the cellular processes regulating this property are not fully understood. In many diseases, self-renewal is enhanced in cancer stem cells (CSC), and in pancreatic ductal adenocarcinoma (PDAC), CSCs are characterized by the surface expression of CD44. In addition to cell adhesion, CD44 impacts cell shape and morphology by modulating the actin cytoskeleton via Ezrin, a member of the Ezrin/Radixin/ Moesin (ERM) family of linker proteins. We examined the expression of Ezrin in PDAC cells and found higher levels of both total and activated Ezrin in CSCs compared with bulk tumor cells. We also found that the knockdown of Ezrin in PDAC cells decreased clonogenic growth, self-renewal, cell migration, and CSC frequency in vitro as well as tumor initiation in vivo. These effects were associated with cytoskeletal changes that are similar to those occurring during the differentiation of normal stem cells, and the inhibition of actin remodeling reversed the impact of Ezrin loss. Finally, targeting Ezrin using a small-molecule inhibitor limited the self-renewal of clinically derived low-passage PDAC xenografts. Our findings demonstrate that Ezrin modulates CSCs properties and may represent a novel target for the treatment of PDAC. Implications: Our findings demonstrate that Ezrin modulates CSCs' properties and may represent a novel target for the treatment of PDAC.

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Section: Ezrin Regulates Csc Functionssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Ezrin Promotes Stem Cell Properties in Pancreatic Ductal Adenocarcinoma

Penchev

Chang

Begum

et al. 2019

Molecular Cancer Research

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“…Cell cycle progression promotes cell proliferation, which in turn leads to clonal expansion of cells during tumor development. 40 Cyclin D1 is an essential protein in the G 1 -phase of tumor cells and is highly expressed in actively proliferating non-small cell lung cancer cells. 41 Cyclin B1, a crucial cell cycle checkpoint protein, promotes mitosis, and the overexpression of cyclin B1 may contribute to uncontrolled cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

<p>Leucine Zipper-EF-Hand Containing Transmembrane Protein 1 Is a Potential Prognostic Biomarker and Promotes Cell Progression in Prostate Cancer</p>

Piao¹,

Li²,

Feng³

et al. 2020

CMAR

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The leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) is a mitochondrial protein that has been associated with the occurrence and development of malignant tumors. Previous studies have shown that LETM1 expression is increased in several types of human cancer and is associated with a poor clinical outcome. However, the role of LETM1 in prostate cancer (PCa) has not yet been determined. In this study, we investigated the clinicopathological significance of LETM1 expression and its role in PCa progression. Methods: We assessed the expression of LETM1 and genes related to cancer stemness, epithelial-mesenchymal transition (EMT), cell cycle, and PI3K/Akt signaling in 133 paraffinembedded PCa tissue samples and cancer cells by using immunohistochemistry, immunofluorescence, and Western blotting. Results: LETM1 expression was significantly increased in PCa, and it was positively correlated with Gleason score, pathologic tumor (pT) stage, clinical stage, and high microvessel density. Survival analysis showed that patients with PCa with a high level of LETM1 expression exhibited a low overall survival. Cox regression analysis indicated that LETM1 is an independent poor prognostic PCa factor. Additionally, the expression of LETM1 was correlated with cancer cell stemness-associated genes, EMT-related genes, cell cycle regulatory genes, and PI3K/Akt signaling gene expression in PCa. Furthermore, knocking down LETM1 expression down-regulated the expression of stemness-related proteins, while inhibiting tumor spheroid formation, EMT-like changes, cell proliferation, migration, and invasion in PCa cells. Importantly, the PI3K inhibitor LY294002 strongly inhibited the expression of LETM1, pPI3K-p85, and pAkt (Thr308, Ser473) in PCa cells. Conclusion: These results indicate that LETM1 expression is associated with cancer cell stemness, promotes EMT-like changes and cell proliferation and is a potential prognostic biomarker for PCa.

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“…Cell proliferation as a consequence of cell cycle progression leads to clonal expansion of cells during tumor promotion [ 35 ]. Zhang et al indicated that decreasing Ezrin expression significantly inhibited cell proliferation, mobility, and invasiveness in hepatocellular carcinoma cell lines, and that Ezrin enhanced the growth of cancer cells by supporting cell division and cell cycle progression from G0/G1 to S and G2/M phases [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Ezrin contributes to cervical cancer progression through induction of epithelial-mesenchymal transition

Kong

Piao

et al. 2016

Oncotarget

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Cervical cancer is the third most common cancer in females worldwide. The treatment options for advanced cervical cancer are limited, leading to high mortality. Ezrin is a membrane-cytoskeleton-binding protein recently reported to act as a tumor promoter, and we previously indicated that the aberrant localization and overexpression of Ezrin could be an independent effective biomarker for prognostic evaluation of cervical cancers. In this study, we identified Ezrin as a regulator of epithelial-mesenchymal transition (EMT) and metastasis in cervical cancer. Ezrin knock-down inhibited anchorage-independent growth, cell migration, and invasion of cervical cancer cell lines in vitro and in vivo. EMT was inhibited in Ezrin-depleted cells, with up-regulation of E-cadherin and Cytokeratin-18 (CK-18) and down-regulation of mesenchymal markers. Ezrin knock-down also induced Akt phosphorylation. These results implicate Ezrin as an EMT regulator and tumor promoter in cervical cancer, and down-regulation of Ezrin suppressed cervical cancer progression, possibly via the phosphoinositide 3-kinase/Akt pathway. Furthermore, the expression pattern of Ezrin protein was closely related with the lymphovascular invasion status of cervical cancer by immunohistochemistry, and the survival analysis revealed that the cervical cancer patients with the perinuclear Ezrin expression pattern had longer survival time than those with the cytoplasmic Ezrin expression pattern. Ezrin thus represents a promising target for the development of novel and effective strategies aimed at preventing the progression of cervical cancer.

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Knockdown of Ezrin by RNA Interference Reverses Malignant Behavior of Human Pancreatic Cancer Cells in Vitro

Cited by 12 publications

References 55 publications

Ezrin Promotes Stem Cell Properties in Pancreatic Ductal Adenocarcinoma

Ezrin Promotes Stem Cell Properties in Pancreatic Ductal Adenocarcinoma

<p>Leucine Zipper-EF-Hand Containing Transmembrane Protein 1 Is a Potential Prognostic Biomarker and Promotes Cell Progression in Prostate Cancer</p>

Ezrin contributes to cervical cancer progression through induction of epithelial-mesenchymal transition

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