Research Papers:

MiR-199a-3p decreases esophageal cancer cell proliferation by targeting p21 activated kinase 4

Pornima Phatak _, Whitney M. Burrows, Ingrid E. Chesnick, Mohan E. Tulapurkar, Jaladanki N. Rao, Douglas J. Turner, Anne W. Hamburger, Jian-Ying Wang and James M. Donahue

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Oncotarget. 2018; 9:28391-28407. https://doi.org/10.18632/oncotarget.25375

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Pornima Phatak1,2, Whitney M. Burrows1, Ingrid E. Chesnick2, Mohan E. Tulapurkar4, Jaladanki N. Rao1,2, Douglas J. Turner1,2, Anne W. Hamburger3, Jian-Ying Wang1,2,3 and James M. Donahue1,2,5

1Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA

2Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, USA

3Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA

4Division of Pulmonary and Critical Care, University of Maryland School of Medicine, Baltimore, MD 21201, USA

5Department of Surgery, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA

Correspondence to:

Pornima Phatak, email: [email protected]

Keywords: microRNA; miR-199a-3p; PAK4; esophageal cancer

Received: December 28, 2017    Accepted: April 25, 2018    Published: June 19, 2018


Although microRNA (miR) 199a-3p functions as a tumor suppressor in multiple malignancies, its expression and role in esophageal cancer have not been studied. Based on our previous observation that miR-199a-3p is markedly downregulated in esophageal cancer cell lines relative to esophageal epithelial cells, we examined the function of miR-199a-3p in these cells. MiR-199a-3p is predicted to bind with high affinity to the mRNA of p21 activated kinase 4 (PAK4). This kinase has been shown to be overexpressed in several malignancies and to modulate proliferation and motility. The current study is designed to determine whether miR-199a-3p regulates the expression of PAK4 in esophageal cancer cells and to understand the functional consequences of this interaction. Herein, we demonstrate reduced expression of miR-199a-3p in human esophageal cancer specimens and cell lines compared to esophageal epithelial cells, with associated increased expression of PAK4. Forced expression of miR-199a-3p decreases expression of PAK4 in esophageal cancer cell lines. Mechanistic studies reveal that miR-199a-3p binds to the 3’UTR of PAK4 mRNA. This interaction results in reduced levels of PAK4 mRNA due to decreased mRNA stability. Downregulation of PAK4 leads to decreased cyclin D1 (CD1) transcription and protein expression, resulting in markedly impaired cellular proliferation. When PAK4 expression is rescued, both CD1 transcription and protein return to baseline levels. Our results show that miR-199a-3p functions as a tumor suppressor in esophageal cancer cells through repression of PAK4. These findings suggest that both miR-199a-3p and PAK4 may be novel therapeutic targets in the treatment of esophageal cancer.

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