Original Research: Disorders of the Pleura |

miR-1 Induces Growth Arrest and Apoptosis in Malignant MesotheliomamicroRNA-1: A Tumor Suppressor in Mesothelioma

Yue Xu, PhD; Ming Zheng, PhD; Robert E. Merritt, MD; Joseph B. Shrager, MD; HeatherA. Wakelee, MD; Robert A. Kratzke, MD; Chuong D. Hoang, MD
Author and Funding Information

From the Division of Thoracic Surgery (Drs Xu, Merritt, Shrager, and Hoang), Department of Cardiothoracic Surgery, Department of Anesthesia (Dr Zheng), and the Division of Oncology (Dr Wakelee), Department of Medicine, Stanford University School of Medicine, Stanford, CA; the Veterans Affairs Palo Alto Healthcare System (Drs Shrager and Hoang), Palo Alto, CA; and the Division of Hematology, Oncology, and Transplant (Dr Kratzke), Department of Medicine, University of Minnesota Medical School, Minneapolis, MN.

Correspondence to: Chuong D. Hoang, MD, Stanford University School of Medicine, Falk Bldg, 300 Pasteur Dr, Stanford, CA 94305-5407; e-mail: cdhoang@stanford.edu

Funding/Support: Dr Hoang is supported by funds from the Mesothelioma Applied Research Foundation. The Kazan, McClain, Abrams, Fernandez, Lyons, Greenwood, Harley & Oberman Foundation, Inc provided support for the purchase of dedicated research equipment for this project.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

Chest. 2013;144(5):1632-1643. doi:10.1378/chest.12-2770
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Background:  We investigated microRNA expression profiles of malignant pleural mesothelioma (MPM) specimens to identify novel microRNA that are potentially involved in the oncogenic transformation of human pleural cells.

Methods:  microRNA microarray transcriptional profiling studies of 25 MPM primary tumors were performed. We used normal pleural tissue from an unmatched patient cohort as normal comparators. To confirm microarray data, we used real-time quantitative polymerase chain reaction. Representative cell lines H513 and H2052 were used in functional analyses of miR-1.

Results:  In addition to several novel MPM-associated microRNAs, we observed that the expression level of miR-1 was significantly lower in tumors as compared with normal pleural specimens. Subsequently, pre-miR of miR-1 was introduced into MPM cell lines to overexpress this microRNA. Phenotypic changes of these altered cells were assayed. The cellular proliferation rate was significantly inhibited after overexpression of miR-1. Early and late apoptosis was increased markedly in miR-1-transfected cell lines. Taken together, these data suggested that overexpression of miR-1 induced apoptosis in these MPM cell lines, acting as a tumor suppressor. We confirmed our observations by assessing in the transduced MPM cells cell cycle-related, proapoptotic, and antiapoptotic genes, which all showed coordinated, significant changes characteristic of the apoptotic phenotype.

Conclusions:  Further investigation and validation of our microRNA database of MPM may elucidate previously unrecognized molecular pathways and/or mechanisms by identifying novel microRNAs that are involved in malignant transformation. Our study has now found miR-1 to be one of these MPM-associated microRNAs, with potential pathogenic and therapeutic significance.

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