Oncotarget

Research Papers: Chromosome:

Replication-incompetent gammaretroviral and lentiviral vector-based insertional mutagenesis screens identify prostate cancer progression genes

Victor M. Bii, Casey P. Collins, Jonah D. Hocum and Grant D. Trobridge _

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Oncotarget. 2018; 9:15451-15463. https://doi.org/10.18632/oncotarget.24503

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Abstract

Victor M. Bii1, Casey P. Collins1, Jonah D. Hocum1 and Grant D. Trobridge1,2

1College of Pharmacy, Washington State University, Spokane 99210, WA, USA

2School of Molecular Biosciences, Washington State University, Pullman 99164, WA, USA

Correspondence to:

Grant D. Trobridge, email: grant.trobridge@wsu.edu

Keywords: prostate cancer (PC); insertional mutagenesis screen; gammaretroviral (γRV) vector; lentiviral (LV) vector; driver genes; Chromosome

Received: November 23, 2016     Accepted: February 10, 2018     Epub: February 15, 2018     Published: March 20, 2018

ABSTRACT

Replication-incompetent gammaretroviral (γRV) and lentiviral (LV) vectors have both been used in insertional mutagenesis screens to identify cancer drivers. In this approach the vectors stably integrate in the host cell genome and induce cancers by dysregulating nearby genes. The cells that contain a retroviral vector provirus in or near a proto-oncogene or tumor suppressor are preferentially enriched in a tumor. γRV and LV vectors have different integration profiles and genotoxic potential, making them potentially complementary tools for insertional mutagenesis screens. We performed screens using both γRV and LV vectors to identify driver genes that mediate progression of androgen-independent prostate cancer (AIPC) using a xenotransplant mouse model. Vector transduced LNCaP cells were injected orthotopically into the prostate gland of immunodeficient mice. Mice that developed tumors were castrated to create an androgen-deficient environment and metastatic tumors that developed were analyzed. A high-throughput modified genomic sequencing PCR (MGS-PCR) approach identified the positions of vector integrations in these metastatic tumors. OR2A14, FER1L6, TAOK3, MAN1A2, MBNL2, SERBP1, PLEKHA2, SPTAN1, ADAMTS1, SLC30A5, ABCC1, SLC7A1 and SLC25A24 were identified as candidate prostate cancer (PC) progression genes. TAOK3 and ABCC1 expression in PC patients predicted the risk of recurrence after androgen deprivation therapy. Our data shows that γRV and LV vectors are complementary approaches to identify cancer driver genes which may be promising potential biomarkers and therapeutic targets.


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