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Wwox deficiency in human cancers: Role in treatment resistance

Schrock, Morgan S
http://rave.ohiolink.edu/etdc/view?acc_num=osu1492793625915816

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
WWOX gene deletions occur in a variety of human cancer types, and reduced Wwox protein expression can be detected early during cancer development. In this study, loss of expression of the fragile site-encoded Wwox protein was found to contribute to radiation and cisplatin resistance of cells, responses that could be associated with cancer recurrence and poor outcome. We found that Wwox loss is followed by mild chromosome instability in genomes of mouse embryo fibroblast cells from Wwox-knockout mice. Human and mouse cells deficient for Wwox also exhibit significantly enhanced survival of ionizing radiation and bleomycin treatment, agents that induce double-strand breaks (DSBs). In a xenograft tumor model of irradiated cells, Wwox-deficient cancer cells exhibited significantly shorter tumor latencies, suggesting that Wwox-deficiency facilitates radiation resistance in vivo. In examining mechanisms underlying Wwox-dependent survival differences, we found that Wwox-deficient cells exhibit enhanced homology directed repair (HDR) and single strand annealing (SSA) repair pathways, but reduced nonhomologous end-joining (NHEJ) and Alternative-NHEJ (Alt-NHJE) repair, suggesting that Wwox contributes to DNA DSB repair pathway choice. We also demonstrated interaction of Wwox with Brca1, a driver of HDR, and show via immunofluorescent detection of repair proteins at ionizing radiation-induced DNA damage foci that Wwox expression suppresses DSB repair at the end-resection step of HDR. We propose a genome caretaker function for Wwox, in which Brca1–Wwox interaction supports NHEJ as the dominant DSB repair pathway in Wwox-sufficient cells. This Wwox effect has important consequences in human disease: in a cohort of brain, ovarian and non-small cell lung cancer patients treated with radiation or cisplatin, Wwox deficiency significantly correlated with shorter overall survival times, indicating that dysregulation of DSB repair by Wwox-deficiency worsens patient outcome via treatment resistance.
Kay Huebner (Advisor)
Paul Goodfellow (Committee Member)
Jeffrey Parvin (Committee Member)
K. John McLaughlin (Committee Chair)
97 p.
Biomedical Research; Molecular Biology
WWOX, FRA16D, chromosome fragile site, tumor suppressor, double strand break repair

Recommended Citations

Citations

  • Schrock, M. S. (2017). Wwox deficiency in human cancers: Role in treatment resistance [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492793625915816

    APA Style (7th edition)

  • Schrock, Morgan. Wwox deficiency in human cancers: Role in treatment resistance. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1492793625915816.

    MLA Style (8th edition)

  • Schrock, Morgan. "Wwox deficiency in human cancers: Role in treatment resistance." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492793625915816

    Chicago Manual of Style (17th edition)

osu1492793625915816
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This open access ETD is published by The Ohio State University and OhioLINK.