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Datar Ila_Dissertation Aug. 2015.pdf (2.66 MB)

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Positive and negative regulators of tumorigenesis and/or metastasis

Datar, Ila
http://rave.ohiolink.edu/etdc/view?acc_num=mco1438962728

Abstract Details

2015, Doctor of Philosophy (PhD), University of Toledo, Biomedical Sciences (Cancer Biology).
The Raf-MEK-ERK pathway is a central pathway in regulating key physiological processes including cell growth, survival, migration and apoptosis. Dysregulation of this pathway has been implicated in several malignancies including breast cancer and melanoma. This study highlights the roles of regulators and effectors of this pathway in breast cancer suppression and melanoma progression respectively. Specifically, B-Raf(V600E) is the most common driver mutation in melanoma and its causal role in melanomagenesis is well documented. Here, we have shown that miR-10b is an effector of B-Raf(V600E)-driven melanomagenesis. We observed a positive correlation between the expression of miR-10b and B-Raf(V600E) mutation status in melanoma cell lines. In line with our in vitro cell-line based studies, we also observed a strong positive correlation in the expression of B-Raf(V600E) and miR-10b in human melanoma tissue samples. Using a combination of loss- and gain-of-function approaches we established that B-Raf(V600E) plays a causal role in the induction of miR-10b expression in melanoma cells. We also show that oncogenic B-Raf increases melanoma cell invasion, anchorage independence and proliferation by inducing the expression of miR-10b in vitro. Thus, we provide evidence that miR-10b is a downstream regulator of B-Raf(V600E)-induced melanomagenesis. miR-10b, is thus an effector of the Raf-MEK-ERK signaling module and plays a role in melanoma progression through this pathway. Likewise, Raf Kinase Inhibitor Protein (RKIP) independent off its role in modulating Raf kinase activity (Raf-1 and B-Raf), is implicated as a broad metastasis suppressor. It has been reported to inhibit breast and prostate cancer metastasis in orthotopic implantation and autochthonous mouse models. Furthermore the expression of RKIP is reduced in metastatic breast cancer and is an indicator of poor prognosis. The mechanism of RKIP’s inhibitory action on breast cancer metastasis remains poorly understood. Here, we establish a novel pathway for RKIP regulation of metastasis inhibition through the negative regulation of RANTES/CCL5 thereby limiting tumor macrophage infiltration and inhibition of angiogenesis. Using a combination of loss- and gain-of-function approaches, we show that RKIP hinders breast cancer cell invasion by inhibiting expression of the CC chemokine CCL5 in vitro. We also show that the expression levels of RKIP and CCL5 are inversely correlated among clinical human breast cancer samples. Using a mouse allograft breast cancer transplantation model, we highlight that ectopic expression of RKIP significantly decreases tumor vasculature, macrophage infiltration and lung metastases. Mechanistically, we demonstrate that the inhibition of CCL5 expression is the cause of the observed effects resulting from RKIP expression. Taken together, our results underscore the significance of RKIP as an important negative regulator of the tumor microenvironment.
Kam Yeung (Committee Co-Chair)
Ivana De la Serna (Committee Co-Chair)
Deborah Chadee (Committee Member)
Kathryn Eisenmann (Committee Member)
William Maltese (Committee Member)
Robert Trumbly (Committee Member)
138 p.
Biochemistry; Biomedical Research
Cancer, invasion, metastasis, metastasis suppressor, miRNA,

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Citations

  • Datar, I. (2015). Positive and negative regulators of tumorigenesis and/or metastasis [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1438962728

    APA Style (7th edition)

  • Datar, Ila. Positive and negative regulators of tumorigenesis and/or metastasis. 2015. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1438962728.

    MLA Style (8th edition)

  • Datar, Ila. "Positive and negative regulators of tumorigenesis and/or metastasis." Doctoral dissertation, University of Toledo, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=mco1438962728

    Chicago Manual of Style (17th edition)

mco1438962728
473
© 2015, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.