Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


18380.pdf (4.9 MB)

ETD Abstract Container

Abstract Header

RhoA as a Potential Target in Lung Cancer

Zandvakili, Inuk
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1445342196

Abstract Details

2015, PhD, University of Cincinnati, Medicine: Molecular and Developmental Biology.
Many cancers are driven by oncogenic K-Ras, yet K-Ras has remained largely undruggable. In this dissertation we explore inhibiting K-Ras signaling by targeting downstream signaling pathways, namely the RhoA and RhoC GTPase pathways. Numerous cellular studies have indicated that RhoA signaling is required for oncogenic Ras-induced transformation. To date very limited data exist to genetically attribute RhoA function to Ras-mediated tumorigenesis in mammalian models. In order to assess whether RhoA is required for K-Ras-induced lung cancer initiation, we utilized the K-RasG12D Lox-Stop-Lox murine lung cancer model in combination with the conditional RhoAflox/flox and RhoC-/- knockout mouse models. We found that deletion of RhoA, RhoC or both did not adversely affect normal lung development. Moreover, we found that deletion of either RhoA or RhoC alone did not suppress K-RasG12D induced lung adenoma initiation. Rather, deletion of RhoA alone increased lung adenoma formation, whereas dual deletion of RhoA and RhoC together significantly reduced K-RasG12D induced adenoma formation. Deletion of RhoA appears to induce a compensatory mechanism that exacerbates adenoma formation. The compensatory mechanism is at least partly mediated by RhoC. These results are in contrast to RhoA knockdown experiments we performed in human lung cancer cell lines, which show dramatic inhibition of malignant phenotypes with RhoA loss. Taken together, this dissertation work suggests that targeting of RhoA alone may allow for compensation and a paradoxical exacerbation of neoplasia, while simultaneous targeting of both RhoA and RhoC is more likely to inhibit oncogenic K-Ras driven lung cancers.
Yi Zheng, Ph.D. (Committee Chair)
Vladimir Kalinichenko, M.D. Ph.D. (Committee Member)
Timothy Lecras, Ph.D. (Committee Member)
John Morris, M.D. (Committee Member)
James Mulloy, Ph.D. (Committee Member)
Kathryn Wikenheiser-Brokamp, M.D. Ph.D. (Committee Member)
119 p.
Surgery
RhoA; KRas; Rho GTPases; Lung Cancer; RhoC; Lung Adenocarcinoma

Recommended Citations

Citations

  • Zandvakili, I. (2015). RhoA as a Potential Target in Lung Cancer [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1445342196

    APA Style (7th edition)

  • Zandvakili, Inuk. RhoA as a Potential Target in Lung Cancer. 2015. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1445342196.

    MLA Style (8th edition)

  • Zandvakili, Inuk. "RhoA as a Potential Target in Lung Cancer." Doctoral dissertation, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1445342196

    Chicago Manual of Style (17th edition)

ucin1445342196
452
© 2015, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.