wang, yifei
(2020)
MYC-binding lncRNA EPIC1 promotes AKT-mTORC1 signaling and Rapamycin resistance in breast and ovarian cancer.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
AKT-mTORC1(mammalian target of rapamycin complex 1) signaling pathway plays a critical role in tumorigenesis and can be targeted by rapamycin. However, the underlying mechanism of how potential lncRNAs (long non-coding RNA) regulate the AKT-mTORC1 pathway remains unclear. EPIC1 is a Myc-binding lncRNA, which has been previously demonstrated to be overexpressed in multiple cancer types. In a pathway analysis including 4962 cancer patients, we observed that lncRNA EPIC1 expression is positively correlated with the AKT-mTORC1 signaling pathway in more than 10 cancer types, including breast and ovarian cancer. RNA-seq analysis of breast and ovarian cancer cells demonstrated that EPIC1-knockdown leads to the downregulation of genes in the AKT-mTORC1 signaling pathway. In MCF-7, OVAR4 and A2780cis cell lines, EPIC1 knockdown and overexpression respectively inhibits and actives pAKT and the downstream phosphorylation levels of 4EBP1 and S6K. Further knockdown of Myc abolishes the EPIC1’s activation of AKT-mTORC1 signaling, suggesting EPIC1 regulation of phosphorylation level of 4EBP1 and S6K depends on the expression of Myc. Moreover, EPIC1 overexpressed MCF-7, A2780cis, and OVCAR4 cells treated with rapamycin showed significant decreasing in rapamycin mediated inhibition of p-S6K and p-S6 comparing with the control group. In addition, colony formation assay and MTT assay indicates that EPIC1 overexpression leads to rapamycin resistance in breast and ovarian cancer cell lines. Our results demonstrated the Myc-binding lncRNA EPIC1 expression can activate the AKT-mTORC1 signaling pathway and lead to rapamycin resistance in breast and ovarian cancer.
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| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
8 April 2020 |
| Date Type: |
Publication |
| Defense Date: |
1 April 2020 |
| Approval Date: |
8 April 2020 |
| Submission Date: |
3 April 2020 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
41 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
lncRNA EPIC1, Myc, AKT-mTORC1, rapamycin resistance |
| Date Deposited: |
08 Apr 2020 15:59 |
| Last Modified: |
08 Apr 2021 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/38217 |
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