Seneviratne, Danushka
(2014)
Hepatocyte Growth Factor Gene Mutation in Human Colorectal Cancer:
Causes and Consequences.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Colorectal cancer (CRC) is currently the third most common form of cancer among developed nations. Given that nearly 50% of patients who undergo surgery and subsequent chemotherapy die of metastatic disease, novel therapeutic targets and more effective therapies are direly needed. Although genomic instability is known to promote colon carcinogenesis, many of the target genes that are mutated and drive tumorigenesis are yet to be elucidated. Based on a series of experiments and properties of hepatocyte growth factor (HGF), we hypothesized that HGF gene is a target of mutagenesis in human CRC. Therefore we aimed to test this hypothesis and determine the underpinning molecular mechanisms involved.
We show that genomic instability provoked by DNA mismatch repair (MMR) deficiency causes deletion mutagenesis of an important repressor element in the HGF gene proximal promoter in human CRC cells. This promoter element, which we have named DATE (DeoxyAdenosine Tract Element) consists of a polyA tract of 30 deoxyadenosine bases. We show that shortening of DATE leads to the activation of the HGF promoter (which otherwise is silent in normal colon epithelium) hence creating an HGF-Met autocrine loop in CRC cells. We show that acquisition of HGF-Met autocrine signaling endows cancer cells with growth advantages,which promotes cell survival and confers resistance to both modes of programmed cell death (apoptosis and necroptosis).
We show that growth factor signaling like the HGF-Met axis can directly impact RIPK-1, a key mediator of necroptosis. This is achieved via tyrosine phosphorylation of RIPK-1 by activated Met, resulting in inhibition of RIPK-1 kinase activity. Furthermore, we discovered that Met activation causes RIPK-1 recruitment to the plasma membrane, its polyubiquitination (Lys-48 linked chain) and its subsequent proteasomal degradation. We also found that aberrant HGF expression in tumor tissues is significantly correlated with low RIPK-1 and with poor clinical prognosis. Collectively, our results shed important mechanistic insights into the molecular mechanisms of human colon carcinogenesis and warrant further investigation of HGF-Met as a viable therapeutic target in CRC, especially in those subsets harboring HGF gene mutation.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Seneviratne, Danushka | dss24@pitt.edu | DSS24 | |
|
| ETD Committee: |
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| Date: |
21 April 2014 |
| Date Type: |
Publication |
| Defense Date: |
3 April 2014 |
| Approval Date: |
21 April 2014 |
| Submission Date: |
18 April 2014 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
138 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Hepatocyte Growth Factor, HGF, HGFR, Met, Microsatellite instability, Colorectal Cancer, Necroptosis, RIPK-1 |
| Date Deposited: |
21 Apr 2014 13:25 |
| Last Modified: |
19 Dec 2016 14:41 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/21345 |
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