Mutant P53 mechanisms and functions in esophageal cancer / Qiaosi Tang.

Format:

Book

Thesis/Dissertation

Author/Creator:

Tang, Qiaosi, author.

Contributor:

Rustgi, Anil K., degree supervisor.

University of Pennsylvania. Department of Cell and Molecular Biology, degree granting institution.

Language:

English

Subjects (All):

Molecular biology.

Cellular biology.

Medicine.

Cell and molecular biology--Penn dissertations.

Penn dissertations--Cell and molecular biology.

Local Subjects:

Molecular biology.

Cellular biology.

Medicine.

Cell and molecular biology--Penn dissertations.

Penn dissertations--Cell and molecular biology.

Genre:

Academic theses.

Physical Description:

1 online resource (132 pages)

Contained In:

Dissertations Abstracts International 82-11B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2021.

Language Note:

English

System Details:

Mode of access: World Wide Web.

text file

Summary:

Esophageal squamous cell carcinoma (ESCC) is the major subtype of esophageal cancer and one of the most lethal cancers worldwide. Invasion and lung metastasis frequently occur in ESCC, thereby leading to poor prognosis. The most frequently mutated gene in ESCC is TP53. P53R175H (homologous to Trp53R172H in mice) is a common "hot spot" mutation. How p53R175H regulates invasion and metastasis in ESCC remains to be investigated. To address this fundamental question in ESCC and possibly applicable to other cancers, we modeled ESCC with a carcinogen exposure toTrp53R172H/- mice. In the primary Trp53R172H/- tumor cell lines, depletion of Trp53R172H reduced cell invasion in vitro and lung metastasis burden in a tail-vein injection model. Furthermore, in order to compare gene expression profiles of metastatic mutant or null p53 cells, we used bulk RNA-seq to identify the YAP-BIRC5 axis as a potential mediator of Trp53R172H driven lung metastasis. Expression of survivin (an anti-apoptotic protein encoded by BIRC5) increased in the presence of Trp53R172H. Depletion of Survivin decreased lung metastasis specifically in the context of Trp53R172H. Mechanistically, we demonstrated that the interaction of YAP and mutant p53 may induce Survivin expression. Furthermore, Survivin high expression level is associated with increased metastasis in several GI cancers. Taken together, this study unravels new insights into how mutant p53 mediates lung metastasis. In a related project, we sought to elucidate additional mechanisms of ESCC mediated invasion, recognizing that invasion is a necessary step prior to metastasis. To that end, we revealed the role of endocytic recycling in contributing to epithelial-to-mesenchymal transition (EMT) and invasion. We identified an important endocytic recycling component, Rab11-FIP1, to be downregulated in primary Trp53R172H/- tumor cell lines compared to wild-type. Depletion of Rab11-FIP1 in murine and human ESCC cells leads to enhanced invasion. Mechanistically, we demonstrated that Zeb1 may be a downstream effector of Rab11-FIP1 to mediate EMT and invasion of ESCC. Taken together, we established the role of Rab11-FIP1 in mediating ESCC EMT and invasion. In summary, our studies demonstrate the role of mutant p53 in invasion and lung metastasis of ESCC through the YAP-Survivin axis. Additionally, we show that ESCC invasion involves dysregulation of endocytic recycling, which may be related to mutant p53 and also independent of mutant p53. Our discoveries will shed light on developing novel therapeutic strategies for ESCC and perhaps be extended to other cancers.

Notes:

Source: Dissertations Abstracts International, Volume: 82-11, Section: B.

Advisors: Rustgi, Anil K.; Committee members: Maureen Murphy; Irfan Asangani; Marcelo Kazanietz; Xiaolu Yang.

Department: Cell and Molecular Biology.

Ph.D. University of Pennsylvania 2021.

Local Notes:

School code: 0175

ISBN:

9798738642043

Access Restriction:

Restricted for use by site license.

This item must not be sold to any third party vendors.