A novel molecular pathway for Snail-dependent, SPARC-mediated invasion in Non Small Cell Lung Cancer pathogenesis - Abstract

Aug 26, 2026

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Lung cancer remains the leading cause of cancer death in the U.S., with limited survival largely driven by insufficient early detection and late metastatic progression. Tumor dissemination requires migratory behavior, basement-membrane degradation and invasion, frequently coordinated by epithelial-to-mesenchymal transition (EMT). Snail, a transcription factor regulating EMT, is implicated in aggressive non-small cell lung cancer (NSCLC). This dissertation demonstrates that Snail overexpression upregulates SPARC and increases SPARC-dependent invasion in vitro and in early pathogenesis models.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages106

Reading Time4 h 27 min

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ABSTRACT OF THE THESIS

Background: lung cancer progression and EMT

Snail–SPARC regulation and invasion findings

TGF-β/MEK-ERK and miR-29b mechanistic pathway

UCLA UCLA Electronic Theses and Dissertations Title A novel molecular pathway for Snail-dependent, SPARC-mediated invasion in Non Small Cell Lung Cancer pathogenesis Permalink [https://escholarship.org/uc/item/2w0509r0](https://escholarship.org/uc/item/2w0509r0) Author Grant, Jeanette Publication Date 2013 Peer reviewed|Thesis/dissertation [eScholarship.org](eScholarship.org) Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA Los Angeles A novel molecular pathway for Snail-dependent, SPARC-mediated invasion in Non Small Cell Lung Cancer pathogenesis A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Cellular and Molecular Pathology by Jeanette Lynn Grant 2013 ABSTRACT OF THE THESIS A novel molecular pathway for Snail-dependent, SPARC-mediated invasion in Non Small Cell Lung Cancer pathogenesis by Jeanette Lynn Grant Doctor of Philosophy in Cellular and Molecular Pathology University of California, Los Angeles, 2013 Professor Steven M. Dubinett, Chair In the U.S., lung cancer is the leading cause of cancer death, with a median survival of eight months following diagnosis and only 16% of patients surviving more than five years. The low survival rate is attributable, in part, to a lack of early detection, limiting the benefit of surgical resection as metastatic progression has already occurred. The early events of lung cancer pathogenesis have not yet been well defined, contributing to the paucity of early detection techniques clinically. For tumors to progress to metastatic disease, they must acquire characteristics that allow them to become migratory, degrade and invade their local basement membrane, and migrate to a new site before forming a micrometastasis. As part of this process, tumors undergo a series of events known as epithelial-to-mesenchymal transition (EMT), where they lose epithelial characteristics and become mesenchymal in phenotype and molecular profile. Snail is a zinc-finger transcription factor that exerts global effects on epithelial cell gene expression profiles, resulting in regulation of EMT. Recent studies by our lab have shown that Snail is upregulated in human non-small cell lung cancer (NSCLC) tissues, is associated with poor prognosis, and promotes NSCLC tumor progression in vivo. Furthermore, Snail overexpression in NSCLC is associated with differential gene expression related to diverse aspects of lung cancer progression, including angiogenesis. Herein we demonstrate that overexpression of Snail leads to upregulation of Secreted Protein, Acidic and Rich in Cysteine (SPARC) . Immunoblot and qRT-PCR analysis of multiple NSCLC cell lines with and without Snail overexpression validated the relationship between Snail and SPARC in established cancers. Similar results were found in Snail-overexpressing Human Bronchial Epithelial Cells (HBECs), a model of early pathogenesis, as well as in human lung adenocarcinomas and squamous cell carcinomas immunostained for Snail and SPARC. Taken together, these data indicate that SPARC is upregulated by Snail at early and late points during lung carcinogenesis and may playa role in lung cancer initiation and progression. In all cell lines evaluated, Snail overexpression leads to increased SPARC-dependent invasion in vitro. The promoter region of SPARC does not contain a binding site for Snail, indicating that Snail upregulates SPARC by an indirect mechanism. Bioinformatic analysis of array data revealed potential intermediaries in Snail-mediated upregulation of SPARC, including miR-29b and the TGF-β and MEK/ERK pathways. Both the TGF-β1 ligand and TGF-βR2 are upregulated following Snail overexpression. In addition, treatment of HBEC cell lines with TGF-β 1 resulted in phosphorylation of ERK1/2 as well as upregulation of SPARC and Snail. Inhibition of TGF-β1 mRNA decreased the Snail-dependent activation of ERK1/2 and

FAQs

What is the main focus of the thesis abstract?

The thesis investigates a molecular pathway where Snail-dependent regulation promotes SPARC-mediated invasion in non-small cell lung cancer.

How does the dissertation connect Snail to SPARC?

Snail overexpression increases SPARC expression and invasion, while the SPARC promoter lacks a direct Snail binding site, supporting an indirect mechanism through signaling intermediates.

Which signaling and microRNA mechanisms are proposed?

The abstract highlights the TGF-β-driven MEK/ERK pathway as necessary for Snail-dependent SPARC upregulation and proposes ERK-mediated downregulation of miR-29b to relieve repression of SPARC.

Aug 26, 2026

Uploaded by Sage