YB-1 Promotes PLXND1 mRNA Translation to Mediate Tumor Migration in Sonic Hedgehog Medulloblastoma Restricted; Files Only

Abstract

Medulloblastoma (MB) is one of the most common malignant pediatric brain cancers.

Tumor metastasis is associated with higher risk, and recurrence is often fatal. The current

treatment regimen is highly toxic and often results in severe complications, including cognitive

and endocrine sequelae. In this study, we propose a novel role of Y-box binding protein-1 (YB-1)

in positively modulating PlexinD1 (PLXND1) translation and its effect on MB migration. We

show that PLXND1, its ligand Semaphorin 3E, and its binding partner Neuropilin-1 promote

migration in Sonic Hedgehog (SHH) MB. Further, we explore the therapeutic potential of a

PLXND1 binding peptide, which has previously been used in pancreatic adenocarcinoma

research. Our findings indicate that the PLXND1 binding peptide reduces cell growth and

epithelial-to-mesenchymal transition in SHH MB cells, suggesting that targeting PLXND1 may

impair tumor growth and migration in SHH MB. Our study offers a potential avenue for

therapeutic inhibition of SHH MB through targeting PLXND1.

Table of Contents

Introduction………………………………………………………………………..….1

Hypothesis and Aims…………………………….……….…….…………....……..6

Materials and Methods…………………………………….……….……..…….….7

Results……………………………………………………...………………..…………10

Discussion………………………………...…………………………………………...25

References…………………………………….………………………………………..28

Figures

Figure 1: YB1 post-transcriptionally drives PLXND1 expression……..…...2

Figure 2: Depiction of specific aims…………………………………………….…7

Figure 3: YB-1 regulates PLXND1 mRNA Translation….…...……….………11

Figure 4: PLXND1 depletion results in reduced tumor cell migration,

proliferation, and select EMT marker shift……….….……….….…………….14

Figure 5: PLXND1 binding peptide results in reduced cell growth and

EMT markers…………………………………………………………..……………...15

Figure 6: SEMA3E and NRP1 colocalize with PLXND1………………...…….16

Figure 7: SEMA3E is elevated in SHH MB, glycosylated, and secreted……18

Figure 8: SEMA3E depletion results in reduced tumor cell migration,

but not proliferation………………………………………………………………...20

Figure 9: SEMA3E depletion results in inconsistent EMT shift……………22

Figure 10: NRP1 depletion results in reduced tumor migration and

EMT shift but not proliferation…………………………..…………………...…24

About this Honors Thesis

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School	Emory College
Department	Neuroscience and Behavioral Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Cell Health Sciences, Oncology Biology, Neuroscience
Palavra-chave	Medulloblastoma Metastasis YB1 Semaphorin3E Cancer PlexinD1
Committee Chair / Thesis Advisor	Anna Kenney, Emory University
Committee Members	Kristen Frenzel, Emory University Sumin Kang, Emory University

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