Full metadata record
DC FieldValueLanguage
dc.contributorDepartment of Applied Biology and Chemical Technologyen_US
dc.contributor.advisorChow, M. C. Larry (ABCT)-
dc.creatorChen, Teng-
dc.identifier.urihttps://theses.lib.polyu.edu.hk/handle/200/10305-
dc.languageEnglishen_US
dc.publisherHong Kong Polytechnic University-
dc.rightsAll rights reserveden_US
dc.titleInhibition of SALL4 suppresses epithelial-to-mesenchymal transition and tumorigenicity of breast cancer cells by targeting β-catenin and vimentinen_US
dcterms.abstractBreast cancer is the second most common malignancy behind lung cancer with more than 1.3 million cases and 450,000 deaths each year worldwide. Although the survival rates for breast cancer have been improved strikingly over the decades, treatments of 'triple-negative' breast cancer (TNBC) which has a higher metastatic potential and poorer prognosis than other types of breast cancer remain challenging. SALL4 plays an important role in early mammalian development. Homozygous loss-of-function mutants are embryonic lethal. It has been reported recently that SALL4 is de-regulated and aberrantly expressed in various cancers, affecting multiple cellular processes including tumorigenesis, tumor growth and metastasis. Several studies have also discovered that SALL4 is overexpressed in breast cancer and contributes to breast cancer progression, but the molecular mechanism remains unknown. Therefore, we performed multiple experiments and demonstrated for the first time that SALL4 facilitated tumorigenicity and metastasis of 'triple-negative' breast cancer cell MDA-MB-231 by direct upregulation of vimentin and indirect activation of Wnt/β-catenin signaling pathway. Here, tissue microarray was conducted to explore the correlation between SALL4 and common clinical features of breast cancer. It was found that SALL4 was associated with higher grade and higher lymph node status of breast cancer. Knockout of SALL4, using CRISPR-Cas9 system, in 'triple-negative' breast cancer cell MDA-MB-231 was performed. It was demonstrated that decrease of SALL4 led to impaired ability in cell proliferation, migration, sphere formation as well as reduced tumor burden and lung metastasis in nude mice. On the other hand, SALL4 gain-of-function study demonstrated that upregulation of SALL4 enhanced cell migration and sphere formation in vitro and increased tumorigenicity in vivo. The mechanism by which SALL4 affected epithelial-to-mesenchymal transition (EMT) and tumorigenicity was investigated. It was found that there was a positive correlation between SALL4 and EMT markers including ZEB1, vimentin, Slug, and Snail. The Chromatin immunoprecipitation (CHIP) experiment indicated that SALL4 enhanced vimentin expression by directly binding to the promoter region (-778 to -550 bp). SALL4 also activated Wnt/β-catenin signaling pathway to enhance cell migration and tumorigenesis through inhibition of GSK-3β kinase activity. Knockout of SALL4 led to reduced GSK-3β (ser9), indicating more active GSK-3β to phosphorylate β-catenin, Snail and Slug for proteasomal degradation. In summary, SALL4 is overexpressed in breast cancer and positively correlated with histological tumor grade and lymph node status of breast cancer patients. Functional studies have demonstrated that inhibition of SALL4 suppressed breast cancer cell proliferation, migration, sphere formation in vitro, tumorigenicity and metastasis in vivo through direct inhibition of vimentin and indirect inactivation of Wnt/β-catenin pathway, probably explaining the clinical relevance of SALL4 and breast cancer.en_US
dcterms.extenti-xx, 200 pages : color illustrationsen_US
dcterms.isPartOfPolyU Electronic Thesesen_US
dcterms.issued2019en_US
dcterms.educationalLevelPh.D.en_US
dcterms.educationalLevelAll Doctorateen_US
dcterms.LCSHHong Kong Polytechnic University -- Dissertationsen_US
dcterms.LCSHBreast -- Canceren_US
dcterms.accessRightsopen accessen_US

Files in This Item:
File Description SizeFormat 
991022289508503411.pdfFor All Users7.09 MBAdobe PDFView/Open


Copyright Undertaking

As a bona fide Library user, I declare that:

  1. I will abide by the rules and legal ordinances governing copyright regarding the use of the Database.
  2. I will use the Database for the purpose of my research or private study only and not for circulation or further reproduction or any other purpose.
  3. I agree to indemnify and hold the University harmless from and against any loss, damage, cost, liability or expenses arising from copyright infringement or unauthorized usage.

By downloading any item(s) listed above, you acknowledge that you have read and understood the copyright undertaking as stated above, and agree to be bound by all of its terms.

Show simple item record

Please use this identifier to cite or link to this item: https://theses.lib.polyu.edu.hk/handle/200/10305