Nasopharyngeal carcinoma (NPC), endemic in southern China and Southeast Asia, was ranked 7th as the most common new malignancy in Hong Kong. Metastatic and recurrent NPC have a poor prognosis despite recent advancement in medicine. Inactivation of tumor suppressor genes (TSGs) through the loss of chromosomal regions is frequently reported in NPC. With the recent discovery of cancer stem cells (CSCs), which are refractory to current therapies, a new paradigm shift in the perspective of cancer therapy development has emerged. For the first time, this study aims to unravel the complexity of NPC tumorigenicity for identifying more effective targets by studying the possible interplay between CSCs and TSGs.
NPC cell lines had different expression profiles of CSC markers, confirming not all CSC markers are applicable to every tumor type. Although CD24/CD44 were expressed in NPC, however CD24+CD44+ NPC cells did not initiate tumor formation. By utilizing a cancer hybrid cell model with a transferred single copy of chromosome 3, physiological β-catenin up-regulated core stem cell markers through the activation of Wnt signaling pathway in NPC. Moreover, the down-regulation of β-catenin suppressed chemoresistance and inhibited cell proliferation, colony formation, angiogenesis, the epithelial-mesenchymal transition (EMT) process, and the tumor microenvironment factors. Amongst the tumor microenvironment factors, chemokine Rantes and matrix metalloproteinase were down-regulated when β-catenin was knocked down. Therefore, activation of Wnt signaling provide an alternative platform for identifying putative CSCs in NPC, leading to the identification of several prospective CSC markers in NPC.
Down-regulation of IKBB, a NF-KB inhibitor, in the majority of NPC patients indicated that IKBB plays a prominent role as a TSG in NPC. In this study, IKBB was found to exert its tumor suppressive functions by abrogating tumor formation, cell migration, invasion and angiogenesis. Angiogenic factors, including Rantes, Upar, IL6 and IL8, were significantly down-regulated by IKBB. In addition, IKBB also suppressed the binding activity of NF-KB. The involvement of Akt/Gsk-3β pathways was also observed. Taken together, IKBB regulated NPC tumorigenesis through NF-KB/Akt/Gsk-3β and interaction with tumor microenvironment.
Collectively, this study demonstrated that the progression of NPC is not simply initiated by a single signaling pathway, but a dynamic and complex interplay between multiple signaling networks and the tumor microenvironment. NPC tumorigenesis is hypothesized to be driven by orchestrated interaction between CSCs and TSGs through crosstalk with the tumor microenvironment. Amongst the major players in the tumor microenvironment, Rantes/CCL5, IL6, and the matrix metalloproteinase are envisaged to induce angiogenesis, EMT, and metastasis in NPC. This dynamic intercommunication between CSCs and tumor suppressor IKBB signaling networks may shed better insights on modulation of the major hallmarks of cancer in orchestrating NPC development. The modulation of the major hallmarks of cancer by CSCs and IKBB, a TSG, involves promotion of aberrant proliferation, enhancement of invasion and metastasis, induction of angiogenesis, circumvention of tumor suppressors, and prevention of cell death.
Taken together, selective and synergistic co-targeting these signaling networks and the tumor microenvironment will provide a more effective new modality of treatments for NPC. / published_or_final_version / Clinical Oncology / Doctoral / Doctor of Philosophy
| Identifer | oai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/206480 |
| Date | January 2014 |
| Creators | Phoon, Yee Peng, 潘依萍 |
| Contributors | Lung, ML |
| Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
| Source Sets | Hong Kong University Theses |
| Language | English |
| Detected Language | English |
| Type | PG_Thesis |
| Rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works., Creative Commons: Attribution 3.0 Hong Kong License |
| Relation | HKU Theses Online (HKUTO) |
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