THE ONCOGENIC ROLE OF TISSUE INHIBITOR METALLOPROTEINASE-1, TIMP-1, THROUGH REGULATION OF YAP IN HEAD AND NECK SQUAMOUS CELL CARCINOMA
Background: Head and neck squamous cell carcinoma (HNSCC) affects more than 600,000 patients per year in the world. Despite the treatment, about half of all patients will die of this disease. More advanced diagnosis and treatment are required. Tissue inhibitor of metalloproteinase-1 (TIMP-1) inhi...
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| Format: | Theses and Dissertations NonPeerReviewed |
| Language: | English English |
| Published: |
2016
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| Subjects: | |
| Online Access: | http://repository.unair.ac.id/66485/1/KG.%20164-17%20Cha%20o%20abstrak.pdf http://repository.unair.ac.id/66485/2/KG.%20164-17%20Cha%20o%20fulltext.pdf http://repository.unair.ac.id/66485/ http://lib.unair.ac.id |
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| Institution: | Universitas Airlangga |
| Language: | English English |
| Summary: | Background: Head and neck squamous cell carcinoma (HNSCC) affects more
than 600,000 patients per year in the world. Despite the treatment, about half of
all patients will die of this disease. More advanced diagnosis and treatment are
required. Tissue inhibitor of metalloproteinase-1 (TIMP-1) inhibits the
degradation of extracellular matrix regulated by matrix metalloproteinases
(MMP). Although this function is unfavorable for cancer cells to invade or
migrate using MMP, TIMP-1 is controversially overexpressed in various types of
cancer including HNSCC. Therefore, an oncogenic aspect of TIMP-1 has been
featured, which can resolve the discrepancy. Actually, TIMP-1 binds to its
receptor CD63 and activate integrinβ1, leading to aberrant cell proliferation.
However, a true role and its mechanism of TIMP-1 in HNSCC is still unclear.
Yes-Associated Protein (YAP), a transcription co-activator, enhances
transcription of specific genes related to cell proliferation, such as CTGF or
Cyr61. YAP is inactivated due to its phosphorylation inducing localization in
cytoplasm and degradation, which is regulated by Hippo-signaling pathway,
composed of MST1/2 and LATS1/2, or Hippo-independent signaling pathway
like actin dynamics by GPCR or integrinβ1. YAP is dysregulated and contributes
to aberrant cell proliferation in a variety of cancer including HNSCC. When I
searched TIMP-1 expression by Oncomine data base analysis, I found that TIMP-
1 was highly overexpressed in association with YAP-associated genes including
CTGF and Cyr61 in HNSCC. Then, I hypothesized TIMP-1 might regulate YAP
in HNSCC.
Purpose: To reveal an oncogenic role of TIMP-1 through regulation of novel
downstream YAP in HNSCC.
Method: HNSCC cell lines (HSC-2, 3, 4 and KOSCC33A) and human embryonic
kidneycells (HEK293) were used. Expressing or shRNA plasmids were
transfected and stable clones were analyzed by western blotting, RT-PCR, Real
time-PCR and proliferation assay. Data were evaluated by student’s t-test with
significant level set at P＜0.05.
Results: TIMP-1, YAP and CTGF expression were positively correlated among
HNSCC cell lines. Stable overexpression or recombinant TIMP-1 induced YAP
activation (dephosphorylation), CTGF expression and accelerated cell
proliferation. In contrast, stable TIMP-1 knockdown inactivated (phosphorylated)
YAP and inhibited proliferation. Furthermore, stable CD63 knockdown
inactivated YAP and disturbed activation triggered by TIMP-1.
Conclusion: I revealed TIMP-1 with its receptor CD63 play an oncogenic role in
HNSCC through regulation of YAP. This finding suggests that targeting of TIMP-
1 and/or its new downstream YAP will be beneficial for the improvement of
diagnosis and treatment for the patients with HNSCC. |
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