THESIS
2012
x, 31 p. : ill. ; 30 cm
Abstract
Nasopharyngeal carcinoma (NPC) is a malignant head and neck cancer usually
originating from ostium of the Eustachian tube in the lateral wall of the nasopharynx.
Although NPC is a rare cancer in most part of the world, it is a leading cancer in
certain geographic regions and for people of certain ethnic origin. The highest
incidence is seen in the Cantonese population in southern China.
MicroRNA deregulation is known to contribute to the initiation and progression of
human cancers. In this study, we try to identify microRNAs with tumor suppressor
function in NPC. Through a quantitative PCR-based microRNA screening platform,
we found that the expression levels of mir-376a were obviously downregulated in two
NPC-derived cell lines. Through WST-1-based proliferation assays, we als...[
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Nasopharyngeal carcinoma (NPC) is a malignant head and neck cancer usually
originating from ostium of the Eustachian tube in the lateral wall of the nasopharynx.
Although NPC is a rare cancer in most part of the world, it is a leading cancer in
certain geographic regions and for people of certain ethnic origin. The highest
incidence is seen in the Cantonese population in southern China.
MicroRNA deregulation is known to contribute to the initiation and progression of
human cancers. In this study, we try to identify microRNAs with tumor suppressor
function in NPC. Through a quantitative PCR-based microRNA screening platform,
we found that the expression levels of mir-376a were obviously downregulated in two
NPC-derived cell lines. Through WST-1-based proliferation assays, we also found
that overexpression of mir-376a can suppress cell growth in both NPC cell lines.
Mir-376a is located in the Dlk1-Gtl2 domain of chromosome 14, which is known to
be frequently silenced by epigenetic mechanisms in several other cancer types. This
suggests that miR376a has a general tumor suppression function. By bioinformatic
analysis, Ezrin, a member of the ezrin-radixin-moesin family of proteins, and MYC,
an oncogenic transcriptional factor, were predicted to be direct targets of miR-376a.
By both luciferase reporter assays and Western blotting analysis, we confirmed that
the two candidate genes are real targets of mir-376a. Ezrin is usually involved in cell
migration and invasion and is known to be over-expressed in different cancer types.
This suggests that Ezrin could be involved in metastasis of NPC. As a transcription
factor, MYC is one of the best known oncogenes in human cancer. Over-expression of
MYC stimulates cell proliferation, cell survival and angiogenesis. Thus both Ezrin
and MYC represent critical targets of mir-376a in NPC.
In summary, our work suggested that miR-376a can function as a tumor suppressor
in NPC by directly targeting Ezrin and MYC, both of which are known oncogenic
proteins over-expressed in many cancer types.
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