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The regulation of tumor suppressor PTEN by microRNAs in breast cancer
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- Author / Creator
- Chengsen Chai
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Breast cancer (BCa) is the most frequently diagnosed cancer in women worldwide. Treatment strategies often target hormone receptors on breast cancer cells. Triple-negative breast cancer (TNBC) is a BCa subtype where estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) are not expressed. Although TNBC accounts for approximately 15% of all BCa cases, the prognosis of these patients is poorer when compared to patients with other BCa subtypes. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) plays an important role in cell proliferation and cell migration by regulating the PI3K–AKT signal pathway negatively. PTEN is one of the most commonly inactivated tumor suppressors gene in BCa, and its inactivity is associated with larger tumor size, considerable lymph node metastases, and an aggressive triple-negative phenotype. MicroRNAs (miRNAs) are small non-coding RNAs that regulate protein expression. In multiple cancers, PTEN is downregulated by miRNAs; however, very few microRNAs target PTEN directly in TNBC.
In this study, nineteen microRNAs predicted to target PTEN were screened using immunoblotting and luciferase reporter assays. Expression levels of miRNA-498 (miR-498) were measured by TaqMan microRNA assays. Clonogenic, cell cycle, and scratch wound assays were performed to examine the oncogenic role of miR-498. I demonstrate that miR-498 directly targeted the 3′ untranslated region of PTEN messenger RNA (mRNA) and reduced PTEN protein levels in TNBC cells. Compared with a non-tumorigenic breast epithelial cell line, TNBC cell lines overexpressed miR-498. Moreover, miR-498 promoted cell proliferation and cell cycle progression in TNBC cells in a PTEN-dependent manner. Suppressing miR-498 overexpression impaired the oncogenic effects of miR-498 on cell proliferation and cell migration. This study identified miR-498, a novel miRNA to be overexpressed in TNBC cells and its oncogenic role in suppressing PTEN. These results provide new insight into the downregulation of PTEN and indicate a potential therapeutic target for treating TNBC. -
- Subjects / Keywords
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- Graduation date
- Fall 2019
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- Type of Item
- Thesis
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- Degree
- Doctor of Philosophy
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- License
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