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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
miR520c blocks EMT progression of human breast cancer cells by repressing STAT3
Nian Wang1, Lan Wei1, Yunxiu Huang1
1Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China.
Abstract:
Breast cancer is one of the most malignant diseases world-wide and it ranks the first among female cancers. Masses of intrinsic and extrinsic factors, especially the inflammatory factors can lead to breast cancer. Aberrant activation and accumulation of key molecules can lead to inflammation associated carcinogenesis. The signal transducers and activators of transcription 3 (STAT3) is one of them. Therefore, to evaluate the novel molecular mechanisms, STAT3 has become our focus for breast cancer targeted therapy. At present, many tumor suppressing microRNAs have been validated, and are the highlights in research on microRNAs. Thus, we predicted microRNAs which could putatively regulate STAT3 through databases and selected six to screen with Dual-luciferase assay. The result hinted that miR520c could bind with STAT3 3'UTR. We mutated the seed sequence of miR520c on STAT3 3'UTR, which illustrated a reverse effect compared with wild-type of STAT3 3'UTR. Subsequently, STAT3, p-STAT3 and miR520c were assessed in three different grades of breast cancer cells, with the degree of malignancy, we found an escalating trend of STAT3 and p-STAT3, on the contrary, a downward trend of miR520c. We observed STAT3 was deactivated by miR520c. Epithelial to mesenchymal transition (EMT) is a fatal transfer of cancer progression. To find out whether the downregulation of STAT3 can repress breast cancer motility and invasion ability, we detected EMT markers. The result implied a suppression effect on EMT. We overexpressed STAT3 to conduct rescue experiments, the result showed a recovery of STAT3 and EMT characteristics. Cell motility and invasion property were regained as well. In the study, we elucidated miR520c could inhibit breast cancer EMT by targeting STAT3. It can enrich the mechanism of breast cancer and may lay the foundation for breast cancer targeted treatment.
Insights
MicroRNA 520c (miR520c) inhibits breast cancer progression by targeting Signal Transducer and Activator of Transcription 3 (STAT3). This discovery offers a new therapeutic strategy for targeting breast cancer by modulating miR520c and STAT3 pathways.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Breast cancer is a leading cause of mortality worldwide, with inflammation playing a key role in its development.
- Aberrant activation of Signal Transducer and Activator of Transcription 3 (STAT3) is implicated in inflammation-associated carcinogenesis.
- MicroRNAs (miRNAs) are emerging as critical regulators in cancer, with tumor-suppressing roles.
Purpose of the Study:
- To investigate the role of miRNAs in regulating STAT3 in breast cancer.
- To explore miR520c as a potential therapeutic target for breast cancer by examining its interaction with STAT3.
- To elucidate the molecular mechanisms by which miR520c affects breast cancer progression, including epithelial-to-mesenchymal transition (EMT).
Main Methods:
- Bioinformatic prediction of miRNAs targeting STAT3, followed by dual-luciferase assays to validate interactions.
- Mutation analysis of the miR520c binding site on STAT3 3'UTR to confirm specificity.
- Assessment of STAT3, phosphorylated STAT3 (p-STAT3), and miR520c levels in breast cancer cell lines of varying malignancy.
- Evaluation of EMT markers and cell motility/invasion assays to determine the functional impact of miR520c and STAT3 modulation.
- Rescue experiments involving STAT3 overexpression to confirm the inhibitory effect of miR520c on EMT.
Main Results:
- miR520c was identified as a direct regulator of STAT3, binding to its 3'UTR.
- Expression levels of STAT3 and p-STAT3 increased with breast cancer malignancy, while miR520c levels decreased.
- miR520c effectively deactivated STAT3 and suppressed EMT, reducing cancer cell motility and invasion.
- Overexpression of STAT3 reversed the inhibitory effects of miR520c, restoring EMT characteristics and invasive properties.
Conclusions:
- miR520c inhibits breast cancer progression by targeting and deactivating STAT3.
- The miR520c/STAT3 axis plays a significant role in regulating EMT in breast cancer.
- Targeting the miR520c/STAT3 pathway represents a promising strategy for novel breast cancer therapies.
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