STAT3/miR-221-3p/Fascin-1轴在三阴性乳腺癌表皮生长因子受体TKI耐药中的相关性和机制

IF 3.5 2区 生物学 Q3 CELL BIOLOGY Molecular and Cellular Biochemistry Pub Date : 2024-11-01 Epub Date: 2023-12-25 DOI:10.1007/s11010-023-04907-9
Lu-Lu Jin, Hua-Jun Lu, Jun-Kang Shao, Yan Wang, Shi-Ping Lu, Bi-Fei Huang, Gui-Nv Hu, Hong-Chuan Jin, Chao-Qun Wang
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引用次数: 0

摘要

表皮生长因子受体 1(EGFR)在各种恶性肿瘤的发展过程中起着至关重要的作用,被认为是治疗三阴性乳腺癌(TNBC)的潜在靶点。然而,用于表皮生长因子受体靶向治疗的代表性酪氨酸激酶抑制剂(TKIs)对 TNBC 患者的疗效有限。在我们的研究中,我们观察到 TNBC 细胞系 MDA-MB-231 和 MDA-MB-468 对吉非替尼表现出耐药性。吉非替尼治疗会导致这些细胞株中的Fascin-1(FSCN1)蛋白表达上调和miR-221-3p下调。然而,抑制FSCN1的表达或过表达miR-221-3p可显著提高这两种细胞系对吉非替尼的敏感性。我们的荧光素酶报告实验证实,FSCN1是miR-221-3p的靶点。此外,吉非替尼治疗会导致MDA-MB-231细胞中磷酸化信号转导和转录激活因子3(p-STAT3)的上调。使用 STAT3 小分子抑制剂 Stattic,我们观察到吉非替尼对 MDA-MB-231 细胞生长、迁移和侵袭的抑制作用显著增强。此外,Stattic还能上调miR-221-3p的表达,下调FSCN1 mRNA和蛋白的表达。在乳腺癌组织中,STAT3 和 FSCN1 的表达呈强正相关。此外,STAT3和FSCN1均高表达的患者预后较差。我们的研究结果表明,FSCN1的高表达与TNBC患者对表皮生长因子受体TKIs的原发性耐药有关。此外,我们还提出,STAT3调节miR-221-3p/FSCN1的表达,从而调节TNBC对EGFR TKI治疗的耐药性。将表皮生长因子受体 TKI 疗法与 FSCN1 或 STAT3 抑制疗法相结合,可能会为 TNBC 提供一种前景广阔的新疗法。
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Relevance and mechanism of STAT3/miR-221-3p/Fascin-1 axis in EGFR TKI resistance of triple-negative breast cancer.

The epidermal growth factor receptor 1 (EGFR) plays a crucial role in the progression of various malignant tumors and is considered a potential target for treating triple-negative breast cancer (TNBC). However, the effectiveness of representative tyrosine kinase inhibitors (TKIs) used in EGFR-targeted therapy is limited in TNBC patients. In our study, we observed that the TNBC cell lines MDA-MB-231 and MDA-MB-468 exhibited resistance to Gefitinib. Treatment with Gefitinib caused an upregulation of Fascin-1 (FSCN1) protein expression and a downregulation of miR-221-3p in these cell lines. However, sensitivity to Gefitinib was significantly improved in both cell lines with either inhibition of FSCN1 expression or overexpression of miR-221-3p. Our luciferase reporter assay confirmed that FSCN1 is a target of miR-221-3p. Moreover, Gefitinib treatment resulted in an upregulation of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in MDA-MB-231 cells. Using Stattic, a small-molecule inhibitor of STAT3, we observed a significant enhancement in the inhibitory effect of Gefitinib on the growth, migration, and invasion of MDA-MB-231 cells. Additionally, Stattic treatment upregulated miR-221-3p expression and downregulated FSCN1 mRNA and protein expression. A strong positive correlation was noted between the expression of STAT3 and FSCN1 in breast cancer tissues. Furthermore, patients with high expression levels of both STAT3 and FSCN1 had a worse prognosis. Our findings suggest that elevated FSCN1 expression is linked to primary resistance to EGFR TKIs in TNBC. Moreover, we propose that STAT3 regulates the expression of miR-221-3p/FSCN1 and therefore modulates resistance to EGFR TKI therapy in TNBC. Combining EGFR TKI therapy with inhibition of FSCN1 or STAT3 may offer a promising new therapeutic option for TNBC.

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来源期刊
Molecular and Cellular Biochemistry
Molecular and Cellular Biochemistry 生物-细胞生物学
CiteScore
8.30
自引率
2.30%
发文量
293
审稿时长
1.7 months
期刊介绍: Molecular and Cellular Biochemistry: An International Journal for Chemical Biology in Health and Disease publishes original research papers and short communications in all areas of the biochemical sciences, emphasizing novel findings relevant to the biochemical basis of cellular function and disease processes, as well as the mechanics of action of hormones and chemical agents. Coverage includes membrane transport, receptor mechanism, immune response, secretory processes, and cytoskeletal function, as well as biochemical structure-function relationships in the cell. In addition to the reports of original research, the journal publishes state of the art reviews. Specific subjects covered by Molecular and Cellular Biochemistry include cellular metabolism, cellular pathophysiology, enzymology, ion transport, lipid biochemistry, membrane biochemistry, molecular biology, nuclear structure and function, and protein chemistry.
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