FN3K抑制铁死亡促进乳腺癌细胞恶性生物学行为的功能及机制研究

Inhibition of Ferroptosis by FN3K Promotes Malignant Phenotypes in Breast Cancer Cells: Functional and Mechanistic Insights

摘要: 目的：探讨FN3K对乳腺癌细胞增殖、迁移、侵袭的影响及相关的分子机制。方法：基于TCGA数据库分析乳腺癌中癌组织与癌旁组织FN3K的表达情况，构建对照组和过表达FN3K组MDA-MB-231、MCF-7细胞株，Western blot验证FN3K过表达效率；CCK8实验和Transwell实验检测FN3K对乳腺癌细胞增殖、迁移、侵袭的影响；Western blot及流式技术评估在乳腺癌细胞中FN3K与铁死亡信号的关系，并回复验证FN3K介导的Nrf2激活在乳腺癌细胞中的调控作用。结果：FN3K在乳腺癌癌组织中高表达并可以促进乳腺癌细胞的恶性生物学行为，此外FN3K通过调控Nrf2和GPX4的表达抑制ROS生成，而抑制Nrf2可逆转FN3K对乳腺癌细胞恶性生物学行为及ROS生成的影响。结论：FN3K在乳腺癌细胞中异常高表达并调控铁死亡，并介导铁死亡抵抗促进乳腺癌细胞的增殖、迁移、侵袭，提示FN3K是乳腺癌潜在的治疗靶点。

Abstract: Objective: The expression levels of FN3K in breast cancer tissues and paired adjacent normal tissues were analyzed using the TCGA database. Methods: The expression of FN3K in breast cancer tissues and adjacent normal tissues was analyzed. MDA-MB-231 and MCF-7 cell lines with control or FN3K overexpression were constructed, and the overexpression efficiency was verified by Western blot. The effects of FN3K on the proliferation, migration, and invasion of breast cancer cells were detected using CCK-8 and Transwell assays. The relationship between FN3K and the ferroptosis signaling pathway in breast cancer cells was assessed by Western blot and flow cytometry. Furthermore, rescue experiments were performed to validate the regulatory role of FN3K-mediated Nrf2 activation in breast cancer cells. Results: FN3K was highly expressed in breast cancer tissues and promoted the malignant biological behaviors of breast cancer cells. Moreover, FN3K inhibited ROS generation by regulating the expression of Nrf2 and GPX4. Inhibition of Nrf2 could reverse the effects of FN3K on the malignant behaviors and ROS production in breast cancer cells. Conclusion: FN3K is aberrantly overexpressed in breast cancer cells and regulates ferroptosis. It mediates resistance to ferroptosis, thereby promoting the proliferation, migration, and invasion of breast cancer cells, suggesting that FN3K is a potential therapeutic target for breast cancer.