国家自然科学基金(11772088, 31700811, 11802056, 31800780)
Department of Biophysics,School of Life Science and Technology,University of Electronic Science and Technology of China
目的：探究肿瘤细胞外基质刚度调控细胞耐药性的详细分子机制。方法：制备不同基质刚度的软基底（10 kPa）、硬基底（38 kPa）和刚性基底（57 kPa）聚丙烯酰胺水凝胶，模拟体内乳腺癌不同阶段的物理基质刚度。结果：(1) 硬基底刚度上的乳腺癌细胞增殖率明显高于软基底和刚性基底。 (2) 乳腺癌细胞对阿霉素的内吞在硬基底上显著低于软基底和刚性基底。 (3) 在硬基底上YAP的入核水平相比软基底和刚性基底显着增加，证实YAP是参与肿瘤细胞耐药性的关键分子。结论：基质刚度可通过YAP活化调节乳腺癌细胞的耐药性。该研究不仅为阐明乳腺癌细胞耐药机制提供了新的方向，也为开发乳腺癌治疗的药物传递系统奠定了新的基础。
Objective: To investigate the detailed molecular mechanism of matrix stiffness regulating cell drug resistance. Methods: Polyacrylamide hydrogels of soft substrate (10 kPa), hard substrate (38 kPa) and rigid substrate (57 kPa) with different matrix stiffness were configured to mimic the physical matrix stiffness at different stages of breast cancer in vivo. Results: (1) The cell proliferation rate on the hard substrate was significantly higher than that of the soft and rigid substrates. (2) The intracellular endocytosis was significantly lower on the hard substrate. (3) The YAP nucleus translocation increased significantly on the hard substrate, compared with soft and rigid substrates, indicating that YAP is a key molecule involved in the drug resistance of tumor cells. Conclusions: Matrix stiffness can regulate the drug resistance of breast cancer cells through YAP activation. This study not only provides a new direction for elucidating the mechanism of drug resistance, but also lays a new foundation for the drug delivery system of breast cancer treatment.