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Lysyl hydroxylase LH1 thúc đẩy sự di chuyển bị hạn chế và di căn của tế bào ung thư bằng cách ổn định Septin2 để tăng cường mạng lưới actin
Tóm tắt
Sự lắng đọng quá mức của ma trận ngoại bào và độ cứng tăng cao là những đặc điểm điển hình của các khối u rắn như carcinoma tế bào gan (HCC) và adenocarcinoma ống tụy (PDAC). Những điều kiện này tạo ra không gian hạn chế cho sự di chuyển và di căn của tế bào khối u. Cơ chế điều chỉnh của sự di chuyển bị hạn chế vẫn chưa rõ ràng. Phương pháp LC–MS đã được áp dụng để xác định các protein biểu hiện khác nhau giữa mô HCC và mô lân cận tương ứng. Thiết bị microfluidic cho di chuyển tập thể và di chuyển tế bào đơn lẻ với các kênh hạn chế cao 6 μm đã được thiết kế và chế tạo để mô phỏng không gian hạn chế trong cơ thể. Thí nghiệm xâm lấn 3D được tạo ra bằng cách điều trị các tế bào bám dính bằng hỗn hợp Matrigel và Collagen I. Việc hình thành spheroid 3D trong môi trường có độ cứng khác nhau được phát triển bằng các tỷ lệ thay thế GelMA khác nhau. Tiến hành kết tủa miễn dịch để kéo xuống các protein liên kết LH1, được xác định bằng LC–MS. Nhuộm miễn dịch huỳnh quang, FRET, RT-PCR, Western blotting, FRAP, CCK-8, di chuyển tế bào transwell, lành vết thương, mô hình chuột tiêm gan chính thống và hình ảnh trong cơ thể được sử dụng để đánh giá sự biểu hiện mục tiêu và kiểu hình tế bào. Lysyl hydroxylase 1 (LH1) thúc đẩy sự di chuyển bị hạn chế của tế bào ung thư ở cả cấp độ tập thể và tế bào đơn lẻ. Thêm vào đó, LH1 tăng cường sự xâm lấn tế bào trong một mô hình sinh học 3D và hình thành spheroid trong các môi trường cứng hơn. Sự biểu hiện cao của LH1 tương quan với tiên lượng kém ở cả bệnh nhân HCC và PDAC, đồng thời cũng thúc đẩy di căn in vivo. Về cơ chế, LH1 liên kết và ổn định Septin2 (SEPT2) để tăng cường quá trình polymer hóa actin, tùy thuộc vào miền hydroxylase. Cuối cùng, phân nhóm với sự biểu hiện cao của cả LH1 và SEPT2 có tiên lượng kém nhất. LH1 thúc đẩy sự di chuyển bị hạn chế và di căn của tế bào ung thư bằng cách ổn định SEPT2 và do đó tạo điều kiện cho sự polymer hóa actin.
Từ khóa
#LH1 #SEPT2 #di chuyển hạn chế #di căn #carcinoma tế bào gan #adenocarcinoma ống tụy #polymer hóa actin #microfluidic #mô hình sinh học 3DTài liệu tham khảo
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