Wnt điều khiển LARGE2 trung gian hóa O-glycosyl hóa dính laminin trong tế bào biểu mô đại tràng người và ung thư đại trực tràng
Tóm tắt
Li tín hiệu Wnt thúc đẩy sự tự tái sinh của biểu mô và sự tiến triển của bệnh trong biểu mô đại tràng người và ung thư đại trực tràng (CRC). Việc xác định các con đường tác động của Wnt là chìa khóa để hiểu biết các quá trình này và để phát triển các chiến lược điều trị nhằm duy trì cân bằng mô. Các protein bề mặt tế bào O-glycosyl hóa, chẳng hạn như α-dystroglycan (α-DG), đóng vai trò trung gian cho sự bám dính tế bào vào các thành phần của ma trận ngoại bào. Chúng tôi đã phát hiện ra một con đường tín hiệu Wnt/LARGE2/α-DG mà làm khởi phát cơ chế tương tác của tế bào biểu mô đại tràng với ma trận trong tình trạng sức khỏe và bệnh tật.
Phát hiện thế hệ tiếp theo trên cơ sở sự silencing trung gian bởi shRNA của gen adenomatous polyposis coli (APC), và phương pháp định lượng kết hợp với CRISPR/Cas9 nhằm nhắm vào vị trí liên kết của yếu tố phiên mã đã xác định
Phát hiện thế hệ tiếp theo đã xác định gen mã hoá glycosyltransferase LARGE2 như một gene biểu hiện khác biệt khi tín hiệu Wnt được kích hoạt trong CRC. Việc silencing APC, biểu hiện có điều kiện của β-catenin gây ung thư và việc giam giữ β-catenin nội sinh đã ảnh hưởng đến biểu hiện của
Chúng tôi kết luận rằng gen mã hóa glycosyltransferase LARGE2 đại diện cho một mục tiêu trực tiếp của tín hiệu Wnt cổ điển và trung gian hóa O-glycosyl hóa chức năng của α-dystroglycan (α-DG) trong các tế bào gốc/progenitor đại tràng của người và CRC được điều khiển bởi Wnt. Công trình của chúng tôi chỉ ra rằng sự kích hoạt Wnt bất thường làm gia tăng sự bám dính của tế bào CRC vào ma trận bằng cách tăng cường tính bám dính laminin do LARGE/α-DG trung gian.
Từ khóa
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