FOXP1 ức chế sự phát triển tế bào và giảm bớt khả năng hình thành khối u của neuroblastoma

BMC Cancer - Tập 14 - Trang 1-16 - 2014
Sandra Ackermann1, Hayriye Kocak1, Barbara Hero1, Volker Ehemann2, Yvonne Kahlert1, André Oberthuer1, Frederik Roels1, Jessica Theißen1, Margarete Odenthal3, Frank Berthold1, Matthias Fischer1
1Department of Pediatric Oncology and Hematology and Center for Molecular Medicine Cologne (CMMC), Children’s Hospital, University of Cologne, Cologne, Germany
2Institute of Pathology (INF 220), University of Heidelberg, Heidelberg, Germany
3Institute of Pathology, University of Cologne, Cologne, Germany

Tóm tắt

Các biến đổi số bản sao gen theo từng đoạn, chẳng hạn như mất đoạn 11q hoặc 3p và tăng đoạn 17q, đã được thiết lập rõ ràng là các chỉ số dự đoán kết quả điều trị xấu ở neuroblastoma. Chúng được cho là chứa các gen ức chế khối u hoặc gen oncogen, tương ứng. Gen forkhead box P1 (FOXP1) nằm trên nhiễm sắc thể 3p14.1, một vị trí ức chế khối u bị thiếu trong nhiều loại ung thư ở người, bao gồm cả neuroblastoma. FoxP1 thuộc về một gia đình các yếu tố phiên mã hình cánh, tham gia vào các quá trình tăng sinh tế bào, biệt hóa và quá trình chuyển đổi khối u. Các hồ sơ biểu hiện microarray của 476 mẫu neuroblastoma đã được tạo ra và các gen biểu hiện khác biệt giữa neuroblastoma thuận lợi và không thuận lợi đã được xác định. Biểu hiện FOXP1 có tương quan với các chỉ số lâm sàng và kết quả của bệnh nhân. Để xác định xem quá trình hypermethyl hóa có liên quan đến sự im lặng của FOXP1 hay không, phân tích methyl hóa vùng 5′ của FOXP1 ở 47 mẫu neuroblastoma đã được thực hiện. Hơn nữa, FOXP1 đã được tái biểu hiện trong ba dòng tế bào neuroblastoma để nghiên cứu ảnh hưởng của FOXP1 đến các đặc điểm tăng trưởng của tế bào neuroblastoma. Biểu hiện FOXP1 thấp có liên quan đến các chỉ số tiên lượng xấu như giai đoạn 4, tuổi > 18 tháng và mức độ khuếch đại MYCN cũng như phân loại dựa trên biểu hiện gen không thuận lợi (P < 0.001 mỗi chỉ số). Hơn nữa, biểu hiện FOXP1 dự đoán kết quả bệnh nhân một cách chính xác và độc lập với các chỉ số tiên lượng đã được thiết lập tốt. Phân tích CGH dựa trên microarray của 159 mẫu neuroblastoma cho thấy đánh mất gen dị hợp tử FOXP1 là một sự kiện hiếm gặp (n = 4), nhưng nếu có, thì liên quan đến biểu hiện FOXP1 thấp. Ngược lại, phân tích methyl hóa DNA ở 47 mẫu neuroblastoma chỉ ra rằng hypermethyl hóa không thường xuyên liên quan đến sự im lặng của gen FOXP1. Việc tái biểu hiện FoxP1 đã làm suy yếu đáng kể sự tăng trưởng tế bào, khả năng sống sót và khả năng hình thành thuộc địa trong môi trường agar mềm. Hơn nữa, sự kích thích biểu hiện FOXP1 dẫn đến tình trạng ngừng chu kỳ tế bào và chết tế bào theo chương trình của các tế bào neuroblastoma. Kết quả của chúng tôi cho thấy rằng việc giảm biểu hiện FOXP1 là một sự kiện phổ biến trong sinh bệnh học neuroblastoma có nguy cơ cao và có thể góp phần vào sự tiến triển của khối u và kết quả bệnh nhân không thuận lợi.

Từ khóa

#neuroblastoma #FOXP1 #biến đổi số bản sao gen #gen ức chế khối u #methyl hóa DNA

Tài liệu tham khảo

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The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/14/840/prepub