Yêu cầu chức năng của một alen hoang dã cho IDH1 đột biến để ức chế sự tăng trưởng độc lập với giá đỡ thông qua cân bằng redox

Springer Science and Business Media LLC - Tập 135 - Trang 285-298 - 2017
Patricia D. B. Tiburcio1,2, Bing Xiao1,3, Shauna Berg1, Sydney Asper1, Sean Lyne1, Yan Zhang3, Xingen Zhu3, Hai Yan4, L. Eric Huang1,2
1Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, USA
2Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Utah, USA
3Department of Neurosurgery, Nanchang University Second Affiliated Hospital, Nanchang, People’s Republic of China
4Department of Pathology, Duke University Medical Center, Durham, USA

Tóm tắt

Các đột biến của gen isocitrate dehydrogenase 1 (IDH1) là phổ biến nhất ở glioma, có thể là nguyên nhân trước tất cả các thay đổi di truyền được biết đến trong quá trình phát triển khối u. Các đột biến IDH1 gần như luôn nhằm vào vị trí hoạt động enzym Arg132, dẫn đến IDH1R132H chiếm ưu thế. Các tế bào mang đột biến IDH1 R132H -heterozygous sản xuất 2-hydroxyglutarate (2-HG), dẫn đến hypermethyl hóa histone và DNA. Mặc dù việc truyền IDH1 R132H từ bên ngoài đã được chứng minh là thúc đẩy sự phát triển độc lập với giá đỡ, vai trò sinh học của IDH1R132H trong glioma vẫn còn tranh cãi. Trong nghiên cứu này, chúng tôi chứng minh rằng IDH1 R132H -heterozygous ức chế nhưng IDH1 R132H -hemizygous thúc đẩy sự phát triển độc lập với giá đỡ. Trong khi việc xóa gen alen hoang dã trong các tế bào IDH1 R132H -heterozygous dẫn đến sự gia tăng rõ rệt việc hình thành neurosphere, việc khôi phục biểu hiện IDH1 trong các tế bào IDH1 R132H -hemizygous lại dẫn đến kết quả ngược lại. Ngược lại, sự phát triển độc lập với giá đỡ đối kháng với chức năng của IDH1 đột biến bằng cách ức chế biểu hiện gen và sản xuất 2-HG. Hơn nữa, chúng tôi xác định rằng trái ngược với neurosphere IDH1 R132H -hemizygous, các tế bào IDH1 R132H -heterozygous duy trì một mức năng lượng khử thấp để ức chế việc hình thành neurosphere, điều này có thể bị vượt qua tuy nhiên thông qua việc thêm chất khử. Tích lũy lại, những kết quả này nhấn mạnh tầm quan trọng chức năng của tính đa hình của đột biến IDH1 trong sinh học glioma và chỉ ra sự mất chức năng của IDH1 đột biến như một cơ chế thoát khỏi sự tiến triển của glioma và con đường cân bằng redox như những mục tiêu điều trị tiềm năng.

Từ khóa

#IDH1 #glioma #đột biến #cân bằng redox #phát triển độc lập với giá đỡ

Tài liệu tham khảo

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