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A Temporarily Distinct Subpopulation
~' d% G3 t0 ~' v2 Nof Slow-Cycling Melanoma Cells
/ `$ Z2 o( f% v( u8 {+ N& Z. G) `Is Required for Continuous Tumor Growth- O" M: K' F9 |: ` }# H8 W
% u D+ g6 M; u# L% `0 W9 gMelanomas are highly heterogeneous tumors, but the biological significance of their different subpopulations is not clear. Using the H3K4 demethylase JARID1B (KDM5B/PLU-1/RBP2-H1) as a biomarker, we have characterized a small subpopulation of slow-cycling melanoma cells that cycle with doubling times of >4 weeks within the rapidly proliferating main population. Isolated JARID1B-positive melanoma cells give rise to a highly proliferative progeny. Knockdown of JARID1B leads to an initial acceleration of tumor growth followed by exhaustion
3 o D x' C4 u' I" N+ Jwhich suggests that the JARID1B-positive subpopulation is essential for continuous tumor growth. Expression of JARID1B is dynamically regulated and does not follow a hierarchical cancer stem cell model because JARID1B-negative cells can become positive and even single melanoma cells irrespective of selection are tumorigenic. These results suggest a new understanding of melanoma heterogeneity with tumor maintenance as a dynamic process mediated by a temporarily distinct subpopulation.
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