LKB1/STK11 失活导致黑色素瘤中促转移肿瘤亚群的扩增。
LKB1/STK11 inactivation leads to expansion of a prometastatic tumor subpopulation in melanoma.
机构信息
Department of Genetics, The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7295, USA.
出版信息
Cancer Cell. 2012 Jun 12;21(6):751-64. doi: 10.1016/j.ccr.2012.03.048.
Abstract
Germline mutations in LKB1 (STK11) are associated with the Peutz-Jeghers syndrome (PJS), which includes aberrant mucocutaneous pigmentation, and somatic LKB1 mutations occur in 10% of cutaneous melanoma. By somatically inactivating Lkb1 with K-Ras activation (±p53 loss) in murine melanocytes, we observed variably pigmented and highly metastatic melanoma with 100% penetrance. LKB1 deficiency resulted in increased phosphorylation of the SRC family kinase (SFK) YES, increased expression of WNT target genes, and expansion of a CD24(+) cell population, which showed increased metastatic behavior in vitro and in vivo relative to isogenic CD24(-) cells. These results suggest that LKB1 inactivation in the context of RAS activation facilitates metastasis by inducing an SFK-dependent expansion of a prometastatic, CD24(+) tumor subpopulation.
摘要
LKB1（STK11）种系突变与 Peutz-Jeghers 综合征（PJS）相关，其包括黏膜皮肤色素沉着异常，而体细胞 LKB1 突变发生于 10%的皮肤黑色素瘤中。通过在鼠黑素细胞中用 K-Ras 激活（±p53 缺失）来体细胞失活 Lkb1，我们观察到色素沉着可变和高度转移性黑色素瘤，其具有 100%的外显率。LKB1 缺失导致 SRC 家族激酶（SFK）YES 的磷酸化增加，WNT 靶基因的表达增加，以及 CD24(+)细胞群体的扩增，与同基因 CD24(-)细胞相比，其在体外和体内表现出增加的转移行为。这些结果表明，在 RAS 激活的背景下 LKB1 失活通过诱导 SFK 依赖性的促进转移的 CD24(+)肿瘤亚群的扩增来促进转移。
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