Serine/Threonine Kinase MLK4 Determines Mesenchymal Identity in Glioma Stem Cells in an NF-κB-dependent Manner

被引：146

作者：

Kim, Sung-Hak ^{[1
]}

Ezhilarasan, Ravesanker ^{[3
]}

Phillips, Emma ^{[4
]}

Gallego-Perez, Daniel ^{[5
,6
,7
,8
]}

Sparks, Amanda ^{[9
]}

Taylor, David ^{[9
]}

Ladner, Katherine ^{[10
]}

Furuta, Takuya ^{[11
]}

Sabit, Hemragul ^{[11
]}

Chhipa, Rishi ^{[12
]}

Cho, Ju Hwan ^{[13
]}

Mohyeldin, Ahmed ^{[9
]}

Beck, Samuel ^{[14
]}

Kurozumi, Kazuhiko ^{[15
]}

Kuroiwa, Toshihiko ^{[16
]}

Iwata, Ryoichi ^{[17
]}

Asai, Akio ^{[17
]}

Kim, Jonghwan ^{[14
]}

Sulman, Erik P. ^{[3
]}

Cheng, Shi-Yuan ^{[18
,19
]}

Lee, L. James ^{[7
,8
,20
]}

Nakada, Mitsutoshi ^{[11
]}

Guttridge, Denis ^{[10
]}

DasGupta, Biplab ^{[12
]}

Goidts, Violaine ^{[4
]}

Bhat, Krishna P. ^{[21
]}

Nakano, Ichiro ^{[1
,2
]}

机构：

[1] Univ Alabama Birmingham, Dept Neurosurg, Birmingham, AL 35294 USA

[2] Univ Alabama Birmingham, UAB Comprehens Canc Ctr, Birmingham, AL 35294 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA

[4] German Canc Res Ctr, Div Mol Genet, D-69120 Heidelberg, Germany

[5] Ohio State Univ, Dept Surg, Columbus, OH 43210 USA

[6] Ohio State Univ, Dept Biomed Engn, Columbus, OH 43210 USA

[7] Ohio State Univ, Ctr Affordable Nanoengn Polymer Biomed, Columbus, OH 43210 USA

[8] Ohio State Univ, Ctr Regenerat Med & Cell Based Therapies, Columbus, OH 43210 USA

[9] Ohio State Univ, James Comprehens Canc Ctr, Dept Neurosurg, Columbus, OH 43210 USA

[10] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Human Canc Genet Program, Columbus, OH 43210 USA

[11] Kanazawa Univ, Dept Neurosurg, Kanazawa, Ishikawa 9208641, Japan

[12] Cincinnati Childrens Hosp Med Ctr, Div Oncol, Cincinnati, OH 45242 USA

[13] Ohio State Univ, Ctr Comprehens Canc, Dept Radiat Oncol, Columbus, OH 43210 USA

[14] Univ Texas Austin, Ctr Syst & Synthet Biol, Inst Cellular & Mol Biol, Dept Mol Biosci, Austin, TX 78712 USA

[15] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Neurol Surg, Okayama 7008558, Japan

[16] Osaka Med Coll, Dept Neurosurg, Osaka 5698686, Japan

[17] Kansai Med Univ, Dept Neurosurg, Osaka 5731191, Japan

[18] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Ken & Ruth Davee Dept Neurol, Chicago, IL 60611 USA

[19] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Northwestern Brain Tumor Inst,Ctr Genet Med, Chicago, IL 60611 USA

[20] Ohio State Univ, Dept Chem & Biomol Engn, Columbus, OH 43210 USA

[21] Univ Texas Houston, Dept Translat Mol Pathol, MD Anderson Canc Ctr, Houston, TX 77030 USA

来源：

CANCER CELL | 2016年 / 29卷 / 02期

基金：

日本学术振兴会;

关键词：

NEGATIVE REGULATOR; INITIATING CELLS; CANCER; GLIOBLASTOMA; GROWTH; PATHWAY; TRANSITION; RESISTANCE; EGFR; MICROENVIRONMENT;

D O I：

10.1016/j.ccell.2016.01.005

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Activation of nuclear factor kappa B (NF-kappa B) induces mesenchymal (MES) transdifferentiation and radioresistance in glioma stem cells (GSCs), but molecular mechanisms for NF-kappa B activation in GSCs are currently unknown. Here, we report that mixed lineage kinase 4 (MLK4) is overexpressed in MES but not proneural (PN) GSCs. Silencing MLK4 suppresses self-renewal, motility, tumorigenesis, and radioresistance of MES GSCs via a loss of the MES signature. MLK4 binds and phosphorylates the NF-kappa B regulator IKK alpha, leading to activation of NF-kappa B signaling in GSCs. MLK4 expression is inversely correlated with patient prognosis in MES, but not PN high-grade gliomas. Collectively, our results uncover MLK4 as an upstream regulator of NF-kappa B signaling and a potential molecular target for the MES subtype of glioblastomas.

引用

页码：201 / 213

页数：13

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