LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling.
LKB1 loss-of-function mutations, observed in ∼30% of human lung adenocarcinomas, contribute significantly to lung cancer malignancy progression. We show that lysyl oxidase (LOX), negatively regulated by LKB1 through mTOR-HIF-1α signaling axis, mediates lung cancer progression. Inhibition of LOX activity dramatically alleviates lung cancer malignancy progression. Up-regulated LOX expression triggers excess collagen deposition in Lkb1-deficient lung tumors, and thereafter results in enhanced cancer cell proliferation and invasiveness through activation of β1 integrin signaling. High LOX level and activity correlate with poor prognosis and metastasis. Our findings provide evidence of how LKB1 loss of function promotes lung cancer malignancy through remodeling of extracellular matrix microenvironment, and identify LOX as a potential target for disease treatment in lung cancer patients.
Gao
Yijun
Y
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
Xiao
Qian
Q
Ma
HuiMin
H
Li
Li
L
Liu
Jun
J
Feng
Yan
Y
Fang
Zhaoyuan
Z
Wu
Jing
J
Han
Xiangkun
X
Zhang
Junhua
J
Sun
Yihua
Y
Wu
Gongwei
G
Padera
Robert
R
Chen
Haiquan
H
Wong
Kwok-kin
KK
Ge
Gaoxiang
G
Ji
Hongbin
H
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D000818:Animals; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008817:Mice, Mutant Strains; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
D016326:Extracellular Matrix Proteins; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C077112:Lox protein, mouse; D008249:Protein-Lysine 6-Oxidase; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases