Implication of metastasis suppressor NM23-H1 in maintaining adherens junctions and limiting the invasive potential of human cancer cells.
Loss of NM23-H1 expression correlates with the degree of metastasis and with unfavorable clinical prognosis in several types of human carcinoma. However, the mechanistic basis for the metastasis suppressor function of NM23-H1 is obscure. We silenced NM23-H1 expression in human hepatoma and colon carcinoma cells and methodologically investigated effects on cell-cell adhesion, migration, invasion, and signaling linked to cancer progression. NM23-H1 silencing disrupted cell-cell adhesion mediated by E-cadherin, resulting in β-catenin nuclear translocation and T-cell factor/lymphoid-enhancing factor-1 transactivation. Further, NM23-H1 silencing promoted cellular scattering, motility, and extracellular matrix invasion by promoting invadopodia formation and upregulating several matrix metalloproteinases (MMP), including membrane type 1 MMP. In contrast, silencing the related NM23-H2 gene was ineffective at promoting invasion. NM23-H1 silencing activated proinvasive signaling pathways involving Rac1, mitogen-activated protein kinases, phosphatidylinositol 3-kinase (PI3K)/Akt, and src kinase. Conversely, NM23-H1 was dispensable for cancer cell proliferation in vitro and liver regeneration in NM23-M1 null mice, instead inducing cellular resistance to chemotherapeutic drugs in vitro. Analysis of NM23-H1 expression in clinical specimens revealed high expression in premalignant lesions (liver cirrhosis and colon adenoma) and the central body of primary liver or colon tumors, but downregulation at the invasive front of tumors. Our findings reveal that NM23-H1 is critical for control of cell-cell adhesion and cell migration at early stages of the invasive program in epithelial cancers, orchestrating a barrier against conversion of in situ carcinoma into invasive malignancy.
Boissan
Mathieu
M
UPMC Université Paris 06, Paris, France. mathieu.boissan@inserm.fr
De Wever
Olivier
O
Lizarraga
Floria
F
Wendum
Dominique
D
Poincloux
Renaud
R
Chignard
Nicolas
N
Desbois-Mouthon
Christèle
C
Dufour
Sylvie
S
Nawrocki-Raby
Béatrice
B
Birembaut
Philippe
P
Bracke
Marc
M
Chavrier
Philippe
P
Gespach
Christian
C
Lacombe
Marie-Lise
ML
D000199:Actins / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D022005:Adherens Junctions / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology; D020868:Gene Silencing; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D054778:NM23 Nucleoside Diphosphate Kinases / Q000096:biosynthesis / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051153:Wnt Proteins / Q000378:metabolism
D000199:Actins; D054778:NM23 Nucleoside Diphosphate Kinases; D051153:Wnt Proteins; C517938:NME1 protein, human; D053511:Matrix Metalloproteinase 14