Cancer esearch or and Stem Cell Biology lication of Metastasis Suppressor NM 23-H 1 in ntaining Adherens Junctions and Limiting the R sive Potential of Human Cancer Cells

nloaded s of NM23-H1 expression correlates with the degree of metastasis and with unfavorable clinical osis in several types of human carcinoma. However, the mechanistic basis for the metastasis suppressor on of NM23-H1 is obscure. We silenced NM23-H1 expression in human hepatoma and colon carcinoma nd methodologically investigated effects on cell-cell adhesion, migration, invasion, and signaling linked cer progression. NM23-H1 silencing disrupted cell-cell adhesion mediated by E-cadherin, resulting in nin nuclear translocation and T-cell factor/lymphoid-enhancing factor-1 transactivation. Further, H1 silencing promoted cellular scattering, motility, and extracellular matrix invasion by promoting inodia formation and upregulating several matrix metalloproteinases (MMP), including membrane type 1 In contrast, silencing the related NM23-H2 gene was ineffective at promoting invasion. NM23-H1 silenctivated proinvasive signaling pathways involving Rac1, mitogen-activated protein kinases, phosphatidytol 3-kinase (PI3K)/Akt, and src kinase. Conversely, NM23-H1 was dispensable for cancer cell ration in vitro and liver regeneration in NM23-M1 null mice, instead inducing cellular resistance to cherapeutic drugs in vitro. Analysis of NM23-H1 expression in clinical specimens revealed high expression malignant lesions (liver cirrhosis and colon adenoma) and the central body of primary liver or colon s, but downregulation at the invasive front of tumors. Our findings reveal that NM23-H1 is critical for l of cell-cell adhesion and cell migration at early stages of the invasive program in epithelial contro cancers, orchestrating a barrier against conversion of in situ carcinoma into invasive malignancy. Cancer Res; 70(19); 7710–22. ©2010 AACR.

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