This study investigates the role of microRNAs (miRNAs) in human cancer metastasis, focusing on the epigenetic silencing of tumor suppressor miRNAs through DNA methylation. The authors used a pharmacological and genomic approach to identify miRNAs that are hypermethylated in metastatic cancer cells. They found that miR-148a, miR-34b/c, and miR-9 were specifically hypermethylated in cancer cells compared to normal tissues. Treatment with a DNA demethylating agent restored the expression of these miRNAs, which inhibited the motility, tumor growth, and metastasis formation in vitro and in vivo. The study also demonstrated that the hypermethylation of these miRNAs was associated with the upregulation of oncogenic target genes such as C-MYC, E2F3, CDK6, and TGF2. Furthermore, the hypermethylation of these miRNAs was significantly associated with the presence of lymph node metastasis in human primary malignancies. These findings highlight the importance of DNA methylation-associated silencing of tumor suppressor miRNAs in the development of human cancer metastasis and suggest potential therapeutic targets for cancer patients with metastatic disease.This study investigates the role of microRNAs (miRNAs) in human cancer metastasis, focusing on the epigenetic silencing of tumor suppressor miRNAs through DNA methylation. The authors used a pharmacological and genomic approach to identify miRNAs that are hypermethylated in metastatic cancer cells. They found that miR-148a, miR-34b/c, and miR-9 were specifically hypermethylated in cancer cells compared to normal tissues. Treatment with a DNA demethylating agent restored the expression of these miRNAs, which inhibited the motility, tumor growth, and metastasis formation in vitro and in vivo. The study also demonstrated that the hypermethylation of these miRNAs was associated with the upregulation of oncogenic target genes such as C-MYC, E2F3, CDK6, and TGF2. Furthermore, the hypermethylation of these miRNAs was significantly associated with the presence of lymph node metastasis in human primary malignancies. These findings highlight the importance of DNA methylation-associated silencing of tumor suppressor miRNAs in the development of human cancer metastasis and suggest potential therapeutic targets for cancer patients with metastatic disease.