Abstract
Human cancers often exhibit attenuated miRNA biogenesis and global underexpression of miRNAs, thus targeting the miRNA biogenesis pathway represents a novel strategy for cancer therapy. Here, we report that miR-26a enhances miRNA biogenesis, which acts as a common mechanism partially accounting for miR-26a function in diverse cancers, including melamona, prostate and liver cancer. miR-26a was broadly reduced in multiple cancers and overexpression of miR-26a significantly suppressed tumor growth and metastasis both
in vitro
and
in vivo
, including melanoma, prostate and liver cancer. Notably, miR-26a overexpression was accompanied by global upregulation of miRNAs, especially let-7, and let-7 expression was concordant with miR-26a expression in cancer cell lines, xenograft tumors and normal human tissues, underscoring their biologic relevance. We showed that miR-26a directly targeted Lin28B and Zcchc11, two critical repressors of let-7 maturation. Furthermore, we have demonstrated that Zcchc11 promoted tumor growth and metastasis and it was prominently overexpressed in human cancers. Our findings thus provide a novel mechanism by which a miRNA acts as a modulator of miRNA biogenesis. These results also define a role of the miR-26a and Zcchc11 in tumorigenesis and metastasis, and have implications to develop new strategies for cancer therapy.
