A precursor microRNA in a cancer cell nucleus: get me out of here!

Abstract

In line with their broad-based effects, microRNAs (miRNAs), small non-coding RNA molecules ~22 nucleotides long that silence target mRNAs, are thought to act as oncogenes or tumor suppressor genes based on their inhibition of tumor-suppressive and oncogenic mRNAs, respectively. We and others previously showed that global downregulation of miRNAs, a common feature of human tumors, is functionally relevant to oncogenesis as impairment of miRNA biogenesis enhanced transformation in both cancer cells and a K-Ras-driven model of lung cancer. The dysregulation of miRNA biosynthesis in cancer emerges as a cancer-specific mechanism that enhances its tumorigenic capacity. These observations are further supported by the fact that frameshift mutations of TARBP2 occur in sporadic and hereditary carcinomas with microsatellite instability and that DICER1 mutations are associated with familial pleuropulmonary blastoma. Accordingly, it was reported that reduced expression of miRNA-processing factors is associated with poor prognosis in lung cancer and ovarian cancer. Recently we have also demonstrated the presence of Exportin 5 (XPO5) inactivating mutations in tumors with microsatellite instability. This observed genetic defect is responsible for nuclear retention of pre-miRNAs, thereby reducing miRNA processing. The characterized mutant form of the XPO5 protein lacks a C-terminal region that contributes to the formation of the pre-miRNA/XPO5/Ran-GTP ternary complex and the protein itself, as well as pre-miRNAs accumulating in the nucleus of cancer cells. Most importantly, the restoration of XPO5 function reverses the impaired export of pre-miRNAs and has tumor suppressor features. Our data suggest a cancer-specific mechanism to guide the subcellular distribution of miRNA precursors and prevent them from being processed to the active mature miRNA. The control of the miRNA biosynthesis pathway is emerging as an important mechanism in defining the spatiotemporal pattern of miRNA expression in cancer cells.

Figure 1

Inefficient nuclear export of a precursor microRNA by the presence of an inactivating mutation in the exportin 5 gene that prevents the formation of a functional XPO5/RAN/GTP/pre-miRNA complex.