The <i>let-7</i> MicroRNA Represses Cell Proliferation Pathways in Human Cells

TLDR

MicroRNAs regulate development, differentiation, and metabolism and are implicated in cancer, with let‑7 controlling cell‑cycle exit in *C. elegans* and being down‑regulated in human lung tumors. The study shows that let‑7 directly or indirectly represses RAS oncogenes and multiple cell‑cycle genes, thereby modulating proliferation pathways. Inhibition of let‑7 increases division in A549 cells, while overexpression suppresses proliferation, demonstrating let‑7 as a master tumor‑suppressive regulator of cell‑cycle pathways.

Abstract

Abstract MicroRNAs play important roles in animal development, cell differentiation, and metabolism and have been implicated in human cancer. The let-7 microRNA controls the timing of cell cycle exit and terminal differentiation in Caenorhabditis elegans and is poorly expressed or deleted in human lung tumors. Here, we show that let-7 is highly expressed in normal lung tissue, and that inhibiting let-7 function leads to increased cell division in A549 lung cancer cells. Overexpression of let-7 in cancer cell lines alters cell cycle progression and reduces cell division, providing evidence that let-7 functions as a tumor suppressor in lung cells. let-7 was previously shown to regulate the expression of the RAS lung cancer oncogenes, and our work now shows that multiple genes involved in cell cycle and cell division functions are also directly or indirectly repressed by let-7. This work reveals the let-7 microRNA to be a master regulator of cell proliferation pathways. [Cancer Res 2007;67(16):7713–22]