The let-7 MicroRNA Represses Cell Proliferation Pathways in Human Cells

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]

MicroRNAs as potential cancer therapeutics

“…In support of the significance of our findings, reduced expression of let-7 is correlated with poor prognosis, as lung cancer patients with the least let-7 expression had shorter time of survival after surgery (Takamizawa et al, 2004;Yanaihara et al, 2006). We and others subsequently showed that let-7 directly regulates multiple oncogenes, including RAS, MYC and HMGA2 (Johnson et al, 2005;Lee and Dutta, 2007;Mayr et al, 2007;Sampson et al, 2007), and promoters of cell-cycle progression, such as CDC25A, CDK6 and Cyclin D2 (Johnson et al, 2007). Moreover, administration of let-7 blocks the growth of cultured lung cancer cells (Johnson et al, 2007).…”

“…We and others subsequently showed that let-7 directly regulates multiple oncogenes, including RAS, MYC and HMGA2 (Johnson et al, 2005;Lee and Dutta, 2007;Mayr et al, 2007;Sampson et al, 2007), and promoters of cell-cycle progression, such as CDC25A, CDK6 and Cyclin D2 (Johnson et al, 2007). Moreover, administration of let-7 blocks the growth of cultured lung cancer cells (Johnson et al, 2007).…”

“…These novel classes of cellular regulators have been shown to be involved in regulating various processes, such as cell cycle, proliferation, apoptosis, differentiation and development (Esquela-Kerscher and Slack, 2006;Johnson et al, 2007;Hermeking, 2009;Wang and Olson, 2009). Recent studies have also provided evidence that aberrant expression of specific miRNAs is implicated in a broad spectrum of human diseases, including diabetes, cardiovascular disease and cancer (Esquela-Kerscher and Slack, 2006;Pandey et al, 2009;Zorio et al, 2009).…”

Genetic modulation of the Let-7 microRNA binding to KRAS 3′-untranslated region and survival of metastatic colorectal cancer patients treated with salvage cetuximab–irinotecan

“…6,7 These findings led to growing interest in Let-7 and its role in cancer development and control. [8][9][10] It has been recently found that polymorphisms may affect miRNA-mediated regulation of cell functions. They can be present in the 3 0 -UTR of a target mRNA and in the genes involved in miRNA genesis and maturation.…”

MicroRNAs in hereditary and sporadic premature aging syndromes and other laminopathies

“…For example, miRNAs are central players during development (e.g., neural or cardiac; Abernathy & Yoo, 2015; Porrello, 2013; Reinhart et al., 2000) or immunity (Zhu, Pan & Qian, 2013). They play an important role in all cellular processes, such as cell proliferation (Johnson et al., 2007; Navarro & Lieberman, 2010), differentiation (Navarro & Lieberman, 2010), and apoptosis (Ghodgaonkar et al., 2009). They have been largely studied in cancer, in which they are described to function as oncogenes or tumor suppressor genes and are grouped under the term “oncomiRs” (Bracken, Scott & Goodall, 2016; Hayes, Peruzzi & Lawler, 2014).…”