RAS expression in human cells All the three RAS genes in human, K-, N-, and H-, have the predicted let-7 binding sequences in their 3'UTRs. In lung cancer patient samples, expression of RAS and let-7 showed reciprocal pattern, which has low let-7 and high RAS in cancerous cells, and high let-7 and low RAS in normal cells. Another oncogene, high mobility group A2 (HMGA2), has also been identified as a target of let-7. Let-7 directly inhibits HMGA2 by binding to its 3'UTR. Removal of let-7 binding site by 3'UTR deletion cause overexpression of HMGA2 and formation of tumor. Cell cycle, proliferation, and apoptosis regulators Microarray analyses revealed many genes regulating cell cycle and cell proliferation that are responsive to alteration of let-7 levels, including cyclin A2, CDC34, Aurora A and B kinases (STK6 and STK12), E2F5, and CDK8, among others. Subsequent experiments confirmed the direct effects of some of these genes, such as CDC25A and CDK6. Let-7 also inhibits several components of DNA replication machinery, transcription factors, even some tumor suppressor genes and checkpoint regulators. Apoptosis is regulated by let-7 as well, through Casp3, Bcl2, Map3k1 and Cdk5 modulation. Immunity Let-7 has been implicated in post-transcriptional control of innate immune responses to pathogenic agents. Macrophages stimulated with live bacteria or purified microbial components down-regulate the expression of several members of the let-7 microRNA family to relieve repression of immune-modulatory cytokines IL-6 and IL-10. Let-7 has also been implicated in the negative regulation of TLR4, the major immune receptor of microbial lipopolysaccharide and down-regulation of let-7 both upon microbial and protozoan infection might elevate TLR4 signalling and expression. Let-7 has furthermore been reported to regulate the production of cytokine IL-13 by T lymphocytes during allergic airway inflammation thus linking this microRNA to adaptive immunity as well. Down-modulation of let-7 negative regulator Lin28b in human T lymphocytes is believed to accrue during early neonate development to reprogram the immune system towards defense. Potential clinical use in cancer Given the prominent phenotype of cell overproliferation and undifferentiation by let-7 loss-of-function in nematodes, and the role of its targets on cell destiny determination, let-7 is closely associated with human cancer and acts as a tumor suppressor. Diagnosis Numerous reports have shown that the expression levels of let-7 are frequently low and the chromosomal clusters of let-7 are often deleted in many cancers. Let-7 is expressed at higher levels in more differentiated tumors, which also