MicroRNAs and cancer

https://doi.org/10.1016/S1044-579X(03)00038-5Get rights and content

Abstract

The general basis of cancer is the loss of cell identity and inappropriate proliferation of cells. Classically, a universal paradigm in oncogenesis is the accumulation of mutations in the open reading frames of protein-encoding oncogenes and tumor suppressors. The identification of new classes of noncoding RNAs (ncRNA) important for development and cell homeostasis will likely change this current paradigm. Recent data suggests that a special class of ncRNAs called microRNAs might be involved in human disease. This review proposes a role for microRNAs in oncogenesis.

Introduction

A fundamental effort of both cancer biology and developmental biology is to determine the genes and cellular mechanisms that establish and maintain the identity of a cell. Cell identity, whether blood, bone, or brain, is established in a highly regulated manner during development. Proliferation and controlled apoptosis, both regulated spatially and temporally, are important factors in sculpting tissue of defined structure. Cancer cells have defects in these regulatory pathways that mitigate the controlled proliferation and differentiation of normal cell homeostasis. As a consequence, normal tissue morphology is lost and the rapidly proliferating tumor cells usurp normal tissue space. Thus, while developmental biology deals with how cells acquire and maintain their normal function, cancer is a result of a cells breaking loose from their correct controls and becoming abnormal. In this way, cancer is simply normal cell development gone awry.

To understand what goes wrong when a cell becomes cancerous requires knowledge of the processes that ensure normal development. This includes the six essential alterations in cell physiology that collectively dictate malignant growth: self-sufficiency in growth signals, insensitivity to growth inhibitory (antigrowth) signals, evasion of programmed cell death (apoptosis), limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis [1]. It is clear that gene expression is altered in cells in cancer, and many labs are aggressively furthering our understanding of the role of these genes.

Most studies in cancer biology have dealt largely with the protein-encoding oncogenes which have clear roles in cancer: cell cycle, telomere maintenance, apoptotic pathways, or pathways which stimulate angiogenesis or metastasis. Many of these proteins were first identified through observations that disruptions or mutations in these genes correlated with the oncogenic state. However, since most cancer cells contain several to many mutated genes, it is a daunting task to map all of the relevant mutations. Even further complicating the task is the fact that mutations may occur in coding genes, noncoding genes, and regulatory sequences. Is it possible that relevant mutations in cancer are occurring in nonprotein-encoding genes? This review discusses this possibility, and offers a new mechanism by which small noncoding RNAs (ncRNA) can participate in cancer.

ncRNA genes produce functional RNA molecules rather than encoding proteins. They can range in size from 21 nt for the large family of developmentally important micro-RNAs (miRNAs) up to >10,000 nt for RNAs such as Xist, which participates in globally silencing expression of the X chromosomal genes (see review by Sean Eddy [2]). Many ncRNA genes are just beginning to be identified, since there has been no general and easy way to pick them out of genomic sequences [3].

Section snippets

MicroRNAs

miRNAs represent a new class of highly conserved ncRNAs whose functions are generally unknown, but believed to be important in development. This belief is based on studies of two miRNA in Caenorhabditis elegans, the lineage-4 (lin-4) and lethal-7 (let-7) small temporal RNAs (stRNAs). The C. elegans lin-4 regulatory gene product is a 22-nucleotide RNA, processed from a ∼60-nucleotide precursor hairpin. It was identified in a screen for mutations that affected the timing and sequence of

mir-15/16

It can be predicted that the involvement of ncRNAs in disease will become an important issue as we struggle to define what functions miRNAs perform. A recent report suggests the involvement of two miRNAs in chronic lymphocytic leukemia (CLL), the most common form of adult leukemia in the western world [24], [25]. Hemizygous and/or homozygous loss at 13q14 constitute the most frequent chromosomal abnormality in CLL. Deletions at this region also occur in approximately 50% of mantle cell

Disruption of miRNA loci

It is also possible that cancer could result from translocations into oncogene loci. One such potential example of this is the translocation of MYC into the mir-142 loci, which causes an aggressive B-cell leukemia due to strong upregulation of MYC expression [35]. The MYC gene translocated only four nucleotides downstream of the mir-142 3′-end, and was probably under control of the upstream miRNA promoter. Alignment of mouse and human miR-142 containing EST sequences indicates ∼20 nt conserved

Bic

It is likely that most miRNAs are transcribed as long precursors (200 to >1000 nt) [37]. In fact, many miRNAs can be found nested within >300 nucleotide long RNAs in EST libraries, some with poly(A) tails, suggesting that polymerase II might be the transcribing polymerase. Several studies have described ncRNAs capable of mitigating biological responses when inappropriately expressed. Such is the case for the mammalian bic ncRNA [38], [39], [40], [41]. The bic RNA locus is a common retroviral

His-1

The His-1 gene is expressed as a 3-kb spliced and polyadenylated RNA that is believed to function as a ncRNA [43]. Although the precise function of the His-1 gene is unknown, its transcriptional activation in a series of mouse leukemias has implicated the His-1 RNA in leukemogenesis when it is abnormally expressed. In situ hybridization detects low-level His-1 expression in some epithelia tissues of the adult mouse, however, the His-1 transcript is readily detectable in mouse leukemias and in

Conclusion

These data can be assimilated into a speculative model where miRNAs could be contributors for oncogenesis (Fig. 2). Thus far, we have seen situations where normal miRNA expression might be lost, as in the case of mir-15/16 or mir-142, where deletion or disruption of the natural locus abrogates expression. In this case, the miRNA might serve the role as a tumor suppressor. In the other case, expression of the ncRNA or miRNA (bic and His-1 RNAs) is inappropriately up-regulated, commensurate with

Note added in press

As the microRNA field is rapidly developing, additional relevant papers have appeared during the time of press. Two additional papers have appeared which study the potential interplay of hormones and microRNAs. Please see [50], [51].

In addition to the above, strong evidence for miRNA involvement in mediating cell death have been recently published. These two reports strengthen the possible role of miRNAs in cancer. Please see [52], [53].

Acknowledgements

I wish to acknowledge Phil Sharp, Alla Grishok, Chris Petersen and Chonghui Cheng for suggestions and insightful comments. M.T.M. is a fellow of the Cancer Research Institute.

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