The Role of MicroRNA in Cancer

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MicroRNA has emerged as a potential biomarker for cancer detection and treatment. This is because a large number of studies have definitely indicated miRNAs as a key player in cancer pathomechanism. This review provides two of dysregulatory mechanisms underlying cancer in which miRNAs play a central role including miRNA gene mutation and aberrant miRNA biogenesis as well briefly reporting miRNA biogenesis.

MicroRNAs (abbreviated miRNAs) are firstly identified in C. elegans in 1993, and today people have found miRNAs in most organisms (Rooij .V and Eva, 2011; Santulli and Gaetano, 2015). MiRNAs are characterized to be non-coding RNAs with a tiny size of about 22 nucleotides in a cell (Cai et al. 2009) and proved to be vital players in the negative regulation of gene expression (Santulli and Gaetano, 2015). MiRNAs significantly contribute to a variety of biological processes especially cell proliferation, differentiation and apoptosis in which abnormalities of miRNA function may cause cancer (Zhang et al. 2007; Santulli and Gaetano, 2015). Additionally, after a breakthrough revealed a correlation between miRNA and cancer in 2003 (Rooij and Eva, 2011), a research of Calin et al. in 2006 showed that the percentage of miRNA genes residing in fragile sites or cancer-related genomic area is up to over 50 percents. Another strong evidence of miRNAs’ role in cancer is served dysregulation of miRNAs. As a result, miRNAs are concerned as an important target in pathomechanism investigation and therapeutic invention in oncology. This paper reviews the previous literature to answer a research question: How do miRNAs involve in cancer formation? Although cancer-relevant miRNA detects are identified in a range of dysregulatory mechanisms, the review focus on two themes including miRNA gene mutation and aberrant miRNA biogenesis. Furthermore, biological synthesis of miRNAs is briefly reported in the paper.

Synthetic process of miRNAs occurs in both nucleus and cytoplasm with help of various proteins. In the nucleus, prior-miRNAs, large primary transcripts possessing a 5’ cap and 3’ polyadenylated tail, are transcribed by RNA polymerase II. Then the prior-miRNAs are sliced into a pre-miRNA with stem-loop shape containing about 85 nucleotides by a DGCR8/RNase Drosha III complex. Following exportation of the pre-miRNAs into the cytoplasm by a couple-protein complex called RanGTP/Exportin 5, miRNA/miRNA duplex with ~ 20 – 22 nucleotides in length is generated through processing the pre-miRNAs by RNase III Dicer and a peer protein TRBP. After that, a strand named mature miRNA is separated from miRNA/miRNA duplex and then bind protein complex RISC and orientate RISC to mRNA target (Peng and CRobe, 2016).

Involvement of MiRNAs is discovered in two biological processes: gene expression regulation and signaling pathway. Regarding inhibition of gene expression, in a majority of situations, miRNAs are complementary with mRNA target at 6-8 nucleotide region near 5’ end of the miRNAs called seed region. Complementarity of mRNA targets and miRNAs at seed region is coined Watson – Crick pairs (Bartel, 2009). In other situations, a recent research conducted by Helwak et al. found an alternative complementary side between miRNAs and cognate targets by using technique CLASH, and this side is independent of seed region. Consequently, if the interaction between miRNAs and mRNA targets is caused by imperfect complementarity, translation of the target will be repressed. In another case, a perfect base pairing leads to degradation of mRNAs. Turning to miRNA role in the signaling pathway, it is indicated that miRNAs portraying a ligand bind to Toll-like receptors, which may indirectly activate tumor growth and metastasis (Fabbi et al).

Biogenesis of miRNAs is under a tight control at the levels including miRNA transcription, miRNA processing, miRNA transportation, miRNA function with the regulation of a range of proteins

Dysregulation mechanisms of miRNAs in cancer

MiRNA synthesis experiences a tight control at many levels with the involvement of a range of proteins. Through a series of studies over past ten years dysregulation of miRNA expression has clearly known as one of the core causes of cancer formation. MiRNA gene mutation and aberrant miRNA biogenesis are two of fundamental mechanisms belong to miRNA dysregulation.

Aberrant miRNA biogenesis

As described above, a series of enzymes and proteins such as Dicer, Drosha, DGCR8, exportin 5, Argonaute proteins, etc. enroll apparatus of miRNA genesis to manipulate and regulate a formation of miRNAs as well correcting mistakes during a course from pri-miRNAs to mature miRNAs. Therefore, if any deviant behaviors of components in the machine due to mutation or abnormal expression arise unexceptionally, miRNAs will be expressed aberrantly.

Regardless of Drosha and Dicer, these RNA polymerase III involving in prior-miRNA and pre-miRNA processing are observed to be uncontrolled in several tumors. In particular, Walz et al. discovered that 15% of 534 Wilms’ tumors have Drosha and DGCR8 with substitution or deletion mutations at a single nucleotide, which negatively impacts the expression of mature Let -7a and miR-200 family. Other study found that Dicer1 decrease in colorectal cancer cells activates tumor formation and metastasis. Furthermore, there is a correlational research on the relationship between the level of Dicer/Drosha and median survival in ovarian cancer. The study identified that if the expression level of Dicer is high, sufferers have higher survival rate. Study of Karube et al. also revealed a positive correlation between Dicer content and let-7 expression in lung cancer.

Turning to Argonaute (AGO) proteins which catalyze RISC and support RNA-silencing process, lose of Argonaute protein coding EIF2C1/hAgo1 gene often occurs in Wilms’ tumors of the kidney. Another example of Argonaute proteins’ impact in cancer, a level of AGO2 gene expression in primary gastric cancer and lymph node metastases is higher than that in control samples.

According to a study by Melo et al., exportin 5 (XPO5) which takes responsibility for pre-miRNA transportation to cytoplasm are not expressed due to an inactivating genomic change in XPO5 gene. This leads to accumulation of pre-miRNAs in the nucleus and reduces expression of miRNAs.

MiRNA gene mutation

Deletion of miR-143 and miR-145 gene located on 5q33 area was often observed in lung cancer, causing reduction of these gene expressions (Calin). Besides of that, miR-17-92 cluster gene is amplified in B cell lymphomas and lung cancer, which leads to overexpression of miRNAs coded by miR-17-92. There are not only two above findings but also many pieces of evidence of miRNA mutation found in various cancers. This highly frequent miRNA gene mutation was also confirmed by experiment in which 227 specimens loading samples from ovarian cancer, breast cancer, and melanoma were tested by using high-resolution array-based comparative genomic hybridization. Further study revealed a half of miRNA genes reside in fragile sites or cancer-related genomic area. Overall, miRNA mutation genes cause abnormal expression of miRNA which generally leads to malignancy. Amplification and deletion are two popular forms of mutation in miRNA genes and these genomic changes occur high frequently (Peng and Crobe, 2016).

Thanks to advanced sequencing technology, abnormal miRNA genes were identified in a variety of malignancies, which is the first clue for a hypothesis of miRNA role in cancer and further research of pathomechanics and therapeutic discovery. This paper has answered a part of the research question in term of gene mutation and misregulation of miRNA biogenesis as well as summarizing how miRNAs are generated and how they function. Based on knowledge gained from this review, I have hypothesized that