|Year : 2014 | Volume
| Issue : 4 | Page : 805-810
Regulatory mechanisms and clinical perspectives of miR-34a in cancer
Department of Radiology, Children's Hospital of Soochow University, Suzhou, China
|Date of Web Publication||9-Jan-2015|
Department of Radiology, Children's Hospital of Soochow University, 303 Jingde Lu, Suzhou 215000
Source of Support: None, Conflict of Interest: None
MicroRNAs (miRNAs) are evolutionarily conserved, endogenous, noncoding RNA molecules of about 22-24 nucleotides in length that repress gene expression at the posttranscriptional level. MiR-34a plays an important role in the initiation, progression, and therapy of cancer. In addition, the miR-34a expression has also been identified as a diagnostic and prognostic cancer signature. This article introduces the roles of miR-34a in cancer development, metastasis as well as its mechanism of actions on target genes and the functional outcomes of its actions on radio-sensitivity. The paper ends with a brief perspective to the future of miR-34a.
Keywords: Cancer, clinical application, miR-34a
|How to cite this article:|
Li L. Regulatory mechanisms and clinical perspectives of miR-34a in cancer. J Can Res Ther 2014;10:805-10
| > Introduction|| |
A microRNA (miRNA) is defined as a small regulatory RNA molecule that consists of noncoding RNA of about 22 nucleotides in length.  miRNA binds to the 3'- untranslated regions of target genes in a complete or an incomplete complementary manner through its "seed sequence" in the 5'-region and controls expression of target genes at the posttranscriptional level.  A miRNA can have several hundreds of targets; and on the contrary, a gene has a variety of target sites for different miRNAs synergizing the down-regulation by multiple miRNAs.  So far, a large number of miRNAs have been denoted in the human genome, and the number is ever increasing, illustrating the potential of miRNAs as significant players in gene regulations. Aberrant expressions of miRNAs have been linked to various diseases including cancers,  highlighting their functions in safeguarding normal cell proliferation, apoptosis, and metabolism. Carcinogenesis is a multistep process whose activity is regulated by sequential alterations in a variety of oncogenes, tumor-suppressor genes, and miRNAs. 
The miR-34 family consists of three members: miR-34a, miR-34b, and miR-34c. miR-34a is located on chromosome 1p36, whereas miR-34b and miR-34c share a common host gene located on chromosome 11q23.  miR-34a is expressed at higher levels than miR-34b/c in most tissues, except in lungs, where miR-34b and miR-34c are predominant. , miR-34a has its own transcript, and usually it is ectopically expressed in multiple diseases, especially in cancers. Ectopic miR-34a expression regulates apoptosis, cell cycle and differentiation, , thereby playing a functional basis for the regulatory role in carcinogenesis. , In addition, miR-34a is reported to be involved in the proliferation and apoptosis of stem cells and as a suppressor of carcinogenesis. , miR-34a is known to regulate target genes that regulate cell cycle, cellular proliferation, apoptosis, DNA repair, and angiogenesis, ,,, therefore, miR-34a has provided new direction for cancer research.
In this review, we primarily illustrate our understanding of the role of miR-34a in carcinogenesis from various aspects, including the process of DNA damage repair, cell cycle, differentiation, and apoptosis. We also highlight the clinical perspectives of miR-34a in the detection, treatment, and prognosis of cancers and further identify the significance of exploring new mechanisms and discovering potential targets to improve the therapeutic effects of radiotherapy.
| > mir-3 a in biogenesis|| |
miRNA is a noncoding small RNA of 22-25 nucleotides, which leads to mRNA degradation or translational inhibition of its target genes.  miRNAs are involved in multiple cellular processes, including cellular differentiation, proliferation, apoptosis, and senescence. Mitotic cell cycle is a constantly reproducible sequence of events, which has four phases: G1 phase, S phase, G2 phase, and M phase. The expression and activation of cyclin-dependent kinases (CDKs) and cyclin may play an important role in proceeding from the G1 to S phase (DNA replication) and from the G2 to M phase (mitosis). miR-34a has many potential target genes, with several of these regular cell cycles, including CCND1, CDK6, c-MET, and platelet-derived growth factor receptor-β, have been experimentally validated, which led to a significant reduction in the number of cells in the S phase of the cell cycle, an increase in the number of cells in the G0/G1 phase. ,, These target genes promote cells to proceed from the G1 to S phase. Silencing of them would induce cell arrest in the G1 phase [Figure 1].
|Figure 1: MiR-34a regulates a plethora of target genes, which induce cell G1 arrest and differentiation|
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miR-34a has also been found to be involved in cellular differentiation. Ichimura et al. found that MEK1 and C-FOS were found to be suppressed by miR-34a during phorbol ester-induced megakaryocyte differentiation in K-562 cells.  Tarantino et al. found that overexpression of a mixture of miR-34a, miR-100, and miR-137 induced mouse embryonic stem cells differentiation through the down-regulation of Wnt1 and SIRT1, which were validated to be the target genes of miR-34a.  De Antonellis et al. reported that down-regulation of Notch ligand delta-like 1 expression by miR-34a negatively regulates cell proliferation and induces apoptosis and neural differentiation in medulloblastoma cells.  These studies suggested a versatile involvement of miR-34a in cellular differentiation [Figure 1].
miR-34a, a direct target of p53, has been showed to induce apoptosis by targeting several genes. ,,,, Welch et al. reported that ectopic miR-34a induces apoptosis when reintroduced into the neuroblastoma cell lines.  Chakraborty et al. found that the restoration of p53/miR-34a axis ensures Bax-dependent apoptosis of nonsmall cell lung carcinoma cells.  Lin et al. concluded that direct suppression of Bcl-2 by miR-34a increased apoptosis rate in pancreatic β-cell.  Furthermore, locked nucleic acids directed against miR-34a protect cells to some extent from the DNA damage-induced apoptosis in wild-type p53-expressing cells. Chang et al. showed that miR-34a-induced apoptosis is dependent on the presence of wild-type p53 indicating that the miR-34a may feed back to p53.  The p53-mediated processes of apoptosis in colon cancer cells could be affected by down-regulation of miR-34a.  Interestingly, a positive feedback loop exists between p53 and miR-34a. ,, Alternative reading frame (ARF) is a tumor suppressor protein triggers p53-dependent responses with apoptosis induction.  Velimezi showed that ARF is positively regulated by the DNA damage response (DDR). ATM, a key factor of the DDR, suppressed ARF protein levels and activity in a transcription-independent manner.  Zhang et al. reported that Nemo-like kinase is required for p53 activation in response to DNA damage.  The effects of DDR, ATM, and ARF in the p53/miR-34a axis can be seen in [Figure 2].
|Figure 2: The effects of DNA damage response, ATM, and ARF in the p53/miR-34a axis|
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| > The Biological Role of m iR-3 a in Cancer|| |
Alterations of miRNA expressions in cancer have been demonstrated in numerous studies. ,, A large number of human malignancies are associated with nonrandom 1p36 deletions, suggesting the existence of tumor suppressors encoded in this region. ,, miR-34a is located in the region of chromosome 1p36,  many studies found that the expression of miR-34a is reduced in cancer cells and miR-34a is regarded as a common tumor suppressor. ,, Cao et al. investigated that miR-34a expression in gastric cancer cells was significantly decreased compared to the normal gastric epithelial cell line GES-1. However, increasing the expression of miR-34a in gastric cancer cells can significantly decrease the proliferation index and induce cellular apoptosis.  Xia et al. reported that treatment of pancreatic cancer cells with a natural compound genistein led to the up-regulation of miR-34a, resulting in the down-regulation of Notch-1, which was correlated with inhibition of cell growth and induction of apoptosis. 
Recent studies have investigated that epigenetic mechanisms, including DNA methylation and histone modification, not only regulate the expression of protein-encoding genes, but also regulate the expression of miRNAs, such as miR-34a, let-7a, miR-124, miR-137, miR-148, and miR-203. ,, DNA methylation refers to the addition of a methyl group (-CH 3 ) to the cytosine ring of a CpG dinucleotide at the carbon 5 position, which is catalyzed by DNA methyltransferases (DNMTs). A CpG island is found in the promoter of miR-34a, according to the characterized promoter regions and transcription start sites. , DNA methylation is regarded as a possible mechanism leading to the silencing of miR-34a.  The epigenetic inactivation of miR-34a has been identified in many common cancers (lung, breast, colon, kidney, bladder, pancreatic cancer, and melanoma) and also in cell lines derived from those cancers. , Taken together, inactivation of the miR-34a presumably is a common event during tumorigenesis [Figure 3].
| > m iR-3 a in Cancer Detection, Prognosis and Therapy|| |
The increasing evidences show that miRNAs can act as oncogenes or tumor suppressors and may play vital roles in tumorigenesis. , The miRNA expression profiles may become useful biomarkers for cancer detection, prognosis, and prediction of therapy-response. ,, It has been demonstrated that miR-34a has potent tumor-suppressing effects on a variety of cancers, ,, suggesting a possible application of miR-34a in tumor detection, metastasis, therapy, and prognosis. , The miR-34a acts as a metastasis suppressor to regulate breast cancer migration and invasion through inhibiting Fra-1 oncogene. , Rokavec et al. showed that miR-34a is known to target epithelial-to-mesenchymal transition and presumably suppress the early phases of colorectal cancer metastasis.  Siemens et al. reported that miR-34a methylation was found in 45.1% of the colon cancer samples and significantly associated with metastases to the liver and lymph nodes.  Kumar et al. investigated that miR-34a inhibited tumor angiogenesis by blocking vascular endothelial growth factor production.  Zhang et al. reported that miR-34a inhibits cell migration and invasion of bladder cancer cells by antagonizes Notch1.  Li et al. reported that the expression level of miR-34a was lower in patients with recurrence compared to those without recurrence after radical surgery.  In the recurrence group, the median disease-free survival of patients with low miR-34a expression was 13.4 months, which was shorter than that of patients with high miR-34a expression. Kashat et al. found that over-expression of miR-34a led to decreased self-renewal capacity of prostate cancer (PCa) cells and conversely inactivation of miR-34a resulted in increased self-renewal capacity. , Taken together, the studies demonstrated that the miR-34a is a strong and independent prognostic marker in cancers , [Figure 4].
Patients with cancers are generally treated effectively using surgical resection, chemotherapy, and radiotherapy. In recent studies, miR-34a is involved in cancer therapy. , Xiu et al. reported that miR-34a expression modulated breast cancer cells response to Adriamycin by targeting Notch-1 and Notch signaling pathway may play a vital role in the acquisition of breast cancer cell resistance to chemotherapeutic agents.  Lou et al. reported that oncolytic adenovirus co-expressing miRNA-34a and IL-24 induces superior antitumor activity in hepatocellular carcinoma cells.  In PCa cells, it was showed that up-regulated miR-34a is associated with the sensitivity of tumor cells to camptothecin and paclitaxel cytotoxic agents. , The treatment combining miR-34a with 5-fluorouracil (5-FU) significantly showed more efficient antitumor effects than a single treatment of 5-FU.  The newly developed synthetic analog of curcumin referred as difluorinated curcumin (CDF) could be a novel demethylating agent for restoring the expression of miR-34 family, and thus, CDF could become a newer therapeutic agent for the treatment of colon cancer.  These findings are of great impact on the functions of miR-34a, and notably improve the efficacy in cancer therapy.
| > m iR-3 a in Radio-Sensitivity of Cancer Cells|| |
Some cancers are difficult to completely cure by surgical treatment alone. Radiation maybe required after surgical treatment. miRNAs are involved in the process related to radiosensitivity.  The cells were transfected with synthetic pre-let-7 molecules or control pre-miRNA containing scrambled sequences, and significant radiosensitization was found in cells treated with pre-let-7b or pre-let-7a compared with control.  Sasaki et al. reported that the high miR-34a expression level in A172 glioblastoma cells after irradiation at 30 and 60 Gy induced the apoptosis of radioresistant A172 glioblastoma cells.  Duan et al. reported that restoration of miR-34a expression enhances radiation-induced apoptosis, partly by suppressing the LyGDI signaling pathway, and miR-34a could possibly be used as a radiosensitizer for nonsmall cell lung cancer therapy.  The research showed that the wild-type p53 is one of the key factors affecting the radiosensitivity of cancer cells, , and the p53-mutated or p53-deficient cancer cells respond poorly to radiation. , Liu et al. showed that the induction of miR-34a by radiation was in a p53 dependent manner and over-expression of miR-34a could significantly enhance the radiosensitivity.  Kang et al. reported that rhamnetin and cirsiliol induce radiosensitization by the increased expression of miR-34a-mediated suppression of Notch-1 expression in nonsmall cell lung cancer cell lines.  Fractionated radiation significantly altered more miRNAs as compared to single-dose radiation. Tumor suppressor miR-34a and let-7 miRNAs were up-regulated by fractionated radiation in radiosensitive LNCaP and PC3 cells. ,
| > Outlook|| |
We summarized current knowledge about miR-34a, which regulated cell cycle, differentiation, and apoptosis through targeting a plethora of genes [Table 1]. The regulatory mechanisms and clinical perspectives of miR-34a in cancers are illustrated. Studies centering on the role and regulation of miR-34a have become a hot topic in the cancer research field.  Notably, miR-34a plays a vital role in various biological processes and the initiation and development of cancer. More and more insights have been focused on the regulatory mechanisms of miR-34a in cancer detection, prognosis, and therapy. ,, The expression of miR-34a has altered after radiation, which can influence the radio-sensitivity of cancers. We hope to provide new directions and insights to improve the radiotherapeutic effect of cancer patients via the expression of miR-34a.
miRNAs have been proposed for clinical applications, and the feasibility of this approach is currently being tested. ,, If specific introduction of miRNAs into cancers is successful, it may be possible to restore miR-34 function for cancer therapeutic purposes in the future. Furthermore, the possibility to detect epigenetic inactivation of miR-34a or loss of miR-34a expression holds cancer diagnostic and prognostic potential for the future.
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