MicroRNAs (miRNAs) are small noncoding RNAs that typically inhibit the translation and stability of messenger RNAs (mRNAs), controlling genes involved in cellular processes such as inflammation, cell-cycle regulation, stress response, differentiation, apoptosis, and migration. Thus, miRNAs have been implicated in the regulation of virtually all signaling circuits within a cell, and their dysregulation has been shown to play an essential role in the development and progression of cancer. Here, after a brief description of miRNA genomics, biogenesis, and function, we discuss the effects of miRNA dysregulation in the cellular pathways that lead to the progressive conversion of normal cells into cancer cells and the potential to develop new molecular miRNA-targeted therapies.

MicroRNAs in cancer.

Tumor-suppressor Pdcd4 inhibits transformation and invasion and is downregulated in cancers. So far, it has not been studied as to whether miRNAs, suppressing target expression by binding to the 3'-UTR, regulate Pdcd4 or invasion. The present study was conducted to investigate the regulation of Pdcd4, and invasion/intra-vasation, by miRNAs. A bioinformatics search revealed a conserved target-site for miR-21 within the Pdcd4-3'-UTR at 228-249 nt. In 10 colorectal cell lines, an inverse correlation of miR-21 and Pdcd4-protein was observed. Transfection of Colo206f-cells with miR-21 significantly suppressed a luciferase-reporter containing the Pdcd4-3'-UTR, whereas transfection of RKO with anti-miR-21 increased activity of this construct. This was abolished when a construct mutated at the miR-21/nt228-249 target site was used instead. Anti-miR-21-transfected RKO cells showed an increase of Pdcd4-protein and reduced invasion. Moreover, these cells showed reduced intra-vasation and lung metastasis in a chicken-embryo-metastasis assay. In contrast, overexpression of miR-21 in Colo206f significantly reduced Pdcd4-protein amounts and increased invasion, while Pdcd4-mRNA was unaltered. Resected normal/tumor tissues of 22 colorectal cancer patients demonstrated an inverse correlation between miR-21 and Pdcd4-protein. This is the first study to show that Pdcd4 is negatively regulated by miR-21. Furthermore, it is the first report to demonstrate that miR-21 induces invasion/intravasation/metastasis.

MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer.

Circulating nucleic acids have been shown to have potential as non-invasive diagnostic markers in cancer. We therefore investigated whether microRNAs also have diagnostic utility by comparing levels of tumour-associated MIRN155 (miR-155), MIRN210 (miR-210) and MIRN21 (miR-21) in serum from diffuse large B-cell lymphoma (DLBCL) patients (n = 60) with healthy controls (n = 43). Levels were higher in patient than control sera (P = 0.009, 0.02 and 0.04 respectively). Moreover, high MIRN21 expression was associated with relapse-free survival (P = 0.05). This is the first description of circulating microRNAs and suggests that microRNAs have potential as non-invasive diagnostic markers for DLBCL and possibly other cancers.

/pdf/detection-of-elevated-levels-of-tumour-associated-micrornas-4i9nv13tw3.pdf

Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma.

COLON ADENOCARCINOMA IS A major cause of cancer mortality worldwide1 Colorectal cancer is the third most common and second leading cause of cancer death in the United States2 Even though 5-year mortality rates have modestly declined over the last 3 decades,3 there is still a need to identify new prognostic biomarkers and therapeutic targets for this disease Currently, chemotherapy has significant therapeutic value, but surgery is the only curative form of treatment4

Ideal therapeutic targets should be causally associated with disease and amenable to designing therapeutic interventions, whereas ideal biomarkers should be easy to measure and have strong associations with clinical outcomes MicroRNAs could match both criteria5-8

MicroRNAs are 18- to 25-nucleotide, noncoding RNA molecules that regulate the translation of many genes9 Since their discovery,10,11 microRNAs have been found to regulate a variety of cellular processes including apoptosis,12-14 differentiation,10,11,15 and cell proliferation16 MicroRNAs may also have a causal role in carcinogenesis5,17,18 MicroRNA expression levels are altered in most tumor types,19,20 including colon tumors20-23 Experimental manipulation of specific microRNAs modulates tumor development in mouse-model systems16,24-26 The prognostic potential of microRNAs has also been demonstrated for chronic lymphocytic leukemia,6 lung cancer,7 pancreatic cancer,27 and neuroblastomas28

If aberrant microRNA expression is causal to carcinogenesis, inhibiting specific microRNAs may have therapeutic implications Modified antisense oligonucleotides can easily be designed to specifically inhibit microRNA function29 Antagomirs are one type of antisense oligonucleotide that has proven effective at inhibiting microRNA function in vivo in mice30 The ease of designing specific inhibitors of microRNA function makes them candidates for therapeutic targets

Given the therapeutic and prognostic potential for microRNAs in cancer, we evaluated microRNA profiles of colon tumors and paired nontumorous tissue to study their potential role in tumor formation, diagnosis, and response to chemotherapy in colon carcinoma

https://jamanetwork.com/journals/jama/articlepdf/1149167/jpc70014_425_436.pdf

MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma

Early studies have shown how aberrantly expressed microRNAs are a hallmark of several diseases like cancer. MicroRNA expression profiling was shown to be associated with tumour development, progression and response to therapy, suggesting their possible use as diagnostic, prognostic and predictive biomarkers. Moreover, based on the increasing number of studies demonstrating that microRNAs can function as potential oncogenes or oncosuppressor genes, with the goal to improve disease response and increase cure rates, miRNA-based anticancer therapies have recently been exploited, either alone or in combination with current targeted therapies. The advantage of using microRNA approaches is based on its ability to concurrently target multiple effectors of pathways involved in cell differentiation, proliferation and survival. Here, we review our current knowledge about the involvement of microRNAs in cancer, and their potential as diagnostic, prognostic and therapeutic tools.

https://www.embopress.org/doi/pdf/10.1002/emmm.201100209

MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review

MicroRNAs (miRNAs) are ∼22 nucleotide non-coding RNA molecules that regulate gene expression post-transcriptionally. Although aberrant expression of miRNAs in various human cancers suggests a role for miRNAs in tumorigenesis, it remains largely unclear as to whether knockdown of a specific miRNA affects tumor growth. In this study, we profiled miRNA expression in matched normal breast tissue and breast tumor tissues by TaqMan real-time polymerase chain reaction miRNA array methods. Consistent with previous findings, we found that miR-21 was highly overexpressed in breast tumors compared to the matched normal breast tissues among 157 human miRNAs analysed. To better evaluate the role of miR-21 in tumorigenesis, we transfected breast cancer MCF-7 cells with anti-miR-21 oligonucleotides and found that anti-miR-21 suppressed both cell growth in vitro and tumor growth in the xenograft mouse model. Furthermore, this anti-miR-21-mediated cell growth inhibition was associated with increased apoptosis and decreased cell proliferation, which could be in part owing to downregulation of the antiapoptotic Bcl-2 in anti-miR-21-treated tumor cells. Together, these results suggest that miR-21 functions as an oncogene and modulates tumorigenesis through regulation of genes such as bcl-2 and thus, it may serve as a novel therapeutic target.

Si Ml

Papers

miR-21-mediated tumor growth