How microRNA as a regulator of CRT (chemoradiation therapy) therapy in esophageal cancer.
A cell, which is the basic unit of a living organism has specific biological mechanism that ensure the cell functions normally in terms of differentiation, mitosis and apoptosis. However if alterations occur in genes that oversee these processes then this could lead to initiation of tumors and cancer. Research of the cause of cancer and its progression is still ongoing but recently researchers have pinpointed small non-coding molecules of RNA called microRNAs (miRNAs) which can function as tumor suppressor genes or oncogenes. These miRNAs have also been implicated as regulators of chemoradiation therapy as their expression alters the efficiency of DNA repair and hence leading to mutational errors during replication. This essay is to focus on the biology and biogenesis of miRNA, the role that miRNA play in cancer, in particular esophageal cancer and how they affect the efficacy of chemotherapy radiation.
2.0 Literature Review
Cancer is one of the leading killer disease in the world. There are very many cancers in the world and research studies have brought the focus mainly on miRNAs as being responsible for cancer initiation. In this review the main focus will be the role of miRNA and its effect as regulators in chemoradiation in esophageal cancer. MicroRNAs are naturally occurring small non-coding RNA molecules involved in regulation of gene expression . The first miRNA was discovered in Caenorhabditis elegans in 1993 during the study of the Lin-4 gene . These miRNA was known to control the timing of larval development by repressing the lin-4 gene of C. elegance. It was isolated and found to produce short non-coding RNAs containing 22 nucleotide RNA. Many other small RNAs were later discovered and the scientists later gave the name microRNAs to these class of small regulatory RNAs.
MicroRNAs are transcribed by RNA polymerase I and II and generate precursors that then go have primary miRNA transcript by RNA polymerase II . The primary miRNA is then processed by a nuclear RNase III enzyme known as Drosha to produce a precursor miRNA which is then transported out of the nuclease into the cytoplasm . Here it is processed further by RNase III familial endonuclease to become 22 base pairing miRNA duplexes . In mature miRNA these duplexes are unwound and RNA induced silencing complexes. MicroRNA regulate the expression of approximately one third of the human genome . Studies show that miRNAs has a main function of down regulating gene expressions through ways like translational repression, deadenylation and mRNA cleavage. They are complimentary to a portion of one or more mRNAs. The miRNA usually binds to the 3’UTR of target transcript but further research has led to a new discovery that the target site may be located outside the 3’UTRs such as the 5’UTR’s or protein coding regions . Recent studies have demonstrated that allelic and sequence variance can create a new miRNA binding site where it was non-existent, it can remove a miRNA binding site or it can change the affinity of a particular miRNA for a binding site .
Another significant property of miRNA is that only one can regulate hundreds of different gene while a single mRNA can be regulated by multiple miRNAs. This suggests that miRNA is capable of regulating mRNA translation and turn over . Up to date very around 2000 miRNAs have been discovered in the human genome and they have been implicated in disease progression in human beings. They may be involved in normal functioning of eukaryotic cells but when dysregulation occurs they are able to cause diseases, particularly cancer, and an example being esophageal cancer. Recent studies has shown that miRNA plays a role in pathogenesis of tumors and is also responsible for the sensitivity, in other words the success or failure of chemoradiation therapy during treatment of esophageal cancer. MiRNA has also been rendered responsible for other diseases like heart disease, kidney diseases and development of the nervous system.
There has been an exponential growth in the study of miRNA in relation to cancer. Studies have established that different types of miRNAs will cause different types of cancers in human beings. MiR-126 causes breast, lung and colon cancer, miR-551a causes gastric cancers and miR-181a/b will cause liver cancer  . There are several theories that attempt to explain how miRNA is related to cancer. Studies have shown that miRNA regulate the expression of certain proteins that are implicated in cancer. These proteins are HMGA proteins which consist of HMGA1a, HMGA1b and HMGA2 . HGMA expression is undetectable in adult tissues but in cancer it is elevated. HGMA are polypeptides of amino acid residues that have a modular organization sequence. Thyroid, cervical, prostatic, ovarian and pancreatic carcinomas presents an increase of HMGA1a and HMGA1b proteins . Baldassare et al in his research discovered that HGMA1 protein bind to the promoter region of the DNA repair gene BRCA1 and inhibits BRCA1 promoter activity.
Acao et al suggested that another theory of how miRNA cause cancer is the expression level of miRNA. This study shows that it is reduced in cancers due to chromosome deletion and epigenetic changes  . As a result of this alterations the resulting cellular phenotype acquires distinct characteristics that cause cells to proliferate excessively and autonomously . These cancer cells are able to resist inhibitory growth signals, they evade programmed cell death pathways, induce and sustain angiogenesis, overcome intrinsic cell replication limits and form new colonies different from the primary tumor . In addition these cells become master regulators of epithelial-mesenchymal transition and are essential in deregulation of tumor micro environment hence acting as managers of heterotypic signaling in cancer associated fibroblasts .
Genes linked to development of cancer are classified into oncogenes and tumor suppressors. Oncogene products can be categorized into six groups based on their functions. They can be growth factors, growth factor receptors, transcriptional factors, chromatin remodelers, signal transducers or apoptosis regulators . These oncogenes can be activated by genetic alterations that amplify the gene, they can alter protein structure to an active site and they can alter promoters to enhance gene expression . On the other hand tumor suppressor gene products are useful in regulation in biological processes. If tumor suppressors experience a reduction in function this results in dysregulation associated with cancer . Profiling of the dysregulation of miRNA expression has been sufficiently researched and demonstrated in tumors . However classification of miRNA as oncogenes or tumor suppressors is challenging especially because of the complex expression patterns of miRNAs .
Yang et al conducted a study to figure out the transformation of Barret’s esophagus to esophageal adenocarcinoma. Barret’s esophagus is a premalignant condition that usually develops to malignant esophageal adenocarcinoma . In this study, expression patterns of 470 miRNAs were analyzed using Agilent miRNA microarray from 32 diseased tissues from 16 patients suffering from Barret’s esophagus. The results obtained from this study were that tissues of Barrett’s esophagus and high-grade dysplasia were noticeably different from their corresponding normal tissues. Similar results were found for esophageal adenocarcinoma. MiRNA were proved to be involved in the development of Barret’s esophagus into malignant esophageal adenocarcinoma. These miRNAs become targets for early detection, chemoradiation therapy and prophylaxis of esophageal cancer.
Esophageal cancer is the sixth most deadly cancer in the world . Research has come with several therapies that can be recommended for controlling the spread of this cancer such as chemotherapy and radiation therapy. The miRNA has been the main focus of study in attempt to figure out whether they can be targeted for better response of the cells to the therapy . Mandal et al conducted a study on how omega 3 polyunsaturated fatty acid regulates cancer and discovered that a bioactive component of fish oil, docosahexaenoic acid (DHA) inhibits miR-21, a pro tumorigenic miRNA . Hu et al, examined the ability of a short chain fatty acid butyrate to target miRNA-dependent p21 during gene expression in human colon cancer. The findings from these research were that a microbe derived short chain fatty acid, a known histone deacetylase (HDAC) inhibitor, and blocks tumorigenesis in colon cancer by inhibiting expression of miR-106b and promoting expression of p21, a direct target of miR-106b . These inhibitors have been approved and are recommended for treatment of a few cancers however they are still been evaluated for other cancers, a field of research that has not yet been sufficiently ventured. The two studies mentioned above clearly shows that miRNA regulates the response of chemotherapy in cancer treatment.
MiRNA has also been thought to regulate the efficacy of reducing cancer cells by radiation therapy . Ionized radiations causes a complex cellular response involving multiple pathways . MiRNA has a role of regulating pathways involved in cellular response to radiation such as cell cycle and DNA repair. The altered expression of miRNA will bring about deficiencies in DNA repair in the cell will result to the accumulation of damage to the DNA and eventually mutational errors during DNA replication . Under expression of miRNA will cause under expression of DNA repair genes leading to mutations during replication.
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