|Year : 2018 | Volume
| Issue : 2 | Page : 249-254
MicroRNA-associated carcinogenesis in lung carcinoma
Pushpendra Pratap, Syed Tasleem Raza, Shania Abbas, Farzana Mahdi
Department of Biochemistry, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India
|Date of Web Publication||8-Mar-2018|
Dr. Syed Tasleem Raza
Department of Biochemistry, Era's Lucknow Medical College and Hospital, Lucknow - 226 025, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Lung carcinoma is the leading cause of cancer-related death worldwide; it has been regarded as the origin of death by melanoma universally. Frequently, lung carcinomas identified in progressive phase and have lowermost roots of existence in any category of the cancer. MicroRNAs (miRNAs) are small having 18–25 nucleotides extended noncoding RNAs regulating gene expression and elaborate in a wide assortment of cellular progressions also. Cumulative indications propose that, miRNA plays imperative and multifarious roles in cases of human lung cancer genetics. Collective studies concern with research related to lung sarcoma by using biomarkers which determine phenotypic signatures on behalf of diagnostic, prognostic, as well as therapeutic rationale. Furthermore, a number of aspects are indispensable to be deliberated while opting for miRNAs as clinical biomarkers in lung cancers, which have been recognized as imperative targets for therapeutic interventions in recent times. This review focuses inclusive information over the biogenesis of miRNA and considerable risk dynamics associated with the genetics of human lung cancer.
Keywords: Biogenesis of microRNA, clinical biomarker, phenotypic signatures, risk dynamics
|How to cite this article:|
Pratap P, Raza ST, Abbas S, Mahdi F. MicroRNA-associated carcinogenesis in lung carcinoma. J Can Res Ther 2018;14:249-54
| > Introduction|| |
At the outset, in 1993, microRNA (miRNA) was described in the worm Caenorhabditis elegans, categorized as a small, noncoding RNA (lin-4) molecule; act as a developmental repressor of the accumulation of lin-14 protein., Successively, the second miRNA, let-7, was spotted in C. elegans. As a group, metazoan miRNA genes are found within the introns or exons, while plant miRNAs are present within the intergenic region, with variable complementary structure and length significantly. A large number of miRNAs has been acknowledged in faunae, floras, and viruses; an individual miRNA can posttranscriptionally target hundreds of mRNAs. miRNAs function in feedback mechanisms under normal physiological conditions by safeguarding key biological processes including cell proliferation, differentiation, and apoptosis. The discovery of miRNAs led to a global research determination to establish their roles in cancer genetics. Basically, miRNAs regulate molecular pathways in the melanoma by targeting many oncogenes, tumor suppressors and contribute in cancer and stem cell biology, angiogenesis, epithelial-mesenchymal transition, drug resistance, and metastasis, for example, let-7 miRNA family has a role in cancer by negatively regulating let-60/RAS12. It has been consider that pulmonary carcinoma is occasionally investigated in sophisticated phase and leading nethermost continued existence rates in the appearance of several forms of cancer throughout the worldwide. Researchers have interested in related to pulmonary carcinoma by using different biomarkers resulting for initial identification and appropriate prognosis as well as broad-spectrum preliminary argument is to equate the profiles of gene manifestation concerning cancerous cell and noncancerous cell or normal lung tissues. It has been considered that miRNAs are small, noncoding RNA molecules which condense gene manifestation and translation of protein over and done with complementary requisite to the 3′ untranslated region (UTR) of objective DNA segments. These class of slight RNA molecules has emerged as fundamental regulators of all essential cellular processes occurring inside the cell, encompassing enlargement of cells, responsibility of anxiety, tissue specification, as well as cell distinction., There are many investigations have been carried out related to lung carcinoma for the identification of new biomarkers; studies of miRNA expression profiles done by using different specimens such as cell lines, serum samples, and tissue samples.,, It has been suggested that various miRNA molecules are articulated in a tissue-specific manner and straight-forwardly standardize genes which engage in recreation a significant role in specifying the progressive providence of cells in which they are expressed. For example, It has been consider that miRNA 449 is especially expressed within the columnar multiciliated airway epithelial cells along with promotes the discrimination of airway ciliated compartment progenitors through repressing the Delta/Notch passageway., In addition, tissue-specific expression of miRNAs is repeatedly misplaced during the process of carcinogenesis, furthermore restoring of their expression profile be able to endorse the redifferentiation of malignant cells to their innovative type of tissue, signifying an approaching opportunity intended for rehabilitation of melanoma., Deregulation of a small subset of miRNAs were reported to have an extreme effect on the expression pattern of several hundred mRNAs, which force the cells toward transformation. Recent studies have suggested that miRNAs binds to 5′UTR or open reading frame of the target mRNA., Since high complementarity is not required for regulation, several hundred mRNAs can be targeted by a single miRNA and the resulting aberrant miRNA expression may affect a multitude of transcripts, which have great influence on cancer-related signaling pathways.
| > Lung-Specific MicroRNA|| |
In the case of warm-blooded vertebrate animals of class Mammalia, miRNAs are predominantly articulated or significantly enriched in an unambiguous organ resembling lung, involving an appendage or handkerchief instantly recognizable profession. Foremost, this was suggested that lung is solitary of the tissue with the most bountiful interpretation of let-7 and elevated throughout situated display places supplementary enlarge the lung-specific miRNAs expression.,,, A microarray having 216 miRNA investigates exposed that there are two miRNAs which were expressed characteristically in the lung of rat and nine miRNAs are co-expressed in the heart as well as the lung of the rat. Recently, a comprehensive meta-analysis of twenty miRNA expression studies in lung cancer, including a total of 598 tumors and 528 noncancerous control samples, was published: the authors identified a statistically significant miRNA meta-signature of seven upregulated (miR-21, miR-210, miR-182, miR-31, miR-200b, miR-205, and miR-183) and eight downregulated (miR-126-3p, miR-30a, miR-30d, miR-486-5p, miR-451a, miR-126-5p, miR-143, and miR-145) miRNAs.miR-26a as an anti-oncogene has been suggested to plays an important role in the molecular mechanism of human lung cancer. Meanwhile, the overexpression of miR-26a in the A549 human lung cancer cell line spectacularly inhibits cell proliferation, and it is also blocks G1/S phase transition which results to inhibits cell metastasis, induces apoptosis and invasion in vitro. let-7, miR-29, and miR-30 were tremendously explicit within in the collaboration of human and mice species.,,,,, Likewise, miR-134 expressed in epithelial-to-mesenchymal transition of nonsmall cell lung cancer (NSCLC) cell and miR-214, 296, and 299 were exceedingly expressed in mutually the neonatal mouse and the fetal human lung.,,, It has been suggested that the majority of the miRNAs which were exceedingly articulated in the both neonatal lung of the mouse along with the fetal human lung were subsequently downregulated in the adult lung. In contrast, miRNAs such as miR-26b which is positioned on chromosome 2, -29a, and -29b located on chromosome 7, -146-3p, and -187 were upregulated in the adult tissue of both mice and human. Thus, no overall tendency of an up- or down-regulation of miR-29 in cancer was found. While twenty most plentiful miRNAs were quite similar, the amount of each miRNAs varied considerably. On symmetrical analysis, it is observed that human miRNA such as miR-15, 126-3p, and miR-30, let-7 are upregulated on behalf of both the E11.5 lung along with the E17.5 lung and for both the neonatal, as well as the adult. During cell differentiation, development, and in diseases such as lung fibrosis and cancer, specific miRNAs are differentially regulated over time and between sexes, the miR-17-92 cluster plays important roles in cell differentiation and growth, whereas the Gata6-regulated cluster miR-302-367 controls multiple aspects of lung endoderm progenitor cell behavior [Table 1].
|Table 1: MicroRNAs with experimental data supporting a tumor suppressor or oncogene function in cancer|
Click here to view
| > Interaction of Microrna With Target Genes|| |
The criterions intended for miRNA target collaborations were demarcated through the transformation of acknowledged miRNA-target positions and challenging on behalf of function in miRNA misexpresion assesses. These studies are concentrated over the importance of pairing of the 5'culmination of the miRNA to the objective location of mRNA called the seed region. There are so many intelligence mentioned; this computationally acknowledged connotation is noteworthy for expression of miRNAs. Zhang et al. demonstrated by investing high-resolution array comparative genomic hybridization, i.e., it is a technique that permits the detection of chromosomal copy number changes without the need for cell culturing that the loci of miRNAs have an extraordinary incidence of genomic amendment in human malignancies. Solitary of the superlative-categorized oncogenic miRNA is miR-17-92, a polycistronic miRNA constellation too nominated as oncomiR-1. The forerunner transcript plagiaristic from the miR-17-92 gene encompasses six tandem stem-loop hairpin configurations that eventually yield six mature miRNAs such as miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92-1. Human miR-17-92 is positioned at13q31.3, a province augmented happening numerous hematopoietic malignancies and compressed tumors, encompassing diffuse large B-cell lymphomas, follicular lymphomas, Burkitt's lymphomas, and lung carcinoma, was initiate to be over-expressed or miss-expressed consuming microarray analysis by He et al. Pak et al. have found unique miRNAs (miR-34c, miR-183, and miR-210) in lung adenocarcinoma groups according to major tyrosine kinase inhibitors sensitive epidermal growth factor receptor mutation status.
| > Overexpression and Misexpression of MicroRNA|| |
Many miRNAs acts as oncogenes or tumor suppressors, and the altered misexpression of miRNAs is a hallmark of many cancer types, including papillary thyroid carcinoma, gastric cancer, lung cancer,, prostate cancer, head and neck squamous cell carcinoma, and bladder cancer. Misexpressed miRNA in a cell close endogenous expression of all of its target genes causing strong phenotype variation. However, miRNA and target gene may not be co-expressed at a time. Misexpression of miRNA can yield remarkable imperfections which necessitate an inadequate application to whatever might be seen autochthonous mutant studies of miRNA. Misexpression of some of the semi-RNAs results in phenotypes similar to that of loss of Notch function. Circumvention expression of miR-iab-5p can internalize Ubx and encourage a homeotic amalgamated of an organism's recognizable physical characteristics or mannerisms. Though, it remains to be determined whether the corresponding miRNAs mutants will influence indentation gesticulating or Ubx consequence in vivo. While the evasion manifestation outcomes give the impression to have an inadequate extrapolative assessment, in numerous occasions, it possibly will support to recognize the perfect objective inheritable factor (gene).
| > Outlining of Microrna as an Extrapolative Implement|| |
Lung melanoma exists the noticeable foundation of bereavement beginning the malignance in males worldwide. Hence, the documentation of innovative predictive indicators (indicators that associate with infection progression) might be a noteworthy improvement for the acknowledgment of patients that would advantage from supplementary efficacious rehabilitation. In incident of univariate investigates, the manifestation of mutually miR-155 (elevated intensities) and let-7a-2 (reduced intensities) has been accessible to associate within underprivileged endurance in 104 integrated countries patients with lung carcinoma, while multivariate investigates the countenance of miR-155 too interrelated through an underprivileged prediction, when entirely experimental variables were deliberated together. Its derivation and expansion are thoroughly related with smoldering of Nicotiana tobaccum (tobacco). Lung melanoma is alienated into dualistic foremost histological assemblages comprising NSCLC (85%) in addition to SCLC (15%). NSCLC can be supplementary subclassified into adenocarcinoma which frequently initiates in peripheral lung tissue and is additional communal in females, squamous cell, enormous compartment, and bronchiole-alveolar sarcomas. It has been acknowledged that hereditary modifications might happen on the chromosomal altitude (e.g., bulky gains and omissions) at the nucleotide level which consist of a phosphate and ribose sugar backbone (e.g., nucleotide alteration) or at cellular and physiological traits (epigenetic) level (e.g., DNA methylation). The above-mentioned transformation might consequence in the stimulation of oncogenes (e.g., Ras and Myc) and additional progression encouraging genes (e.g., ERBB1 and IGF-IR), and inactivation of anti-oncogenes (e.g., p53, p16INK4A, Rb, and FHIT). The molecular network of lung carcinogenesis has been partially known at the levels of genes and proteins in the last decade.,, Nevertheless, consequently 1970 tremendous impermanence frequency (80–85% indoors 5 years) has not been enhanced distinctly. Actually, nonexistence operational modalities for early stage diagnosis and insufficiency of therapeutic managements toward the later juncture of the disease are the dualistic main rationalizations. At present, lung-sarcoma dramatization respites proceeding histopathological and experimental moralities necessitate inadequate domain to predict deterioration and endurance. Foremost exertion to progress the regulator of lung malignancy encompasses the convention of molecular outlining to symbolize cancers and to support precise expectations of the aftermath subsequently customary or innovative administrations.
| > Pathogenesis as Well as Diagnosis of Lung Sarcoma Through MicroRNA|| |
The miRNAs have the capacity to regulate cell growth and apoptosis has established the natural application in cancer pathogenesis which itself is a consequence of dysregulation of growth and apoptosis of the cells. Happening mandate to ascertain protagonist of miRNAs in cancer pathogenesis, specific miRNAs overexpression or misexpression can be explored to elucidate commencement, as well as enlargement of distinguishing categories regarding melanomas. Acknowledgment of those miRNAs, which are differentially communicated concerning cancerous and common tissues, might support on behalf of the classification of those miRNAs which intricate in humanoid malignancies and supplementary inaugurate the role of miRNA as a biomarkers in the diagnostic of cancers. Similarly various mammalian miRNAs such as miR-21 also known as has-miR-21 and miR-155 too recommended as biomarkers for diagnosis of NSCLC.
| > Therapeutic Application of Microrna in Lung Melanoma|| |
miRNAs are appear to be involved in various biological and cellular processes such as proliferation, apoptosis, and receptor-driven pathways. The delivery of miRNAs to the target tissues and their efficacy to target tissues endure a foremost problem for uninterrupted RNA-located therapeutics. For cancer rehabilitation, miR-15a/16-1 introduce as a clustered around 0.5 kb at chromosome position 13q14 encourages programmed cell death (PCD) in leukemic MEG01 compartments and restricts cancer progression although quieting gene that has potential to cause cancer, i.e., miR-21 also known as has-miR-21 with single-stranded RNA (antisense RNA) oligonucleotides engenders a proapoptotic and antiproliferative comeback in vitro in the distinctive cellular representations, plummeting tumor improvement in addition to metastatic prospective in vivo. Approaching on behalf of expending of miRNAs in malignancy is nowadays existence reconnoitered comprehensively. Speculative justification is established on the evidence that miRNAs are expected antisense interactors which standardize various genes intricate in eukaryotic persistence and propagation. Manifestation outlines of miRNAs too have been exposed to transformation throughout administration with gemcitabine, as well as the intonation of certain miRNAs (encompassing the overexpression of miR-21) intensifications approachability of the cholangiocarcinoma tumor compartments toward this chemotherapeutic representative in vitro. Aforementioned outcomes intention the investigational origins designed for the application of miRNAs as a therapeutic destination. Prospective in vivo experiments concerning transgenic and knockouts miRNAs will offer treasured information about protection and productivity.
| > Conclusions|| |
The potential of a single miRNA to influence the expression of hundreds diverse miRNAs can help to identify the novel biological pathways. Yet, we are still far away from getting an observable understanding of the precise roles of various miRNAs in different cellular processes. The biological roles of miRNA in the improvement and progression of disease states along with their mode of action may vary in the different biological conditions. What has realistically emerged that the dysregulation of miRNAs is associated with lung cancer initiation and progression by the modulation of apoptosis and their possible role in cancer diagnosis, prognosis, and rehabilitation. Conceivable directing genes in lung sarcoma on behalf of miRNA constructed RNAi comprises oncogenes (e.g., Ras family and Myc family), autocrine/paracrine spheres (e.g., EGBB family and IGF reduces), anti-PCD genes (e.g., BCL-2 family and XIAP), other genes which encourage cancer vasculature enlargement (e.g., VEGF family and VEGFR family), MMP household, compartment sphere interconnected genes (e.g., Skp-2, Cyclin family, and Cdk family), as well as metastasis interconnected genes (e.g., E-cadherin and COX2), chemo-resistant genetic factors (e.g., FGF family and GSTP1), and supplementary hereditary aspects (e.g., CT120A and DDH). Popularly in the lung malignancy, these hereditary traits are projected by artificial small interfering RNAs (siRNAs) have been moderately considered. Moreover medication based-siRNAs has enrolled Stage I/II trajectories then resulted through remarkable prospective (e.g., ALN-RSV01, Cand5, and Sirna-027). This oligo-based therapeutic had better assist the progress of miRNAs to investigational consumption on behalf of their extraordinary comparability. The reimbursements of exhausting miRNAs concluded siRNAs might be for the reason that (a) long-standing movement, (b)in vivo permanency, (c) tremendous RNA supporter-compatibility, and (d) not one evident poisonousness. Nevertheless, miRNAs are of diversified objectives when distinguished through siRNAs. Steadiness, as well as attentiveness requisite, is occupied inside contemplation as the fundamental conveyance of miRNAs might omnipotence to undesirable gene silencing. The prospective of miRNAs in furthering documentation, prognostication, and persistence outcomes intended for lung melanoma should correspondingly be completed additional practicable. Next stage validation is needed to ascertain the prognostic implications of miRNAs in the population.
Financial support and sponsorship
The study was supported by intramural grant from the Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India.
Conflicts of interest
There are no conflicts of interest.
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