Importance of Micro RNA (miRNA) in lung cancer diagnosis and treatment

By Avishek Majumder on December 21, 2018

Micro RNA (miRNA) is 22 nucleotides long, single-stranded RNA molecules which play a crucial role in regulating the gene expression by translational repression. Micro RNA are found in abundance in both plants and animals. Micro RNA are non-coding in nature and are found to be evolutionarily conserved in nature. There is evidence that micro RNA have various roles in the development and progression of lung cancer. Lung cancer subtypes can be classified by using micro RNA profiles, and there is also specific micro RNA expression signature that helps in the prognosis of lung cancer i.e., better prognosis and worst prognosis (Galloway et al., 2016). Micro RNA serves as a biomarker for early diagnosis of lung cancer as they circulate in body fluids. Apart from that, micro RNA is also used to predict the prognosis of lung cancer in patients.

Micro RNA as a biomarker

Micro RNA performs a variety of body functions as it is a key regulator of various fundamental biological processes such as cell development and proliferation, neural development and tumorigenesis (Florczuk, Szpechcinski, and Chorostowska-wynimko, 2017). Micro RNA plays an important role in cancer diagnosis and treatment. Micro RNA in cancer cells are misregulated in all types of human cancers. They are either overexpressed and may function as oncogenes or Micro RNA that possess tumour suppressor activity are down-regulated in the normal cells in case of cancer (Paranjape, Slack, and Weidhaas, 2009).

Micro RNA are better molecular markers than the messenger RNA because of their small size and resistance to RNAase degradation. Also, there are unique patterns of micro RNA expression in each type of cancer and have a prominent presence in serum makes miRNA potent biomarkers of the disease. Tissues with cancer and normal tissue have their own miRNA signature that is used to distinguish normal from neoplastic tissue with the help of tumour profiling studies. Also, different tumour types can also be distinguished by studying differentially expression of miRNA. The image below indicates the types of miRNA biomarkers in breast cancer.

Types and role of miRNA biomarkers in case of Breast Cancer (Bertoli, Cava and Castiglioni, 2015)
Types and role of miRNA biomarkers in case of Breast Cancer (Bertoli, Cava and Castiglioni, 2015)

Biogenesis of micro RNA (miRNA)

A series of well-orchestrated steps are involved in the biogenesis of miRNA as shown in the figure below. The miRNA biology in lung cancer is a complex phenomenon and it has its role as oncogenes, tumour suppressors, or, in some cases, both. Furthermore, it is clear that they have the capacity to regulate aspects of fundamental tumour biology, including proliferation, apoptosis, angiogenesis, and epithelial-mesenchymal transition. Mechanisms for miRNA deregulation in lung cancer involve global impairment in miRNA processing, epigenetic modifications, and regulatory effects of cigarette smoke. In fact, early studies determined that global reduction in miRNA processing through targeting of key processing components such as Drosha, DGCR8, and Dicer could promote tumour development (Rotunno et al., 2010).

Steps involving in biogenesis of miRNA. MicroRNA processing. AGO = Argonaute proteins; DGCR8 = DiGeorge syndrome critical region gene 8; ORF = open reading frame; RISC = RNA-induced silencing complex; TRBP = transactivating response RNA-binding protein. (Gregory et al., 2005)
Steps involving in biogenesis of miRNA processing. AGO = Argonaute proteins; DGCR8 = DiGeorge syndrome critical region gene 8; ORF = open reading frame; RISC = RNA-induced silencing complex; TRBP = transactivating response RNA-binding protein. (Gregory et al., 2005)

Types of miRNA in lung cancer diagnosis and treatment

After years of research, it is found out that miRNA is a potential diagnostic biomarker used for early clinical diagnosis of the disease (Leng et al., 2017). There are several reasons to consider miRNA over other biomarkers. For example, high abundance in tissues, easy availability in body fluids, etc. These characteristic natures of miRNA make it possible for the development of diagnostics, prognostics and targeted therapeutics.

S.no.
Types of Biomarker
Micro RNA
Post-state
Changes in physiology
References
1. Tumour suppressor genes Let-7 family

miR-34 family miR-200 family

 Down- regulated Promotion of cell cycle progression (Ruvkun et al., 2000).
2. Oncogenes miR-21 miR-17-92 cluster  mi R-221/222 Up-regulated Suppression of apoptosis (Matsubara et al., 2007)
3. Diagnostic microRNAs miR-21, miR-210, miR-182, miR-31, miR-200b, miR-2015, miR-183.

miR-126-3p, miR-30a, miR-30d,

miR-486-5p, miR-451a, miR-126-5p, miR-143, miR-145

 Up-regulated
Down-regulated		 Formation of malignant solitary pulmonary nodules (Vosa et al., 2013)
4. Prognostic micro RNAs let-7 Down-regulated reduced DICER-1 expressions  (Karube, 2005)
5. Therapeutic microRNAs miR-374a miR-548b Up-regulated Somatic mutations in tyrosine kinases (Wang et al., 2014)

Although micro RNA (miRNA) is a potential tool for the treatment of the lung cancer there are many obstacles that need to be overcome to make it a novel biomarker and enhance its clinical application. These obstacles include the development of nontoxic targeted delivery to the lung, improved understanding of how miRNA interact with other components of the genome, and standardization of miRNA detection. There is a need for standardization of miRNA detection with the improved understanding of the interaction of miRNA with other components of the genome. Also, there is a requirement of nontoxic targeted delivery of miRNA to the lungs as well as there should be a proper selection of delivery method.

References

  • Bertoli, G., Cava, C. and Castiglioni, I. (2015) ‘Micrornas: New biomarkers for diagnosis, prognosis, therapy prediction and therapeutic tools for breast cancer’, Theranostics, 5(10), pp. 1122–1143. doi: 10.7150/thno.11543.
  • Florczuk, M., Szpechcinski, A. and Chorostowska-wynimko, J. (2017) ‘miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer : Current Perspectives’, Targ Oncol, 12(2), pp. 179–200. doi: 10.1007/s11523-017-0478-5.
  • Galloway, D. A. et al. (2016) ‘HHS Public Access’, 109(7), pp. 87–92. doi: 10.1016/j.coviro.2015.09.001.Human.
  • Gregory, R. I. et al. (2005) ‘MicroRNA Biogenesis and Cancer MicroRNA Biogenesis and Cancer’, (9), pp. 3509–3512. doi: 10.1158/0008-5472.CAN-05-0298.
  • Karube, Y. (2005) ‘Reduced expression of Dicer associated with poor prognosis in lung cancer patients’, Cancer Sci., 96(2), pp. 111–115.
  • Leng, Q. et al. (2017) ‘A plasma miRNA signature for lung cancer early detection.’, Oncotarget, 8(67), pp. 111902–111911. doi: 10.18632/oncotarget.22950.
  • Matsubara, H. et al. (2007) ‘Apoptosis induction by antisense oligonucleotides against miR-17-5p and miR-20a in lung cancers overexpressing miR-17-92’, Oncogene, 26(41), pp. 6099–6105. doi: 10.1038/sj.onc.1210425.
  • Paranjape, T., Slack, F. J. and Weidhaas, J. B. (2009) ‘MicroRNAs: Tools for cancer diagnostics’, Gut, 58(11), pp. 1546–1554. doi: 10.1136/gut.2009.179531.
  • Rotunno, M. et al. (2010) ‘Inherited polymorphisms in the RNA-mediated interference machinery affect microRNA expression and lung cancer survival’, British Journal of Cancer. Nature Publishing Group, 103(12), pp. 1870–1874. doi: 10.1038/sj.bjc.6605976.
  • Ruvkun, G. et al. (2000) ‘Conservation of the sequence and temporal expression of let-7\nheterochronic regulatory RNA’, Nature, 408(6808), pp. 86–89. doi: 10.1038/35040556.
  • Vosa, U. et al. (2013) ‘Meta-analysis of microRNA expression in lung cancer’, Int J Cancer, 132(12), pp. 2884–2893. doi: 10.1002/ijc.27981.
  • Wang, Y. et al. (2014) ‘Axl-altered microRNAs regulate tumorigenicity and gefitinib resistance in lung cancer’, Cell Death and Disease. Nature Publishing Group, 5(5), pp. e1227–11. doi: 10.1038/cddis.2014.186.

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