Human genetics

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MiRNAs and Cancer diagnosis

Micro RNAs are a class of small non-coding RNAs of about 20-22 nucleotides and play a key role
in key biological processes such as cell proliferation, differentiation and apoptosis. These RNAs
are capable of reducing the translation of target mRNAs by binding to their 3’ untranslated
region. More than 300 different human miRNAs targeting 1000s of genes have been identified
as of now. The discovery and functionalization of miRNA have revolutionized the studies in
molecular biology. Various studies have been conducted on the ability of individual miRNAs to
regulate the expression of oncogenes and tumor suppressor genes. The mutation or loss of
miRNA and their contribution to tumorigenesis have also been identified. The developmental
origins of tumors have been characterized effectively using miRNA expression patterns more
effectively than m RNA expression signatures. Several approaches have been developed in
order to block the function of miRNAs and prevent their oncogenic effect. These endeavors
have revealed a potential for miRNAs to be used in clinical diagnosis of cancer and as a target
for therapy.

Downregulation or loss of miRNAs possessing tumor suppressor function leads to the increased
translation of oncogenes and therefore oncogenic proteins. Upregulation of oncogenic miRNAs
block tumor suppressor genes and thereby inducing tumor formation.
Several reports have indicated the widespread disruption in mi-RNA expression levels and their
link to numerous diseases such as cancer. Cultured tumor cells and tissues have been observed
to exhibit significantly reduced expression of mature miRNAs. Three different mechanisms for
aberrant expression of mi-RNA are documented. These are: -

(1) Genetic alterations and Single nucleotide polymorphism (SNP)

A great majority of the miRNA genes are associated with fragile sites, cancer specific
translocation breakpoints, repetitive sequences and CpG islands that are amplified or deleted in
human cancer. SNP’s have also known to influence the mi-RNA functionalization. A gain in
function due to an SNP may cause the enhancement in its regulatory function such as in the
role as a tumor suppressor gene, while the loss in function may lead to overexpression of
miRNA which may act as an oncogene.

(2) Epigenetic silencing

Since many miRNAs are located close to the CpG islands, it was suspected that methylation at
these sites might have an effect on the miRNA gene activity. Comparative data analysis in colon
cancer has indicated that the expression of about 10%miRNAs were regulated by methylation
and that partial methylation reductions were not sufficient for the recovery of miRNAs.
Investigations in colorectal cancer were able to identify the influence of methylation on miR-9
family genes. Epigenetic silencing of miR-34b and miR-34c were instigated due to hyper-
methylation of neighboring CpG islands. In colorectal cancer cells, methylation of miR-9-1 were
associated with metastasis in the lymph nodes.

In breast cancer cells, positive correlation was obtained between methylation of miR-220C/141
and the invasiveness of the cancer cells. In non-small lung cancer, promoter methylation caused
loss of miR-200c expression and in turn effected differentiation, led to lymph node metastasis
and caused weaker E-cadherin expression.

Histone acetylation, another epigenetic phenomenon was also associated with deregulated
cancers. Alteration in miRNA levels were observed in breast cancer cells with inhibited histone
deacetylase activity. In bladder cancer cells, activation of miRNA-127 by 5-aza-2′-deoxycytidine
(5-Aza-CdR) and histone deacetylase (HDAC) inhibitor 4-phenylbutyric acid (PBA) suppressed
transcription of zinc-finger repressor BCL6 and thus induced apoptosis.

(3) Defects in the miRNA biosynthesis pathway

Majority of the miRNAs are encoded by introns, however some of them are encoded by exonic
regions. The genes coding for miRNA are usually clustered and transcribed polycistronically or
excised from mRNAs. The miRNA genes are known to be affected by transcription factors,
promoters, RNA stability or cellular stress.

It has been shown that Ser/Thr kinase/ endoribonuclease IRE1α are activated by endoplasmic
stress and cleaved pre- miRNAs such as pre-miR-17, pre-miR-34a, pre-miR-96 and pre-miR125b,
causing the translational reduction of pro-apoptotic caspase 2. Similarly, it has been found that
Myc activation caused the repressed expression of multiple miRNAs which led to several anti-
proliferative, tumor suppressive and pro-apoptotic effects.

Detection of miRNA in body fluids

such as plasma, serum, urine and
saliva are conducted using qPCR and
their presence are of diagnostic,
prognostic and predictive significance
as cancer biomarkers. This technique
is also advantageous as it is cost
effective and utilizes minimally
invasive procedures for the
accumulation of samples. Although
still in its infancy, miRNA analyses
offer possibilities for early detection
and prognosis, tumor classification
and therapeutic decision making. The
possibility of developing novel
treatment strategies by inhibition of
oncogenic miRNAs or substitution of tumor suppressive miRNAs have also been explored.
References

1. T. Paranjape, F. Slack and J. Weidhaas, "MicroRNAs: tools for cancer diagnostics", Gut,

vol. 58, no. 11, pp. 1546-1554, 2009. Available: 10.1136/gut.2009.179531.
2. L. Galvão-Lima, A. Morais, R. Valentim and E. Barreto, "miRNAs as biomarkers for early
cancer detection and their application in the development of new diagnostic
tools", BioMedical Engineering OnLine, vol. 20, no. 1, 2021. Available: 10.1186/s12938-
021-00857-9.
3. M. Ferracin and M. Negrini, "Micromarkers 2.0: an update on the role of microRNAs in
cancer diagnosis and prognosis", Expert Review of Molecular Diagnostics, vol. 15, no. 10,
pp. 1369-1381, 2015. Available: 10.1586/14737159.2015.1081058.
4. K. Reddy, "MicroRNA (miRNA) in cancer", Cancer Cell International, vol. 15, no. 1, 2015.
Available: 10.1186/s12935-015-0185-1 [Accessed 31 January 2022].
5. Y. Peng and C. Croce, "The role of MicroRNAs in human cancer", Signal Transduction
and Targeted Therapy, vol. 1, no. 1, 2016. Available: 10.1038/sigtrans.2015.4 [Accessed
31 January 2022].