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JOMR | Review of MicroRNA Proposed Target Genes in Oral … IDENTICAL

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3.3 Diagnostic sensitivity and specificity for both miRNAs

The AUC of the ROC curve drawn to differentiate OSCC, OPMD, and controls for miRNA-21 and miRNA-184
is shown in fig 2 and fig 3 respectively. The optimum cut-off for miRNA-21 and miRNA-184 to differentiate
OSCC from controls were 6.79 fold increase (sensitivity= 80% and specificity= 70%) and 0.92 fold decrease
(sensitivity= 80% and specificity= 74%) respectively, those to discriminate OPMD from controls were 5.40
fold increase (sensitivity= 70% and specificity= 53%) and 1.32 fold decrease (sensitivity= 70% and
specificity= 60%) respectively, and those to discriminate OSCC from OPMD were 2.2 fold increase
(sensitivity= 70% and specificity= 60%) and 0.35 fold decrease (sensitivity= 70% and specificity= 60%)
respectively.
4. DISCUSSION
miRNAs are involved in the regulation of gene expression at the translational level. In this way, miRNA can
promote or suppress the pathogenesis of cancer. Because of the scarcity of evidence determining the
diagnostic significance of salivary miRNAs in oral cancers, the present study was conducted to assess the
diagnostic significance of miRNA-21 and miRNA-184 in oral cancer.
miRNA-21 is one of the earliest studied oncomirs found increased in diverse cancers and is a proven
oncogene.18 In the present study, there was a 2.7-fold and 1.70-fold increase in salivary miRNA-21 levels
in OSCC and OPMD respectively, than controls [Table 2]. It is upregulated in the proliferation, cell cycle,
invasiveness, apoptosis, and metastasis of tumors.19-22 miRNA-21 targets tumor suppressor genes, such
as member 5 (SERPINB5), tropomyosin 1, clade B (ovalbumin), serpin peptidase inhibitor, signifying its
function in tumor invasion and metastasis.23 Kawakita et al. showed similar results to our research, where
miRNA-21 expression was significantly higher in OSCC tissues than in adjacent normal tissues suggesting
its role in tumorigenesis and invasiveness through the Wnt/β-catenin pathway, by targeting DKK2.24
Maheswari et al. showed upregulated miRNA-21 in patients with leukoplakia and severe dysplasia.19
Previous studies on OPMDs revealed miRNA-21 upregulation as an early event in cancer progression
connected with the development of invasive OSCC from premalignant leukoplakia.23,25 Zahran et al. and
Manikandan et al. showed a highly significant increase in salivary miRNA-21 in OSCC and OPMD compared
to healthy and diseased controls.13,26 Other studies have suggested several molecules, such as
programmed cell death 4, PTEN, and matrix metalloproteinase inhibitor RECK, were all targets for miRNA-
21, signifying its close relation to tumor invasion.20-21,27-28 A positive correlation between miRNA-21
and myofibroblast marker α-SMA has been demonstrated by Yang et al. in OSMF tissues.19 Prasad et al.
concluded that miRNA-21 is a risk indicator for OSMF development and progression to cancer by showing
a 4.5-fold increase in miRNA-21 in cases that transformed into OSCC.29 The present study demonstrates
significantly increased miRNA-21 in OSCC, highlighting its significance in delineating malignancy from non-
neoplastic conditions.
4.1 miRNA-184: tumor suppressor or promoter?
The effects of miRNA-184 on malignant progression are controversial, whether it acts as a tumor promoter
or suppressor. This incongruity may be explained by the 'imperfect complementarity' of the interactions
among miRNAs and target genes.30
In the present study, the mean salivary level of miRNA-184 in OSCC and OPMD showed 0.66-fold and 0.49-
fold decrease respectively, in comparison to controls. Also, a 0.17 ± 0.50-fold reduction of miRNA-184 in
OSCC than OPMD was found [Table 2], suggesting that miRNA-184 has a tumor-suppressive role in
cancers. It has been found that the cells transfected with miRNA-184 mimic display less cell migration,
proliferation, and increased cell apoptosis.30 Our results are in concordance with Santhi et al., who
showed that miRNA-184 had a down-regulated expression during oral cancer progression (from tumor to
leukoplakia to cancer tissues) and in oral surgical margins (from tumor to surgical margin to extra
tissues).31 Hence, there is a possible role of miRNA-184 in modulating tumor progression.
Our study disagrees with previous studies that have reported increased levels of miRNA-184 in OSCC.
Zahran et al. showed a significant increase in the salivary level of miRNA-184 in OSCC and OPMD
compared to any other group.13 Wong et al. showed a 59-fold higher miRNA-184 expression in OSCC cells
than in normal cells.15 It was postulated that miRNA-184 acts as an oncogene by inducing proliferation
and potentially inhibiting apoptosis by targeting c-Myc. It was also concluded that inhibition of miRNA-184
in tongue SCC cell lines could reduce cell proliferation rate. However, Yu et al. presented a different
explanation for the effects of miRNA-184 on epithelial cells and cancer cell lines, including Cal27 (an
aggressive cell line) via AKT signaling. Suppression of the AKT pathway that is associated with increased
cell apoptosis and death was demonstrated with ectopic expression of miRNA-184.14
We infer that these two miRNAs might play role in the pathogenesis of premalignant and malignant
conditions of the oral mucosa. These miRNAs from the tumor tissue appear in saliva which might have
some diagnostic potential.
Subsequently, we did an ROC analysis and it was found that these two levels can differentiate OSCC and
OPMD from controls as well as premalignant conditions from malignant conditions by measuring salivary
miRNA-21 and miRNA-184. So, we hypothesize that salivary miRNA-21 and miRNA-184 can act as tumor
markers that can be used in the diagnosis of OPMD and OSCC and also can be used in differentiating
premalignant conditions from malignant conditions of the oral mucosa.
However, the limitation that should be kept in mind while applying the results in clinical practice is that
this is a case-control study and not a prospective one.
It is worth evaluating the difference in salivary miRNA-21 and miRNA-184 levels in different clinical stages
and histopathological grades of OSCC as we have presented here clinical data which validate in-silico data
observed by other authors using TCGA data set in the reviewed literature.
We finally conclude that salivary miRNA-21 and miRNA-184 have the potential to be used as tumor
markers for the diagnosis of OSCC and OPMD.
Acknowledgements: Nil
Funding Information: This research did not receive any specific grant from funding agencies in the public,
commercial, or not-for-profit sectors.
Disclosure of prior presentation: The research was accepted and presented at the Japanese Society of
Medical Oncology Annual Meeting 2022. The abstract has been published in the Annals of Oncology under
the conference section.