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Page 10 of 18 Malentacchi et al. J Cancer Metastasis Treat 2020;6:34 I http://dx.doi.org/10.20517/2394-4722.2020.34

plasma and serum. mtDNA does not have protective histones and sophisticated DNA repair mechanisms,
which underscore its susceptibility to oxidative stress and other genotoxic insults. The abnormal alteration
[56]
of mtDNA copy number is well documented for numerous malignancies. Recently, Cicchillitti et al.
evidenced an association among cfmtDNA (by qPCR), EC grading, and hypertension and inflammation
markers, suggesting its role as a predictive biomarker [57-62] .

miRNA
miRNA expression
miRNAs are involved in the pathogenesis of various human cancers, such as lung, prostate, colorectal, and
leukemia, as either oncogenes or onco-suppressors. The main emerging evidence of miRNAs is related
to their use as biomarkers due to their higher stability in comparison to longer RNAs and their relatively
high concentration in body fluids, such as serum, plasma, saliva, and urine, initiating a new era of disease
research.

Circulatory miRNAs are reported mainly from monocytes, plasma, and exosomes, and they are resistant
to degradation by RNase enzyme, thus stable in the blood and urine. Consequently, the potential roles of
miRNAs in clinical practice are related to early diagnosis and classification of tumors, in the identification
of poorly differentiated malignancies, and in the use as biomarkers potential use in the prediction of
survival and response to treatment.

Recent studies have expanded our knowledge of the roles of miRNA in the pathology of gynecologic
malignancies: in ovarian cancer, miRNAs participate in the development of drug resistance, while, in EC,
they play essential roles in oncogenic processes, including cell proliferation, migration, and metastasis. The
most critical aspect, more than in CTCs and ctDNA, is the lack of standard procedures for the analytical
and pre-analytical phases (e.g., the absence of housekeeping genes for relative quantification) that leads to
the identification of a broad range of miRNAs but none of them with strong confirmation for clinical use.

[63]
Tan et al. showed a higher expression of the serum level of miR-155 in differentiated EEC in comparison
to healthy controls and associated it with cancer stage, lymph node involvement, and metastasis. Zhai
obtained the same results for miR-194 . Torres found that the expression of miR-99a, miR-100, and miR-199b
[64]
was upregulated in plasma of EEC patients, and a combination of miR-99a and miR-199b was more
[65]
accurate in distinguishing EEC disease when compared with single miRNAs . Another genome-wide
serum miRNA expression profile identified a combination of four serum miRNAs (miR-222, miR-223,
miR-186, and miR-204) as a fingerprint for EEC detection .
[66]

Other investigations of miRNA profiling in EEC have tried to find associations between circulating
miRNAs and clinic-pathological characteristics such as FIGO stage, grade, relapse, and nodal metastases.
The miRNAs expression is mostly linked to that in corresponding tumor tissue [24,67-72] . In this regard,
[73]
Wang et al. found that miR-15b, -27a, -223, miR-3145, and miR-4638, obtained by genome-wide miRNA
expression profiles, are differentially expressed in the EEC plasma between the two cohorts [73,74] .

Nevertheless, only one meta-analysis was performed on the discovered miRNAs related to EC. However,
inconsistencies or discrepancies about diagnostic accuracy of circulating miR-21 remain. EC patients
[75]
showed higher miR-21 expression compared with benign lesion patients .
miRNA methylation
Mainly focusing on their role as biomarkers, several miRNAs have been explored for their methylation
profile in tissue and their correspondent expression in serum, but it has only been confirmed for
[76]
miRNA-203 .