KDM3A, A NOVEL BLOOD-BASED BIOMARKER
IN COLORECTAL CARCINOGENESIS
Polat D.1, Onur E.2,*, Yılmaz N.3, Sökücü M.4, Gerçeker O.F.1
*Corresponding Author: Assoc. Prof. Elif Onur, Department of Medical Biology, Faculty of Medicine,
SANKO University, 27090 Gaziantep, Turkey; Phone:+90 342 211 6562; Fax: +90 342 211
6566; Email: elif.onur@sanko.edu.tr
page: 23
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DISCUSSION
Hypoxia is a very common characteristic in solid
tumors. While normal cells cannot resist prolonged hypoxia
and undergo either apoptosis or necrosis, cancer
cells can adapt to hypoxia by changing the expression of
genes involved in many cellular processes like proliferation,
metabolic reprogramming, and angiogenesis (16).
Chronic tumor hypoxia is linked to poor cancer outcomes
and activates the transcription HIF-1, which regulates the
expression of many cancer-related genes, particularly those
involved in angiogenesis (17).
HIF-1α is shown to be related to CRC (18), and experimental
in-vitro studies have revealed consistent findings
regarding the effect of hypoxia on colorectal cancer.
Martinez et al. found that HIF-1α protein increased in
HCT116 colorectal cancer cells exposed to O2 changes.
This changed gene and protein expressions in pathways
regulating hypoxia, glycolysis, and extracellular matrix
remodeling (17). In addition, several studies proposed
that the expression level of HIF-1α is associated with the
prognosis, recurrence, and metastasis of CRC (19). Also,
it was reported that high expression levels of HIF-1α in
patients with CRC might be a potential biomarker for the
progression of CRC. In our study, we demonstrated that
HIF-1α expression was significantly increased in leukocytes
samples of CRC patients. To the best of our knowledge,
this is the first study to show expression changes in
peripheral leukocytes.
KDM3A is also one of the hypoxic response genes,
and HIF-1α up-regulates its expression. It was shown that
loss of KDM3A reduced tumor growth in-vivo, consistent
with its role in regulating histone methylation during hypoxia
(9). In another study, it was emphasized that KDM3A
was mainly overexpressed in human CRC specimens, and
knock-down of KDM3A significantly suppressed CRC
cell proliferation, colony formation, invasion, migration,
and metastasis (2). These studies identify a regulatory
mechanism in which the induction of KDM3A by HIF-1
acts as an epigenetic signal enhancer (9). Several types of
research have shown that abnormal expression of KDM3A
exists in numerous types of cancers (9, 11, 20, 21). In this
study, this gene has demonstrated to be a novel prognostic
marker and a therapeutic target for CRC. It was detected to
be statically significant in CRC groups, and the AUC was
calculated as 66.4%. We could not find a study investigating
KDM3A in CRC patients from human blood samples
in our literature searches.
EMT is a dynamic process in which epithelial cells
obtain a mesenchymal phenotype with decreased intercellular
adhesion and increased cell mobility. Many transcription
factors, including Slug and ZEB-1 have been
reported to induce EMT by downregulating E-cadherin and
Claudin (22, 23). In our study, E-cadherin and Claudin-1
were not statistically significant between groups. However,
the significance determined between the groups at Slug
and ZEB-1 expression levels was found to be compatible
with KDM3A. These results indicate that mesenchymal
markers are more important in CRC.
In conclusion, clinical in-vivo studies have been very
limited investigating KDM3A and colorectal carcinogenesis
relation. Furthermore, the existing ones are either
animal or cell culture studies. Concerning all our data,
KDM3A is a novel biomarker in the development of CRC,
which deserves more detailed research.
Acknowledgments
Overall funding was provided by a PhD Thesis Research
Project Grant (No: FEF.DT.18.17) through the
Gaziantep University Scientific Research Projects Coordination
Unit. Declaration of Interest
The authors report no conflicts of interest. The authors
alone are responsible for the content and writing of
this article.
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