Pituitary adenoma is a benign brain tumor that could invade the sphenoid, cavernous sinus, or dura mater and some of them are described as aggressive, with a high proliferation rate and short postoperative time to recurrence [
1,
19]. Therefore, an epigenetic marker to predict a greater malignant potential of PAs still remains to be established.
STAT3 gene may be a promising target because it is aberrantly activated in a wide variety of human cancers and plays crucial roles in tumor cell proliferation, survival, invasion and tumor-promoting inflammation [
20‐
26].
We conducted this study to examine the prognostic significance of
STAT3 gene promoter methylation and mRNA expression in 102 PA patients and to determine the associations with patient clinical data. We determined 10.78% (11/102)
STAT3 promoter methylation frequency. Also, in our study invasive PAs showed low
STAT3 methylation status. Only in 12.07% (7/58) invasive PAs,
STAT3 promoter was methylated (Table
1). We also demonstrated that PRL, IGF-1, ACTH and more than one hormone hypersecretion mostly occur with non-methylated
STAT3 gene (Fig.
2). Low
STAT3 gene methylation status indicates that this gene is little suppressed in PAs and might be constantly activated. However, mechanisms related to this are still unknown. Numerous studies showed the activation of STAT3 in a wide variety of tumors [
20‐
26] and the proposed role for STAT3 in tumor formation or progression is based on the link between its activation and transformation [
10]. For example, Morikawa T et al. (2011) found that individuals with STAT3-activated colorectal cancers experience a poorer prognosis, suggesting a potential tumor-promoting role of p-STAT3 expression as a prognostic biomarker [
20]. Increased expression of phosphorylated STAT3 and JAK/STAT activation in glioma samples has also been correlated with significantly shorter overall survival and has been associated with more aggressive tumors, indicating that STAT3 is a key contributor to glioma pathogenesis by mediating cell survival, growth, and proliferation [
21‐
23]. Moreover, in breast carcinoma cells, the STAT3 activation has been correlated with cell proliferation [
24], in colon cancer STAT3 has been shown to be overexpressed [
25], as well as in high-grade prostate cancer patients [
26]. In these mentioned studies, STAT3 has been described as an oncogene, however, there are some other publications in which STAT3 has been shown to be a tumor suppressor. For example, in colorectal carcinoma biopsies STAT3 overexpression has been associated with an improvement in median survival of about 30 months [
27]. French patient cohort by Monnien et al. (2010) provided evidence for a association of phosphorylated STAT3 appearance with prolonged survival of rectal cancer patients [
28]. Therefore, STAT3 can act as an oncogene or a tumor suppressor, depending on tumor tissue. In our results, there were no other associations between
STAT3 gene promoter methylation, mRNA expression and PA invasiveness, recurrence or patient clinical characteristics. Only a gender of male and patient group older than 60 years were significantly associated with reduced
STAT3 mRNA expression (Mann-Whitney test,
p = 0.025,
p = 0.047, respectively). However, the mechanism of
STAT3 expression changes in PA proliferation and invasion has not been reported yet, making it necessary to further research on the pro- and anti-tumorigenic effects of
STAT3 gene activation.
It is important to mention, that Zhou et al. (2015) made a research of STAT3 expression in somatotroph adenomas. They found that STAT3 expression was significantly enhanced in somatotroph adenomas (67% ± 5%) as compared with non-secreting pituitary tumor expression (unpaired t test,
P < 0.001) [
29]. Also, they showed that GH induces somatotroph cell STAT3 phosphorylation and nuclear translocation. Based on these results, Zhou et al. (2015) postulated that GH participates in a positive autocrine or paracrine feedback for STAT3 induction and supported the hypothesis that blocking STAT3 suppresses somatotroph tumor growth and inhibits GH hypersecretion [
29]. Our results also showed a tendency that the highest amount of GH was determined at “high”
STAT3 mRNA expression level (Fig.
4), making it necessary for further investigation.