| Abstract |
CRH is a very important regulator of stress in mammals. Although initially reported to be
expressed in the CNS where it inhibits the inflammatory reaction, several studies have
shown that CRH is as well expressed in several peripheral tissues mediating the stress
effect and stimulating local inflammation. CRH is involved in human pathophysiology
since pathogenesis is considered a disturbance of homeostasis, and therefore a stress
condition. Based on these data, carcinogenesis and tumor progression were expected to
be related to CRH. Despite the fact that CRH expression has been described in several
gynecological cancers (breast, ovarian, and endometrial carcinomas), CRH expression
was never studied in cervical cancer cells.
Human beta-defensins (HBDs) are small natural secreted antimicrobial and antiviral
peptides, having direct anti-microbial, anti-fungal, anti-viral activity and main role in
initiation, spread and regulation of the immune-inflammatory responses. Act locally as
key regulators of the influenced innate immune system, attracting iDCs and increasing
their numbers, trying to prevent and viral infections. HBDs considered to affect the
initiation of innate immunity, but there is evidence that they perform an important role
in the development of adoptive immunity. They are expressed in the epithelial cells of
the female reproductive system and to various tissues of the reproductive system, such
us endometrium, placenta, and in situations of ovarian malignancy. HBD1 is constantly
produced in various tissues epithelial cells, while HBD2 expression, in contrast, is
mediated by inflammation and it is known for its antimicrobials and anti-viral activity
and that is contributes to the production or induction of anti-inflammatory mediators.
Although specific anti-inflammatory peptides are sufficiently studied, no evidence for
their expression and their role in the initiation and progression of cancer of the cervix
exists. This doctoral thesis focused on the study of the expression of CRH, HBD1, HBD2
peptides in Cervical Intraepithelial Neoplasia (CIN) and squamous cell carcinoma of the
cervix. Their expression was also studied in vitro, using HeLa cell line.
The study was also extended to other neuropeptides, such as UCN, CRH-R1 and CRH-R2,
in HeLa, in vitro. An additional purpose of this research was the effect of CRH in the
XXII
proapoptotic FasL, in conditions of cervical cancer In vitro. FasL was recently found to be
expressed in cervical cancer, while the system CRH-Fas/FasL exist in malignant ovarian
conditions. It was found that human cervical cancer HeLa line, expresses CRH. The fact
that FasL expression, has been shown to induce apoptosis of T lymphocytes, thus
facilitating the immune escape of cancer, highlights the contribution of FasL in cervical
carcinogenesis and development.
HeLa cell line was proved to express FasL. Interestingly, for the first time was
demonstrated in vitro, in HeLa, that FasL expression was induced through CRH. The
above findings, potential are the first significant points that the immune escape of
tumor cells in the cervix, may be associated with stress. But it is necessary to conduct
further experiments to confirm these findings and in vivo.
The existence of receptors CRH (CRH-R1, CRH-R2) have been confirmed in reproductive
tissues such as the ovaries, endometrium, myometrium and placenta. Recently, a study
of our laboratory confirmed the co-expression of CRH, FasL and CRH-R1 peptides in
ovarian cancer. The findings of this thesis, suggesting that the CRH-induced FasL is
through receptor CRH-R1. The pharmacological blockade of CRH-R1 was with
antalarmin. Furthermore, we assume that both the expression of CRH and FasL may be
associated with HPV infection. Additional findings of this thesis is the expression of UCN
in HeLa In vitro. Furthermore, expression of CRH-R2 receptor proved in vitro. These
findings are in conjunction with previous studies; suggest that CRH modulates local
immune escape. Further studies are needed to clarify the mechanism of CRH expression
and its action towards being the single/main FasL inducer or not. If CRH was proven as
the sole or the main FasL inducer, anti-CRH interventions would be an option to block
the immuno-escape mechanisms, allowing local T cells to restrict tumor growth and
progression. In this thesis, was found HBD1 and HBD2 expression in HeLa, cell line, in
vitro and in CIN1,2,3 and SCC. The defensins have potential cytotoxic effect to tumor
cells and may be able to contribute to the recovery of immune capacity differentiates
the progression of cervical carcinogenesis and this gives additional growth potential new
anti-cancer approach.
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