Glycodelin [gene name, progesterone associated endometrial protein (PAEP)] was initially described as an immune system modulator in reproduction. Today, it is also known to be expressed in several types of cancer, including nonsmall cell lung cancer (NSCLC). In this cancer type, the feasibility of its usage as a followup biomarker and its potential role as an immune system modulator were described. It is assumed that NSCLC tumours secrete glycodelin to overcome immune surveillance. Therefore, targeting glycodelin might be a future approach with which to weaken the immune system defence of NSCLC tumours. In this context, it is important to understand the regulatory pathways of PAEP/glycodelin expression, as these are mostly unknown so far. In this study, we analysed the influence of several inducers and of their downstream pathways on PAEP/glycodelin expression in a human lung adenocarcinoma carcinoma (ADC; H1975) and a human lung squamous cell carcinoma (SQCC) cell line (2106T). PAEP/glycodelin expression was notably stimulated by the canonical transforming growth factor (TGF)beta pathway in SQCC cells and the PKC signalling cascade in both cell lines. The PI3K/AKT pathway inhibited PAEP/glycodelin expression in the ADC cells and an antagonizing role towards the other investigated signalling cascades is suggested herein. Furthermore, the mitogenactivated protein kinase kinase (MEK)/extracellularsignal regulated kinases (ERK) pathway was, to a lesser extent, found to be associated with increased PAEP/glycodelin amounts. The phosphoinositide 3kinase (PI3K)/protein kinase B (AKT), MEK/ERK pathway and TGFbeta are targets of NSCLC drugs that are already approved or are currently under investigation. On the whole, the findings of this study provide evidence that inhibiting these targets affects the expression of glycodelin and its immunosuppressive effect in NSCLC tumours. Moreover, understanding the regulation of glycodelin expression may lead to the development of novel therapeutic approaches with which to weaken the immune system defence of NSCLC tumours in the future.
- Weber, R.
- Meister, M.
- Muley, T.
- Thomas, M.
- Sultmann, H.
- Warth, A.
- Winter, H.
- Herth, F. J. F.
- Schneider, M. A.
Keywords
- Carcinoma, Non-Small-Cell Lung/*genetics/immunology/pathology
- Cell Line, Tumor
- Cell Proliferation/*genetics
- Gene Deletion
- Gene Expression Regulation, Neoplastic
- Glycodelin/*genetics/immunology
- Humans
- Immunologic Factors/*genetics/immunology
- Phosphatidylinositol 3-Kinases/genetics
- Protein Kinase C/genetics
- Proto-Oncogene Proteins c-akt/genetics
- RNA, Small Interfering/genetics
- Signal Transduction/genetics
- Transforming Growth Factor beta/genetics