NOS1-, NOS3-, PIK3CA-, and MAPK-pathways in skin following radiation therapy
In an interdisciplinary and individual oncological treatment concept for cancers of the oral cavity, Radiation Therapy (RT) is next to the surgical resection, and chemotherapy one of the most important columns for local and regional disease control. However, RT is also accompanied with multiple side effects, which can be subdivided in short- and long-term radiation associated toxicity. In cases, when patients received RT preoperatively in a neo-adjuvant setting or in cases of disease recurrence, surgeons have to deal with wound healing disorders (WHD) in previously irradiated tissue [1]. Factors, which might influence the onset of WHDs after RT appear to be immanent in terms of a reduced angiogenesis and the development of radiation-induced skin fibrosis [2–4]. Reactive oxygen and nitrogen species (RONS) in the context of oxidative stress also seem to play an important role in the pathogenesis of post-radiogenic WHDs, yet more research has to be conducted to fully understand the underlying molecular pathways and to find starting points for therapeutic interventions [5]. This current PCR-based study aims to evaluate the role of certain crucial pathways in the development of post-radiogenic WHDs following RT to the head and neck.
Nitric oxide (NO) is considered to be a short-living radical, which is involved in many important biological functions, such as vasodilation, anti-microbial activities, immunoregulation, and activities in which it functions as a neurotransmitter [6–10]. Its relevance in wound healing has been described elsewhere [11, 12]. NO is produced by nitric oxide synthase (NOS) in different isoforms. Neuronal NOS (NOS1) and endothelial NOS (NOS3), collectively referred to as cNOS are constitutively expressed depending on intracellular calcium levels [11]. The influence of comorbidities such as protein calorie malnutrition, diabetes, and steroid use, which might be accompanied with impaired wound healing have all been shown to be associated with an reduced NOS expression [13, 14]. Wang and co-workers were able to show, that NO production by dermal fibroblasts could be important during inflammatory stages of wound healing after skin injury [15].
The catalytic p110 subunit of class one phosphatidylinositol 3-kinase (PIK3CA) regulates pathways important for cell proliferation, survival, and motility [16, 17]. Samuels et al. were able to identify PIK3CA as an oncogene, with capacities as a useful marker for detection of cancers and for monitoring tumor progression [18]. The effects of UV exposure on PIK3CA mutations in skin have been described in the context of the pathogenesis of solar lentigo and benign lichenoid keratosis [19, 20].
Moreover, reports from the current literature suggest, that UVA radiation can activate mitogen-activated protein kinase (MAPK) pathway [21]. Its activation leads to activator protein-1(AP-1) induction and consequently the regulation of matrix metalloproteinase (MMP) genes. The breakdown of dermal collagen in photo-related aging has been shown to be associated with UV-induced MMPs expression, also being regulated by underlying MAPK-pathways [22, 23].
However, no distinct reports about of the influence therapeutic ionizing radiation on the MAPK pathway, NO signalling system, or PIK3CA as an essential oncogene exist in the current literature. All pathways and underlying regulatory functions build a complex network responsible for fundamental cell characteristics such as proliferation and apoptosis. This study aims to evaluate the expression of NOS isoforms, PIK3CA, and MAPK in a PCR-based study. Further understanding of essential pathways and corresponding turning points might add up to the knowledge about radiation-induced toxicity.