Downregulation of the α1- and β1-subunit of soluble guanylyl cyclase in Arterial Smooth Muscle Cells of oropharyngeal squamous cell carcinoma is HPV-Independent

Introduction:

The nitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC) is an enzyme comprising α and β subunits. NO binds to heme in the β1-subunit of sGC and activates the enzyme in vascular smooth muscle cells (VSMCs). In the tumor milieu with high levels of reactive oxygen species (ROS), the heme iron of sGC is oxidized and subsequently may become insensitive to NO signaling. Thus far, the expression and subunit composition of sGC subunits α1 and β1 at protein level in arterial VSMCs of oropharyngeal squamous cell carcinoma (OPSCC) is unclear. Therefore, we compared expression of sGCα1β1 in arterial VSMCs of HPV-positive and -negative OPSCC.

Material and Methods:

HPV-positive (n = 11) and negative (n = 10) OPSCC were selected for immunohistochemical incubations. Consecutive sections of each sample were incubated with antibodies specific for the respective subunits α1 and β1. Staining intensity was determined by densitometric analysis of the arterial VSMC layer of both tumor-containing and non-tumorous areas within the same sample. Results were correlated with clinicopathological data.

Results:

In comparison to tumor-free regions, a significant decrease in expression of both α1- and β1-subunits in the arterial VSMC layer of the tumor-containing areas was found. The OPSCC-induced significant downregulation of the α1- and β1-subunits was HPV-independent.

Conclusion:

The response of sGC to NO in tumor arterial VSMCs may be impaired by high concentrations of ROS. This might lead to oxidation of the β1 heme iron followed by subsequent degradation of both subunits. The degradation of sGCα1β1 in VSMCs may result in increased proliferation of VSMCs, promoting tumor arteriogenesis in OPSCC. This can be interrupted by preserving the active heterodimer sGCα1β1 in arterial VSMCs.

Publication History

Publication Date:
23 April 2019 (online)