the defect and high pressure of CSF.This algorithm may pave the way to wider use of endonasal endoscopic corridors to the skull base, resulting in a remarkable decrease of surgical morbidity.

The high invasiveness of head-and-neck squamous cell carcinoma (HNSCC) contributes to local radiation therapy failure. We sought to dissect the molecular mechanisms governing the tumor invasive and radioresistant phenotype in HNSCC. Invasive and non-invasive tumor cell populations from three different human HNSCC cell lines FaDu, Cal27 and SCC25 were separated using matrigel-covered Boyden-chambers. Both populations were irradiated with 0, 0.5, 1, 2, 5, 10 Gy and their clonogenic survival was determined. In parallel, microRNAs (miRs) were isolated from both populations and expression profiling was performed using NanoString technology and TaqMan real-time qRT-PCR. The pro-invasive function of identified miRs was confirmed using pre-miR and anti-miR constructs and transwell invasion assay. The modulatory role of miRs was further confirmed by clonogenic survival assay. A murine orthotopic floor-of-mouth squamous cell carcinoma model was used to show the regulation of miRs in primary vs. recurrent tumors. The Boyden chamber-separated invasive HNSCC cells were more resistant to radiation therapy as compared to their respective non-invasive population. The clonogenic survival fraction was reduced by 25.1%, 32.7% and 21.2% in non-invasive FaDu, Cal27 and SCC25 cells, while the survival of invasive cells was diminished by 21.7%, 16.7% and 4.9% after 2 Gy irradiation. MiR profiling was performed to dissect master regulators of HNSCC invasiveness and their crosstalk with observed tumor radioresistance. The regulation of 12 differentially expressed miRs was confirmed by qRT-PCR. Functional validation for involvement of 3 miRs was provided by pre-miR and anti-miR transfection and transmigration assay. Overexpression of miR-106a and -196b inhibited tumor invasion and was correlated with decreased urokinase-type plasminogen activator (uPA) expression. The regulation of miR-106a and -196b was further confirmed in murine locally recurrent HNSCC as compared to their primary counterparts. Ongoing clonogenic survival experiments indicate a modulatory role for miR-106a in the development of radioresistance. Evidence is provided for a direct link between HNSCC invasion and the development of radioresistance. Moreover, miR regulators governing this crosstalk are identified.