Increased NBS1 Expression Is a Marker of Aggressive Head and Neck Cancer and Overexpression of NBS1 Contributes to Transformation

• Published in: Clinical cancer research Vol. 12; no. 2; pp. 507 - 515
• Main Authors: YANG, Muh-Hwa, CHIANG, Wei-Chung, CHOU, Teh-Ying, CHANG, Shyue-Yih, CHEN, Po-Min, TENG, Shu-Chun, WU, Kou-Juey
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.01.2006
• Subjects: Adult; Aged; Akt; Antineoplastic agents; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Blotting, Western; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Transformation, Neoplastic; Class I Phosphatidylinositol 3-Kinases; Female; head and neck cancer; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Humans; Male; Medical sciences; Middle Aged; NBS1; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Otorhinolaryngology (head neck, general aspects and miscellaneous); Otorhinolaryngology. Stomatology; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; prognosis; Proto-Oncogene Proteins c-akt - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering - pharmacology; Signal Transduction; transformation; Tumor Cells, Cultured; Tumors; Biological marker; Gene overexpression; ENT disease; Head and neck cancer; Malignant tumor; Gene expression; High malignancy
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-1231

Purpose: Head and neck squamous cell carcinoma (HNSCC) represents the sixth most frequent type of cancer worldwide. However, the molecular genetic alterations underlying its malignant behavior and progression are little known. We showed previously that c-MYC directly activates the expression of the DNA double-strand break repair gene NBS1 , and NBS1 overexpression contributes to transformation. Here, we investigate the role of NBS1 overexpression in HNSCC. Experimental Design: Immunohistochemistry analysis of NBS1 expression was done in 81 locally advanced HNSCC patients. Real-time PCR and Western blot analysis were used to confirm immunohistochemistry results. Human hypopharyngeal cancer cell lines (FADU) with overexpressing NBS1 (FADUNBS) or inducible short interference RNA to repress endogenous NBS1 (FADUNBSi) were generated by stable transfection. Soft agar clonogenicity assay was used to determine the transformation activity. Western blot analysis and phosphatidylinositol 3-kinase (PI3K) assay were done to evaluate the signaling pathways that were involved. Results: NBS1 overexpression was identified in 45% of advanced HNSCC patients. It was an independent marker of poor prognosis. NBS1 expression levels correlated with the transformation activity of FADU clones and also correlated with the phosphorylation levels of Akt and its downstream target mammalian target of rapamycin (mTOR). PI3K activity was increased in NBS1-overexpressing FADU clones. NBS1 overexpression also correlated with increased Akt phosphorylation levels in tumor samples. Conclusions: Increased NBS1 expression is a significant prognostic marker of advanced HNSCC, and the underlying mechanism may involve the activation of the PI3K/Akt pathway.