Major causes of head and neck squamous cell carcinoma (HNSCC)-related deaths are cervical node and distant metastasis. We previously demonstrated that overexpression of the DNA double-strand break repair protein Nijmegen breakage syndrome 1 (NBS1) is a prognostic marker of advanced HNSCCs. Epithelial-mesenchymal transition (EMT) was demonstrated to be the major mechanism responsible for mediating invasiveness and metastasis of late-stage cancers. We therefore investigated the role of NBS1 overexpression in mediating EMT and metastasis. NBS1 overexpression was associated with metastasis of HNSCC patients using tissue microarray-immunohistochemistry approach. Induction of EMT was observed in an NBS1-overexpressing HNSCC cell line (FADUNBS), whereas short-interference RNA (siRNA)-mediated repression of endogenous NBS1 reversed the shift of EMT markers. Increased migration/invasiveness of FADUNBS was shown by in vitro and in vivo assays. NBS1 overexpression upregulated the expression of an EMT regulator Snail and its downstream target matrix metalloproteinase-2. EMT phenotypes and increased migration/invasiveness of FADUNBS cells were reversed by siRNA-mediated repression of Snail expression or a phosphatidylinositol 3-kinase-specific inhibitor. In HNSCC samples, co-expression of NBS1/Snail in primary tumors correlated with metastasis and the worst prognosis. These results indicate that NBS1 overexpression induces EMT through the upregulation of Snail expression, and co-expression of NBS1/Snail predicts metastasis in HNSCCs.

Head and neck squamous cell carcinoma (HNSCC) is a global malignancy. The insulin-like growth factor (IGF) signalling axis plays a critical role in tumourigenesis. This study defined the clinical and functional roles of insulin-like growth factor binding protein-5 (IGFBP-5) in HNSCC. Down-regulation of IGFBP-5 mRNA expression was found during the progression from pre-cancer to HNSCC. The down-regulation in HNSCC was associated with a higher propensity to nodal metastasis. SAS and OECM-1 are HNSCC cells that do, or do not, express IGFBP-5, respectively. Recombinant IGFBP-5 reduced the proliferation of OECM-1 cells and this was exerted mainly through blockade of the IGF pathways. Either IGFBP-5 or IGF-I treatment alone promoted OECM-1 migration, but a combination of treatments generated antagonistic effects. Overexpression of IGFBP-5 reduced the proliferation and anchorage-independent growth of both OECM-1 and SAS cells. Conversely, knockdown of IGFBP-5 expression significantly induced the proliferation and anchorage-independent growth of SAS cells. It also induced the growth of xenografted SAS tumours. SAS transfectants that expressed mutant or truncated IGFBP-5, which lack IGF binding activity, exhibited significantly lower anchorage-independent growth than vector control. This suggests that IGFBP-5 possesses an IGF-independent suppressor function. The suppressive effects of IGFBP-5 on the tumourigenesis of HNSCC might be invaluable to future neoplastic intervention.

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults with a dismal prognosis. Current therapy of surgical removal combined with Temozolomide (TMZ) and radiation therapy only slightly prolongs the survival of GBM patients. Thus, it is essential to elucidate mechanism underlying its highly malignant properties in order to develop efficacious therapeutic regimens. In this study, we showed that progranulin (PGRN) was overexpressed in most GBM cell lines and the majority of human tumor samples. PGRN overexpression conferred GBM cells with tumorigenic properties and TMZ resistance by upregulating DNA repair (PARP, ATM, BRCA1, Rad51, XRCC1 and so on) and cancer stemness (CD133, CD44, ABCG2) genes, in part via an AP-1 transcription factor, specifically cFos/JunB. Curcumin, an AP-1 inhibitor, was also found to regulate PGRN promoter activity and expression including its downstream effectors aforementioned. These data suggested a feedforward loop between PGRN signaling and AP-1. PGRN depletion significantly decreased unlimited self-renewal and multilineage differentiation and the malignant properties of GBMs cells S1R1, and enhanced their vulnerability to TMZ. In addition, S1R1 depleted of PGRN also lost the ability to form tumor in an orthotopic xenograft mouse model. In conclusion, PGRN had a critical role in the pathogenesis and chemoresistance of GBM and functioned at the top of the hierarchy of cellular machinery that modulates both DNA repair pathways and cancer stemness. Our data suggest that a new strategy combining current regimens with compounds targeting PGRN/AP-1 loop like curcumin may significantly improve the therapeutic outcome of GBM.

No abstract