Multiple genetic and epigenetic events, including the aberrant expression and function of molecules regulating cell signaling, growth, survival, motility, angiogenesis, and cell cycle control, underlie the progressive acquisition of a malignant phenotype in squamous carcinomas of the head and neck (HNSCC). In this regard, there has been a recent explosion in our understanding on how extracellular components, cell surface molecules, and a myriad of intracellular proteins and second messenger systems interact with each other, and are organized in pathways and networks to control cellular and tissue functions and cell fate decisions. This emerging ability to understand the basic mechanism controlling inter-and intra-cellular communication has provided an unprecedented opportunity to understand how their dysregulation contributes to the growth and dissemination of human cancers. Here, we will discuss the emerging information on how the use of modern technologies, including gene array and proteomic studies, combined with the molecular dissection of aberrant signaling networks, including the EGFR, ras, NFκB, Stat, Wnt/β-catenin, TGF-β, and PI3K-AKT-mTOR signaling pathways, can help elucidate the molecular mechanisms underlying HNSCC progression. Ultimately, we can envision that this knowledge may provide tremendous opportunities for the diagnosis of premalignant squamous lesions, and for the development of novel molecular-targeted strategies for the prevention and treatment of HNSCC.

Head and neck cancer (SCCHN) is a common, aggressive, treatment-resistant cancer with a high recurrence rate and mortality, but the mechanism of treatment-resistance remains unclear. Here we describe a mechanism where the AAA-ATPase TRIP13 promotes treatment-resistance. Overexpression of TRIP13 in non-malignant cells results in malignant transformation. High expression of TRIP13 in SCCHN leads to aggressive, treatment-resistant tumors and enhanced repair of DNA damage. Using mass spectrometry, we identify DNA-PKcs complex proteins that mediate non homologous end joining (NHEJ), as TRIP13 binding partners. Using repair-deficient reporter systems, we show that TRIP13 promotes NHEJ, even when homologous recombination is intact. Importantly, overexpression of TRIP13 sensitizes SCCHN to an inhibitor of DNA-PKcs. Thus, this study defines a new mechanism of treatment resistance in SCCHN and underscores the importance of targeting NHEJ to overcome treatment failure in SCCHN and potentially in other cancers that overexpress TRIP13.

Cisplatin-based chemotherapy is the standard treatment of choice for head and neck squamous cell carcinoma (HNSCC). The efficiency of platinum-based therapies is directly influenced by the development of tumor resistance. Multiple signaling pathways have been linked to tumor resistance, including activation of nuclear factor kappa B (NFκB). We explore a novel mechanism by which NFκB drives HNSCC resistance through histone modifications. Post-translational modification of histones alters chromatin structure, facilitating the binding of nuclear factors that mediate DNA repair, transcription, and other processes. We found that chemoresistant HNSCC cells with active NFκB signaling respond to chemotherapy by reducing nuclear BRCA1 levels and by promoting histone deacetylation (chromatin compaction). Activation of this molecular signature resulted in impaired DNA damage repair, prolonged accumulation of histone γH2AX and increased genomic instability. We found that pharmacological induction of histone acetylation using HDAC inhibitors prevented NFκB-induced cisplatin resistance. Furthermore, silencing NFκB in HNSCC induced acetylation of tumor histones, resulting in reduced chemoresistance and increased cytotoxicity following cisplatin treatment. Collectively, these findings suggest that epigenetic modifications of HNSCC resulting from NFκB-induced histone modifications constitute a novel molecular mechanism responsible for chemoresistance in HNSCC. Therefore, targeted inhibition of HDAC may be used as a viable therapeutic strategy for disrupting tumor resistance caused by NFκB.

Objectives The presence of titanium (Ti) particles around dental implants has been reported in the literature for decades. The prospective presence of Ti debris on soft tissues surrounding dental implants has not been systematically investigated and remains to be explored. Hence, this review aimed to evaluate the origin, presence, characteristics, and location of Ti particles in relation to dental implants. Material and methods Literature searches were conducted by two reviewers independently based on the PRISMA guidelines. The systematic review identified studies on Ti particles derived from dental implants. We evaluated several parameters, including anatomical location, and the suspected methods of Ti particles release. Results The search resulted in 141 articles, of which 26 were eligible and included in the systematic review of the literature. The investigations reported Ti and metal‐like particles in the soft (i.e., epithelial cells, connective tissue, and inflammatory cells) and hard (bone crest and bone marrow) tissues around the dental implants. Shape and size of the particles varied. The current literature reported a size range from 100 nm to 54 µm identified by multiple particles identification methods. Conclusion Ti particles surrounding peri‐implant tissues are a common finding. Peri‐implantitis sites presented a higher number of particles compared to healthy implants. The particles were mostly around the implants and inside epithelial cells, connective tissue, macrophages, and bone. Various mechanisms were described as causes of Ti release, including friction during implant insertion, corrosion of the implant surface, friction at the implant–abutment interface, implantoplasty, and several methods used for implant surface detoxification.