ABSTRACT
CONTENTS 12.1 Introduction .................................................................................................................................. 250
12.1.1 Types of Oral Cancers ......................................................................................................251 12.1.2 Epidemiology ................................................................................................................... 253
12.1.2.1 Age Distribution ............................................................................................... 254 12.1.2.2 Sex Distribution ............................................................................................... 254 12.1.2.3 Socioeconomic Status ...................................................................................... 254 12.1.2.4 Survival ............................................................................................................ 254 12.1.2.5 Risk Factors ..................................................................................................... 255
12.1.3 Available Diagnoses ........................................................................................................ 255 12.1.4 Treatment ......................................................................................................................... 256
12.2 p16INK4a and p21Waf1/CIP1 as Cell-Cycle Regulators in OSCC ........................................................ 257 12.2.1 p16INK4a Expression in OSCC .......................................................................................... 257 12.2.2 Genetic and Epigenetic Alterations in p16INK4a Expression Pattern ................................ 258 12.2.3 p21Waf1/CIP1 Expression in OSCC and Its Correlation with Clinical
and Pathological Parameters ........................................................................................... 259 12.2.4 p21Waf1/CIP1 Expression in Precancerous Lesions ............................................................. 260 12.2.5 Genetic Alterations in p21Waf1/CIP1 Expression Pattern .................................................... 260 12.2.6 Conclusions ...................................................................................................................... 260
12.3 HIFs and CA-IX as Regulators of the Hypoxia of the Microenvironment in OSCC ...................261 12.3.1 Effects of HIF Expression in OSCC Tumorigenesis and Its Relationship with
Clinicopathological Parameters ...................................................................................... 262 12.3.2 HIF-1α as a Therapeutic Target in OSCC ....................................................................... 262 12.3.3 CA-IX Expression in OSCC and Its Correlation with Clinical and Pathological
Parameters CA-IX in Other HNSCCs ............................................................................. 263 12.3.4 CA-IX and Its Relationship with Angiogenesis and Resistance to Treatment ................ 264 12.3.5 Conclusions ...................................................................................................................... 265
12.4 Tissue Inhibitors of Metalloproteinases as Metastasis Regulators in OSCC .............................. 265 12.4.1 Expression of TIMPs in OSCC ....................................................................................... 265 12.4.2 Exogenous TIMPs and Matrix Metalloproteinase Inhibitors in OSCC Antitumor Therapy ....267 12.4.3 Conclusions ...................................................................................................................... 267
12.5 Altered mRNA Transcripts .......................................................................................................... 268 12.5.1 IL-8 and IL-1B ................................................................................................................ 268 12.5.2 DUSP1 ............................................................................................................................. 269 12.5.3 H3 Histone, Family 3A .................................................................................................... 270 12.5.4 Ornithine Decarboxylase Antizyme 1 ............................................................................ 270 12.5.5 S100 Calcium Binding Protein P ..................................................................................... 270 12.5.6 Spermidine/Spermine N1-Acetyltransferase1 ................................................................. 270 12.5.7 Conclusions ...................................................................................................................... 270
References .............................................................................................................................................. 271
ABSTRACT Oral squamous cell carcinomas (OSCCs) are the most frequent malignancy of the oral cavity, representing 90%–95% malignancies in the oral region. The development of OSCC is a multistep process requiring the accumulation of multiple genetic and epigenetic alterations, inuenced by the patient’s genetic predisposition and environmental factors. Cell-cycle regulation is crucial for tumorigenesis. This control in eukaryotic cells involves the sequential activation of cyclins, cyclin-dependent kinases (CDKs), and two great CDK inhibitors (CDK-Is): the INK4 family, comprised by inhibitors p16, p15, p18, and p19, and the Cip/Kip family, comprised by p27, p57, and p21. The inactivation of p16INK4a and p21Waf1/CIP1 has been widely associated with this type of tumors. The OSCC is a characteristic locally aggressive tumor that presents large areas of tumoral necrosis, in which the levels of acidity and hypoxia are very high, causing low response to chemotherapy. Hypoxia-inducible factors (HIFs) include hypoxia-inducible factor 1 α (HIF-1α), hypoxia-inducible factor 1 β (HIF-1β), hypoxia-inducible factor 2 α (HIF-2α), and hypoxia-inducible factor 3 α (HIF-3α). HIF-1α overexpression has been associated with tumor cell growth and survival of these in head and neck tumors. Carbonic anhydrases (CAs), mainly CA-IX expression, have been thoroughly described in different tumors, including cervical carcinoma, lung, bladder, breast, esophagus, and colorectal cancers; however, this has not been so for head and neck carcinomas. Tumor development and progression are complex processes involving oncogenes, tumor suppressor genes, and tumoral microenvironment, through their contact with malignant cells, surrounding stromal cells (broblasts, endothelial cells, and inammatory cells), and the extracellular matrix (ECM), formed by structural proteins (such as collagen and elastin), specialized proteins (such as brillin, bronectin, and laminin), and proteoglycans. There are several proteases responsible for remodeling the ECM that enable dissemination and metastasis of tumor cells, such as serine proteases, cysteine cathepsins, and matrix metalloproteinases (MMPs). There is a group of specic and strong MMPs called endogenous tissue inhibitors of metalloproteinases (TIMPs), and although the expression of MMPs has been largely described in almost all the tumors of the body, the expression of TIMPs has been studied in a lesser degree. Altered mRNA transcripts are also a promising eld for OSCC detection. Therefore, the goal of this chapter is to describe the expression of p16INK4a; p21Waf1/CIP1; HIFs; CA-IX; TIMPs; IL-8 and IL-1B; DUSP1; H3 histone, family 3A (H3F3A); ornithine decarboxylase antizyme 1 (OAZ1); S100 calcium binding protein P (S100P); and spermidine/spermine N1-acetyltransferase1 (SAT1) in OSCC, determining their relation with clinical, histological, and prognostic factors regarding the different stages of the evolution of the tumors, looking for their detection through noninvasive techniques as exfoliative cytology.
