Mario Pérez-Sayáns

Multidrug resistance in oral squamous cell carcinoma: The role of vacuolar ATPases

Resistance to chemotherapy agents is the main reason for treatment failure in patients with cancer. Multidrug resistance (MDR) is the primary mechanism that leads to the acquisition of the multiresistant phenotype through the overexpression of drug efflux transporters such as the P-glycoprotein (Pgp), encoded by the MDR1 gene, at the plasma membrane. Other molecules that have been implicated in drug resistance include multidrug resistance-associated proteins, glutathione S-transferase-pi, and DNA topoisomerase II. These molecules, however, cannot fully explain MDR in oral squamous cell carcinoma. Vacuolar ATPase (V-ATPase), which is largely responsible for regulating acidity in the microenvironment of solid tumors (and hence interfering with the absorption of chemotherapy drugs), seems to be the most important molecule involved in MDR in such tumors. Specific V-ATPase inhibitors, thus, may be useful, not only as coadjuvants in antitumor treatments but also as a mechanism for controlling resistance to antitumor drugs.

Hypoxia-inducible factors in OSCC.

Oral squamous cell carcinoma (OSCC) is a characteristic locally aggressive tumor in which hypoxia levels are very high, causing a low response to chemotherapy and providing basic resistance to anticancer drugs. Tumoral hypoxia directly depends on hypoxia-inducible factors (HIF). The goal of this paper is to describe HIF basic biology and tumor cells (HIF-1α, mainly), analyzing the effects of its expression in OSCC, study its relation with other molecules such as nitric oxide (NO), carbonic anhydrase (CA) or VEGF and assess the possibility of its manipulation as a therapeutic target.

Measurement of ATP6V1C1 expression in brush cytology samples as a diagnostic and prognostic marker in oral squamous cell carcinoma

Background: Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity. Brush cytology has reemerged as a molecular tool for diagnosing this cancer. ATP6V1C1, one of the main genes regulating V-ATPase activity, has been implicated in metastasis and multiple drug resistance. The aim of this study was to measure ATP6V1C1 expression levels in OSCC and to evaluate the value of this test in the diagnosis and prognosis of OSCC. Material and Methods: Patients with OSCC and a control group of healthy individuals were studied. The clinical and demographic variables analyzed included age, sex, smoking, tumor location, and tumor stage. Brush cytology samples were obtained using a cytology brush and analyzed by real-time quantitative polymerase chain reaction for ATP6V1C1 expression. Results: The differences in ATP6V1C1 expression between patients and controls were statistically significant (Mann-Whitney U test = 26, p

p16INK4a/CDKN2 expression and its relationship with oral squamous cell carcinoma is our current knowledge enough?

Oral squamous cell carcinomas (OSCC) are the most common malignancy of the oral cavity and their multistep development requires the accumulation of multiple genetic and epigenetic alterations. Inactivation of p16(INK4a), encoded by the CDKN2 gene has been widely associated with this type of tumors. The purpose of this review is to elucidate the relationship between p16(INK4a) expression and the different clinical and pathological aspects of OSCC, analyze the variation in results between studies, detailing the described genetic/epigenetic alterations that result in gene silencing and the relationship between p16(INK4a) and HPV infection.

Expression of CA-IX is associated with advanced stage tumors and poor survival in oral squamous cell carcinoma patients

INTRODUCTION Carbonic anhydrases (CAs), a group of ubiquitously expressed metalloenzymes, are involved in numerous physiological and pathological processes, including tumorigenicity. Specifically, CA-IX has been primarily found in hypoxic tumor tissues. MATERIAL AND METHODS This is a retrospective study of tumors from the Tissue Bank of the Pathology Department of the University Hospital of Santiago de Compostela. We selected 50 oral squamous cell carcinomas (OSCCs) using Tissue Microarray (TMA) technology. The immunohistochemical study was performed to determine CA-IX expression. The resulting data were subject to statistical analysis and survival curves. RESULTS Of the 50 cases, 23 were detected in early stages (I and II) and 27 in advanced stages (III and IV). In the first year, almost 50% of patients in stages III-IV died, which contrasted with those patients in initial stages who registered a survival rate of 80% (P = 0.019). Regarding the expression of CA-IX, nine cases (18%) were negative, 18 cases (36%) were moderate, while 23 cases (46%) were intense. Tumors in stages I-II showed a positivity of 52.6%; however, in advanced stages, the percentage reached 95.5% (P = 0.002). Regarding CA-IX expression and survival, patients with tumors with strong staining had a lower average survival time (13.8 months) than patients with negative or weak-moderate staining (33.4 and 32.8 months, respectively), log-rank=6.1, P value=0.0484. CONCLUSIONS Early diagnosis of these tumors is essential to improve patient survival. CA-IX expression augments with increasing tumor stage, probably related with the degree of hypoxia; thus, its measurement can be used as a prognostic factor.

The role of the adenomatous polyposis coli (APC) in oral squamous cell carcinoma.

The main cause of death in oral squamous cell carcinomas (OSCC) is metastasis. Intercellular adhesion is mediated by a family of glycoproteins called cadherins and other molecules like catenins and APC (adenomatous polyposis coli) among other. The WNT (wingless-type) gene family is a group of genes, key signaling pathway for embryonic development and oncogenesis. The goal of this paper is to describe the role of the APC gene, and its derivatives, in the carcinogenicity pathway of WNT-1, identifying its role as a tumor suppressor gene in OSCC, while describing the genetic (loss of heterozygosity and mutations) and epigenetic alterations that modulate its expression and evaluate its relationship with the clinicopathological parameters of this type of tumors. As for APC, its activity as a tumor suppressor gene appears muted on a relatively frequent basis in these tumors, either by LOH, mutations or epigenetic control mechanisms, thus resulting in a low degree of agreement between the results of different studies.

What real influence does the proto-oncogene c-myc have in OSCC behavior?

The influence of c-myc in the carcinogenic process has been previously described although in the specific case of oral tumors it has been poorly tested. Myc proteins are a family of proto-oncogenes involved in the cell proliferation regulation, differentiation and apoptosis. The goal of this paper is to describe the functions of c-myc and its role as oncogene, assessing its expression by immunohistochemistry and genetic amplification studies, and studying its relationship with tumoral clinical and pathological variables, and describing genetic and molecular interactions in OSCC.

Current trends in miRNAs and their relationship with oral squamous cell carcinoma

A micro RNA (miRNA) is a single-stranded endogenous, non-coding RNA, with length ranging between 18 and 24 nucleotides and the ability of regulating the expression of other genes on a post-transcriptional level by means of various processes, degradation or repression of target mRNA. miRNAs play a crucial role in regulating fundamental processes such as cell cycle, differentiation and apoptosis; thus, their deregulation can affect normal cell growth and development, and even participate in carcinogenesis. The goals of this paper are: to outline the formation and functions of miRNAs; to determine their role in oral squamous cell carcinoma; to analyze the different miRNAs described and their roles as oncogenes or tumor suppressor genes, depending on their overexpression or subexpression; to describe the different polymorphisms and epigenetic alterations identified; and to determine their role in multidrug resistance.

The role of p21Waf1/CIP1 as a Cip/Kip type cell-cycle regulator in oral squamous cell carcinoma (Review).

Oral Squamous Cell Carcinoma (OSCC) is biologically characterized by the accumulation of multiple genetic and molecular alterations that end up clinically characterized as a malignant neoplasm through a phenomenon known as multistep. The members of the Cip/Kip family, specifically p21Waf1/CIP1, are responsible for cell cycle control, blocking the transition from phase G1 to phase S. We made a search of articles of peer-reviewed Journals in PubMed/ Medline, crossing the keywords. The goal of this paper is to determine the relationship between p21Waf1/CIP1 expression and several clinical and pathological aspects of OSCC, their relationship with p53 and HPV, as well as genetic alterations in their expression pattern, their use as a prognosis market in the evolution of precancerous lesions and their roles in anticancer treatments. The results of p21WAF1/CIP1 expression in OSCC showed mixed results in terms of positivity/negativity throughout different studies. It seems that, although p21Waf1/CIP1 expression is controlled in a p53-dependent manner, coexpression of both in OSCC is not intrinsically related. Although the presence of HPV viral oncoproteins increases p21Waf1/CIP1 levels, the small number of studies, have forced us to disregard the hypothesis that HPV infected lesions that present better prognosis are due to a p21Waf1/CIP1–dependent control. The role of p21WAF1/CIP1 as cell-cycle regulator has been well described; however, its relationship to OSCC, the clinical and pathological variables of tumors, HPV and different treatments are not entirely clear. Thus, it would be very interesting to pursue further study of this protein, which may have a significant value for the diagnosis, prognosis and therapy of this type of tumors. Key words:p21Waf1/CIP1, Cip/Kip type cell-cycle regulator, Oral squamous cell carcinoma (OSCC), p53, genetic alterations.

The role of carbonic anhydrase IX in hypoxia control in OSCC

Tumoral microenvironments play a key role in the evolution of solid tumors. Tumor hypoxia is actively involved in the promotion of genetic instability, the invasive capacity of tumor cells, metastasis, and a worsening of the clinical evolution. Endogenous hypoxia markers are controlled by hypoxia-related genes, formed by HIF-1, which is related to several target genes that involve the energy metabolism, angiogenesis, and transmembrane carbonic anhydrases (CAs), mainly CA-IX that is one of the tumor-related carbonic anhydrases. The goal of this paper is to establish the role of CA-IX as a hypoxia marker in OSCC, while analyzing its expression in this type of tumors and its relationship with several clinical and pathological parameters and prognosis, evaluating its relationship with angiogenesis, other hypoxia markers, and clarifying its role in chemotherapy and radiotherapy resistance.