Paraoxonase-2 shRNA-mediated gene silencing suppresses proliferation and migration, while promotes chemosensitivity in clear cell renal cell carcinoma cell lines.

Clear cell renal cell carcinoma (ccRCC) represents the most common subtype of renal tumor. Despite recent advances in identifying novel target molecules, the prognosis of patients with ccRCC continues to be poor, mainly due to the lack of sensitivity to chemo- and radiotherapy and because of one-third of renal cell carcinoma patients displays metastatic disease at diagnosis. Thus, identifying new molecules for early detection and for developing effective targeted therapies is mandatory. In this work, we focused on paraoxonase-2 (PON2), an intracellular membrane-bound enzyme ubiquitously expressed in human tissues, whose upregulation has been reported in a variety of malignancies, thus suggesting its possible role in cancer cell survival and proliferation. To investigate PON2 involvement in tumor cell metabolism, human ccRCC cell lines were transfected with plasmid vectors coding short harpin RNAs targeting PON2 transcript and the impact of PON2 silencing on cell viability, migration, and response to chemotherapeutic treatment was then explored. Our results showed that PON2 downregulation was able to trigger a decrease in proliferation and migration of ccRCC cells, as well as an enhancement of cell sensitivity to chemotherapy. Thus, taken together, data reported in this study suggest that the enzyme may represent an interesting therapeutic target for ccRCC.

Enzymes Dysregulation in Cancer: From Diagnosis to Therapeutical Approaches.

The metabolic reprogramming that occurs in cancer cells is a hallmark of cancer [...].

Role Played by Paraoxonase-2 Enzyme in Cell Viability, Proliferation and Sensitivity to Chemotherapy of Oral Squamous Cell Carcinoma Cell Lines.

Oral squamous cell carcinoma represents the most aggressive and frequent form of head and neck cancer. Due to drug resistance, the 5-year survival rate of patients with advanced disease is less than 50%. In order to identify molecular targets for effective oral cancer treatment, we focused on paraoxonase-2 enzyme. Indeed, based on data previously obtained from preliminary immunohistochemistry and Western blot analyses performed on tissue specimens, the enzyme was found to be upregulated in tumor compared with normal oral mucosa. Therefore, paraoxonase-2 gene silencing was achieved in HSC-3 and HOC621 oral cancer cell lines, and the effect on cell proliferation, viability, apoptosis induction and sensitivity to cisplatin and 5-fluorouracil treatment was evaluated. Fourier Transform InfraRed Microspectroscopy analyzed alterations of cellular macromolecules upon treatment. Enzyme level and cell proliferation were also determined in cisplatin-resistant clones obtained from HOC621 cell line, as well as in parental cells. Reported data showed that paraoxonase-2 knockdown led to a reduction of cell proliferation and viability, as well as to an enhancement of sensitivity to cisplatin, together with the activation of apoptosis pathway. Spectroscopical data demonstrated that, under treatment with cisplatin, oxidative damage exerted on lipids and proteins was markedly more evident in cells down-regulating paraoxonase-2 compared to controls. Interestingly, enzyme expression, as well as cell proliferation were significantly higher in cisplatin-resistant compared with control HOC621 cells. Taken together these results seem to candidate the enzyme as a promising target for molecular treatment of this neoplasm.

C. spinosa L. subsp. rupestris Phytochemical Profile and Effect on Oxidative Stress in Normal and Cancer Cells.

Spices, widely used to improve the sensory characteristics of food, contain several bioactive compounds as well, including polyphenols, carotenoids, and glucosynolates. Acting through multiple pathways, these bioactive molecules affect a wide variety of cellular processes involved in molecular mechanisms important in the onset and progress of human diseases. Capparis spinosa L. is an aromatic plant characteristic of the Mediterranean diet. Previous studies have reported that different parts (aerial parts, roots, and seeds) of C. spinosa exert various pharmacological activities. Flower buds of C. spinosa contain several bioactive compounds, including polyphenols and glucosinolates. Two different subspecies of C. spinosa L., namely, C. spinosa L. subsp. spinosa, and C. spinosa L. subsp. rupestris, have been reported. Few studies have been carried out in C. spinosa L. subsp. rupestris. The aim of our study was to investigate the phytochemical profile of floral buds of the less investigated species C. spinosa subsp. rupestris. Moreover, we investigated the effect of the extract from buds of C. spinosa subsp. rupestris (CSE) on cell proliferation, intracellular ROS levels, and expression of the antioxidant and anti-apoptotic enzyme paraoxonase-2 (PON2) in normal and cancer cells. T24 cells and Caco-2 cells were selected as models of advanced-stage human bladder cancer and human colorectal adenocarcinoma, respectively. The immortalized human urothelial cell line (UROtsa) and human dermal fibroblast (HuDe) were chosen as normal cell models. Through an untargeted metabolomic approach based on ultra-high-performance liquid chromatography quadrupole-time-of-flight mass spectrometry (UHPLC-QTOF-MS), our results demonstrate that C. spinosa subsp. rupestris flower buds contain polyphenols and glucosinolates able to exert a higher cytotoxic effect and higher intracellular reactive oxygen species (ROS) production in cancer cells compared to normal cells. Moreover, upregulation of the expression of the enzyme PON2 was observed in cancer cells. In conclusion, our data demonstrate that normal and cancer cells are differentially sensitive to CSE, which has different effects on PON2 gene expression as well. The overexpression of PON2 in T24 cells treated with CSE could represent a mechanism by which tumor cells protect themselves from the apoptotic process induced by glucosinolates and polyphenols.

Actin-spectrin scaffold supports open fenestrae in liver sinusoidal endothelial cells.

Fenestrae are open transmembrane pores that are a structural hallmark of healthy liver sinusoidal endothelial cells (LSECs). Their key role is the transport of solutes and macromolecular complexes between the sinusoidal lumen and the space of Disse. To date, the biochemical nature of the cytoskeleton elements that surround the fenestrae and sieve plates in LSECs remain largely elusive. Herein, we took advantage of the latest developments in atomic force imaging and super-resolution fluorescence nanoscopy to define the organization of the supramolecular complex(es) that surround the fenestrae. Our data revealed that spectrin, together with actin, lines the inner cell membrane and provided direct structural support to the membrane-bound pores. We conclusively demonstrated that diamide and iodoacetic acid (IAA) affect fenestrae number by destabilizing the LSEC actin-spectrin scaffold. Furthermore, IAA induces rapid and repeatable switching between the open vs closed state of the fenestrae, indicating that the spectrin-actin complex could play an important role in controlling the pore number. Our results suggest that spectrin functions as a key regulator in the structural preservation of the fenestrae, and as such, it might serve as a molecular target for altering transendothelial permeability.

Paraoxonase-2: A potential biomarker for skin cancer aggressiveness.

BACKGROUND: Cutaneous neoplasms include melanoma and non-melanoma skin cancers (NMSCs). Among NMSCs, basal cell carcinoma (BCC) represents the most common lesion. On the contrary, although accounting for less than 5% of all skin cancers, melanoma is responsible for most of cutaneous malignancy-related deaths. Paraoxonase-2 (PON2) is an intracellular enzyme exerting a protective role against production of reactive oxygen species within mitochondrial respiratory chain. Recently, a growing attention has been focused on exploring the role of PON2 in cancer. The aim of this study was to investigate the diagnostic and prognostic role of PON2 in skin neoplasms. MATERIALS AND METHODS: 36 cases of BCC, distinguished between nodular and infiltrative lesions, as well as 29 melanoma samples were analysed by immunohistochemistry to evaluate PON2 protein expression. Subsequent statistical analyses were carried out to explore the existence of correlations between intratumour enzyme levels and clinicopathological features. RESULTS: Results obtained showed PON2 overexpression in BCCs compared with controls. In particular, distinguishing between less and more aggressive tumour forms, we found no significant differences in enzyme levels between nodular BCCs and controls. Conversely, PON2 expression was significantly higher in infiltrative BCCs compared with controls. Moreover, the enzyme was strongly upregulated in melanoma samples with respect to controls. Interestingly, PON2 levels were positively correlated with Breslow thickness, Clark level, regression, mitoses, lymph node metastases, primary tumour (pT) parameter and pathological stage. CONCLUSIONS: Reported findings seem to suggest that PON2 expression levels could be positively related with tumour aggressiveness of both BCC and melanoma.

Cancer stem cell enrichment is associated with enhancement of nicotinamide N-methyltransferase expression.

The cancer stem cell theory states that a subset of tumor cells, termed cancer stem cells (CSCs), has the ability to self-renew and differentiate within the tumors. According to this theory, CSCs would be mainly responsible for tumor initiation, progression, resistance to therapy, recurrence, and metastasis. In this study, a culture system was setup to enrich CSCs from bladder cancer (T24), lung cancer (A549), colorectal cancer (CaCo-2), and osteosarcoma (MG63) cell lines, through sphere formation. Magnetic-activated cell sorting was also used to further increase CSC enrichment. Subsequently, molecular characterization of CSC-enriched cell populations and parental cells was carried out, by exploring the expression levels of stem markers and the enzyme nicotinamide N-methyltransferase (NNMT). Results obtained showed a significant upregulation of stem cell markers in CSC-enriched populations, obtained upon sphere formation, compared with parental counterparts. Moreover, NNMT expression levels were markedly increased in samples enriched with CSCs with respect to control cells. Considering the fundamental role played by CSCs in carcinogenesis, reported data strengthen the hypothesis that sustains a pivotal role of NNMT in cancer growth and metastasis. In addition, these findings could represent an important achievement for the development of new and effective anticancer therapies, based on CSC-associated targets.

Overexpression of nicotinamide N-methyltransferase in HSC-2 OSCC cell line: effect on apoptosis and cell proliferation.

OBJECTIVES: Oral squamous cell carcinoma (OSCC) is the most common malignancy of oral cavity. Despite advances in therapeutic approaches, the 5-year survival rate for oral cancer has not improved in the last three decades. Therefore, new molecular targets for early diagnosis and treatment of OSCC are needed. In the present study, we focused on the enzyme nicotinamide N-methyltransferase (NNMT). We have previously shown that enzyme expression is upregulated in OSCC and NNMT knockdown in PE/CA PJ-15 cells significantly decreased cell growth in vitro and tumorigenicity in vivo. MATERIAL AND METHODS: To further explore the role of the enzyme in oral cancer cell metabolism, HSC-2 cells were transfected with the NNMT expression vector (pcDNA3-NNMT) and the effect of enzyme upregulation on cell proliferation was evaluated by MTT assay. Subsequently, we investigated at molecular level the role of NNMT on apoptosis and cell proliferation, by exploring the expression of ß-catenin, survivin, and Ki-67 by real-time PCR. Moreover, we performed immunohistochemistry on 20 OSCC tissue samples to explore the expression level of NNMT and survivin ΔEx3 isoform. RESULTS: Enzyme upregulation significantly increased cell growth in vitro. Moreover, a positive correlation between NNMT and survivin ΔEx3 isoform expression levels was found both in HSC-2 cells and in OSCC tissue samples. CONCLUSION: Taken together, our results indicate a possible involvement of NNMT in the proliferation and tumorigenic capacity of OSCC cells and seem to suggest that the enzyme could represent a potential target for the treatment of oral cancer. CLINICAL RELEVANCE: The involvement of NNMT in cell growth and anti-apoptotic mechanisms seems to suggest that this enzyme could be a new therapeutic target to improve the survival of OSCC patients.

Involvement of transforming growth factor beta 1 in the transcriptional regulation of nicotinamide N-methyltransferase in clear cell renal cell carcinoma.

Renal cell carcinoma (RCC) is the most common tumor of the kidney and its major histologic subtype is clear cell RCC (ccRCC). About 30% of diagnosed ccRCCs already have metastasis. Traditionally, localized ccRCC is treated with nephrectomy but the relapse rate is 30%. Thus, the discovery of effective biomarkers for early detection, as well as the identification of new targets for molecular-based therapy of ccRCC are urgently required. In this study, we focused on molecules that could modulate the trascription of the enzyme nicotinamide N-methyltransferase (NNMT) that is known to be up-regulated in ccRCC. Signal transducer and activator of transcription 3 (STAT3), interleukin 6 (IL-6), hepatocyte nuclear factor 1 beta (HNF-1ß) and transforming growth factor beta 1 (TGF-ß1) expression levels were determined in tumor and non tumor samples obtained from 30 patients with ccRCC, using Real-Time PCR. Results obtained showed that TGF-ß1 is significantly (p<0.05) overexpressed in tumor compared with normal tissue samples of ccRCC patients. Conversely, we did not find any statistically significant difference concerning STAT3, IL-6, HNF-1ß gene expression levels. TGF-ß1 up-regulation could be responsible for the high levels of NNMT observed in ccRCC. Targeting TGF-ß1 could improve the outcome of ccRCC patients due to its role in epithelial-mesenchymal transition (EMT), that is known to be associated with a worse overall survival (OS) in this neoplasm.

Curcumin and its Analogues in Oral Squamous Cell Carcinoma: State-of-the-art and Therapeutic Potential.

Oral Squamous Cell Carcinoma (OSCC) is the most common cancer arising from squamous epithelium in the oral cavity and is characterized by high aggressiveness and metastatic potential, which together with a late diagnosis results in a 5-year survival rate of only 50% of patients. The therapeutic options for OSCC management are limited and largely influenced by the cancer stage. While radical surgery can be curative in early stage of disease, most cases require adjuvant therapies, including chemotherapy and radiotherapy which, however, often achieve poor curative rates and are associated with important negative effects. Therefore, there is an urgent need to discover new alternative treatment strategies to improve patients' outcomes. Several medicinal herbs are being studied for their preventive or therapeutic effect in several diseases, including cancer. In particular, the Indian spice curcumin, largely used in oriental countries, has been studied as a chemopreventive or adjuvant agent for different malignancies. Indeed, curcumin is characterized by important biological properties, including antioxidant, anti-inflammatory, and anticancer effects, which could also be exploited in OSCC. However, due to its limited bioavailability and poor aqueous solubility, this review is focused on studies designing new synthetic analogues and developing novel types of curcumin delivery systems to improve its pharmacokinetic and biological properties. Thus, this review analyses the potential therapeutic role of curcumin in OSCC by providing an overview of current in vitro and in vivo studies demonstrating the beneficial effects of curcumin and its analogues in OSCC.

Contribution of the Paraoxonase-2 Enzyme to Cancer Cell Metabolism and Phenotypes.

Paraoxonase-2 (PON2) is a ubiquitously expressed intracellular protein that is localized in the perinuclear region, the endoplasmic reticulum (ER), and mitochondria, and is also associated with the plasma membrane. PON2 functions as an antioxidant enzyme by reducing the levels of reactive oxygen species (ROS) in the mitochondria and ER through different mechanisms, thus having an anti-apoptotic effect and preventing the formation of atherosclerotic lesions. While the antiatherogenic role played by this enzyme has been extensively explored within endothelial cells in association with vascular disorders, in the last decade, great efforts have been made to clarify its potential involvement in both blood and solid tumors, where PON2 was reported to be overexpressed. This review aims to deeply and carefully examine the contribution of this enzyme to different aspects of tumor cells by promoting the initiation, progression, and spread of neoplasms.

In Vitro Study of the Proliferation of MG63 Cells Cultured on Five Different Titanium Surfaces.

The use of dental implants for prosthetic rehabilitation in dentistry is based on the concept of osteointegration. This concept enables the clinical stability of the implants and a total absence of inflammatory tissue between the implant surface and the bone tissue. For this reason, it is essential to understand the role of the titanium surface in promoting and maintaining or not maintaining contact between the bone matrix and the surface of the titanium implant. MATERIALS AND METHODS: Five types of titanium discs placed in contact with osteoblast cultures of osteosarcomas were studied. The materials had different roughness. Scanning electron microscopy (SEM) photos were taken before the in vitro culture to analyze the surfaces, and at the end of the culturing time, the different gene expressions of a broad pattern of proteins were evaluated to analyze the osteoblast response, as indicated in the scientific literature. RESULTS: It was demonstrated that the responses of the osteoblasts were different in the five cultures in contact with the five titanium discs with different surfaces; in particular, the response in the production of some proteins was statistically significant. DISCUSSION: The key role of titanium surfaces underlines how it is still possible to carry out increasingly accurate and targeted studies in the search for new surfaces capable of stimulating a better osteoblastic response and the long-term maintenance of osteointegration.

Knockdown of nicotinamide N-methyltransferase suppresses proliferation, migration, and chemoresistance of Merkel cell carcinoma cells in vitro.

Merkel cell carcinoma (MCC) is an aggressive skin cancer, with a propensity for early metastasis. Therefore, early diagnosis and the identification of novel targets become fundamental. The enzyme nicotinamide N-methyltransferase (NNMT) catalyzes the reaction of N-methylation of nicotinamide and other analogous compounds. Although NNMT overexpression was reported in many malignancies, the significance of its dysregulation in cancer cell phenotype was partly clarified. Several works demonstrated that NNMT promotes cancer cell proliferation, migration, and chemoresistance. In this study, we investigated the possible involvement of this enzyme in MCC. Preliminary immunohistochemical analyses were performed to evaluate NNMT expression in MCC tissue specimens. To explore the enzyme function in tumor cell metabolism, MCC cell lines have been transfected with plasmids encoding for short hairpin RNAs (shRNAs) targeting NNMT mRNA. Preliminary immunohistochemical analyses showed elevated NNMT expression in MCC tissue specimens. The effect of enzyme downregulation on cell proliferation, migration, and chemosensitivity was then evaluated through MTT, trypan blue, and wound healing assays. Data obtained clearly demonstrated that NNMT knockdown is associated with a decrease of cell proliferation, viability, and migration, as well as with enhanced sensitivity to treatment with chemotherapeutic drugs. Taken together, these results suggest that NNMT could represent an interesting MCC biomarker and a promising target for targeted anti-cancer therapy.

NAD+ Homeostasis and NAD+-Consuming Enzymes: Implications for Vascular Health.

Nicotinamide adenine dinucleotide (NAD+) is a ubiquitous metabolite that takes part in many key redox reactions. NAD+ biosynthesis and NAD+-consuming enzymes have been attracting markedly increasing interest since they have been demonstrated to be involved in several crucial biological pathways, impacting genes transcription, cellular signaling, and cell cycle regulation. As a consequence, many pathological conditions are associated with an impairment of intracellular NAD+ levels, directly or indirectly, which include cardiovascular diseases, obesity, neurodegenerative diseases, cancer, and aging. In this review, we describe the general pathways involved in the NAD+ biosynthesis starting from the different precursors, analyzing the actual state-of-art of the administration of NAD+ precursors or blocking NAD+-dependent enzymes as strategies to increase the intracellular NAD+ levels or to counteract the decline in NAD+ levels associated with ageing. Subsequently, we focus on the disease-related and age-related alterations of NAD+ homeostasis and NAD+-dependent enzymes in endothelium and the consequent vascular dysfunction, which significantly contributes to a wide group of pathological disorders.

Recent Advances in the Management of Clear Cell Renal Cell Carcinoma: Novel Biomarkers and Targeted Therapies.

Renal cell carcinoma (RCC) belongs to a heterogenous cancer group arising from renal tubular epithelial cells. Among RCC subtypes, clear cell renal cell carcinoma (ccRCC) is the most common variant, characterized by high aggressiveness, invasiveness and metastatic potential, features that lead to poor prognosis and high mortality rate. In addition, diagnosis of kidney cancer is incidental in the majority of cases, and this results in a late diagnosis, when the stage of the disease is advanced and the tumor has already metastasized. Furthermore, ccRCC treatment is complicated by its strong resistance to chemo- and radiotherapy. Therefore, there is active ongoing research focused on identifying novel biomarkers which could be useful for assessing a better prognosis, as well as new molecules which could be used for targeted therapy. In this light, several novel targeted therapies have been shown to be effective in prolonging the overall survival of ccRCC patients. Thus, the aim of this review is to analyze the actual state-of-the-art on ccRCC diagnosis, prognosis and therapeutic options, while also reporting the recent advances in novel biomarker discoveries, which could be exploited for a better prognosis or for targeted therapy.

Paraoxonase-2 is upregulated in triple negative breast cancer and contributes to tumor progression and chemoresistance.

Triple negative breast cancer (TNBC) displays a high aggressive behavior, tendency to relapse and early metastasize, leading to poor prognosis. The lack of estrogen receptors, and human epidermal growth factor receptor 2, prevents the use of endocrine or molecular targeted therapy, being therapeutical options for TNBC managements mostly limited to surgery, radiotherapy and mainly chemotherapy. While an important number of TNBCs initially responds to chemotherapy, they are prone to develop chemoresistance over the time. Thus, there is an urgent need to identify novel molecular targets to improve the outcome of chemotherapy in TNBC. In this work we focused on the enzyme paraoxonase-2 (PON2) which has been reported to be overexpressed in several tumors contributing to cancer aggressiveness and chemoresistance. Through a case-control study, we analyzed PON2 immunohistochemical expression in breast cancer molecular subtypes Luminal A, Luminal B, Luminal B HER2+, HER2 + and TNBC. Subsequently, we evaluated the in vitro effect of PON2 downregulation on cell proliferation and response to chemotherapeutics. Our results showed that the PON2 expression levels were significantly upregulated in the infiltrating tumors related to the subtypes Luminal A, HER2+ and TNBC compared to the healthy tissue. Furthermore, PON2 downregulation led to a decrease in cell proliferation of breast cancer cells, and significantly enhanced the cytotoxicity of chemotherapeutics on the TNBC cells. Although further analyses are necessary to deeply understand the mechanisms by which the enzyme could participate to breast cancer tumorigenesis, our results seem to demonstrate that PON2 could represent a promising molecular target for TNBC treatment.

Nicotinamide N-Methyltransferase as Promising Tool for Management of Gastrointestinal Neoplasms.

Gastrointestinal (GI) neoplasms include esophageal, gastric, colorectal, hepatic, and pancreatic cancers. They are characterized by asymptomatic behavior, being responsible for diagnostic delay. Substantial refractoriness to chemo- and radiotherapy, exhibited by late-stage tumors, contribute to determine poor patient outcome. Therefore, it is of outmost importance to identify new molecular targets for the development of effective therapeutic strategies. In this study, we focused on the enzyme nicotinamide N-methyltransferase (NNMT), which catalyzes the N-methylation reaction of nicotinamide and whose overexpression has been reported in numerous neoplasms, including GI cancers. The aim of this review was to report data illustrating NNMT involvement in these tumors, highlighting its contribution to tumor cell phenotype. Cited works clearly demonstrate the interesting potential use of enzyme level determination for both diagnostic and prognostic purposes. NNMT was also found to positively affect cell viability, proliferation, migration, and invasiveness, contributing to sustain in vitro and in vivo tumor growth and metastatic spread. Moreover, enzyme upregulation featuring tumor cells was significantly associated with enhancement of resistance to treatment with chemotherapeutic drugs. Taken together, these results strongly suggest the possibility to target NNMT for setup of molecular-based strategies to effectively treat GI cancers.

The Double-Edged Sword of Oxidative Stress in Skin Damage and Melanoma: From Physiopathology to Therapeutical Approaches.

The skin is constantly exposed to exogenous and endogenous sources of reactive oxygen species (ROS). An adequate balance between ROS levels and antioxidant defenses is necessary for the optimal cell and tissue functions, especially for the skin, since it must face additional ROS sources that do not affect other tissues, including UV radiation. Melanocytes are more exposed to oxidative stress than other cells, also due to the melanin production process, which itself contributes to generating ROS. There is an increasing amount of evidence that oxidative stress may play a role in many skin diseases, including melanoma, being the primary cause or being a cofactor that aggravates the primary condition. Indeed, oxidative stress is emerging as another major force involved in all the phases of melanoma development, not only in the arising of the malignancy but also in the progression toward the metastatic phenotype. Furthermore, oxidative stress seems to play a role also in chemoresistance and thus has become a target for therapy. In this review, we discuss the existing knowledge on oxidative stress in the skin, examining sources and defenses, giving particular consideration to melanocytes. Therefore, we focus on the significance of oxidative stress in melanoma, thus analyzing the possibility to exploit the induction of oxidative stress as a therapeutic strategy to improve the effectiveness of therapeutic management of melanoma.

The Utility of Nicotinamide N-Methyltransferase as a Potential Biomarker to Predict the Oncological Outcomes for Urological Cancers: An Update.

Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation reaction of nicotinamide, using S-adenosyl-L-methionine as the methyl donor. Enzyme overexpression has been described in many non-neoplastic diseases, as well as in a wide range of solid malignancies. This review aims to report and discuss evidence available in scientific literature, dealing with NNMT expression and the potential involvement in main urologic neoplasms, namely, renal, bladder and prostate cancers. Data illustrated in the cited studies clearly demonstrated NNMT upregulation (pathological vs. normal tissue) in association with these aforementioned tumors. In addition to this, enzyme levels were also found to correlate with key prognostic parameters and patient survival. Interestingly, NNMT overexpression also emerged in peripheral body fluids, such as blood and urine, thus leading to candidate the enzyme as promising biomarker for the early and non-invasive detection of these cancers. Examined results undoubtedly showed NNMT as having the capacity to promote cell proliferation, migration and invasiveness, as well as its potential participation in fundamental events highlighting cancer progression, metastasis and resistance to chemo- and radiotherapy. In the light of this evidence, it is reasonable to attribute to NNMT a promising role as a potential biomarker for the diagnosis and prognosis of urologic neoplasms, as well as a molecular target for effective anti-cancer treatment.

Beyond Nicotinamide Metabolism: Potential Role of Nicotinamide N-Methyltransferase as a Biomarker in Skin Cancers.

Skin cancers (SC) collectively represent the most common type of malignancy in white populations. SC includes two main forms: malignant melanoma and non-melanoma skin cancer (NMSC). NMSC includes different subtypes, namely, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), Merkel cell carcinoma (MCC), and keratoacanthoma (KA), together with the two pre-neoplastic conditions Bowen disease (BD) and actinic keratosis (AK). Both malignant melanoma and NMSC are showing an increasing incidence rate worldwide, thus representing an important challenge for health care systems, also because, with some exceptions, SC are generally characterized by an aggressive behavior and are often diagnosed late. Thus, identifying new biomarkers suitable for diagnosis, as well as for prognosis and targeted therapy is mandatory. Nicotinamide N-methyltransferase (NNMT) is an enzyme that is emerging as a crucial player in the progression of several malignancies, while its substrate, nicotinamide, is known to exert chemopreventive effects. Since there is increasing evidence regarding the involvement of this enzyme in the malignant behavior of SC, the current review aims to summarize the state of the art as concerns NNMT role in SC and to support future studies focused on exploring the diagnostic and prognostic potential of NNMT in skin malignancies and its suitability for targeted therapy.