DigitalUM :: Browsing by Subject "Carcinogenesis"

Browsing by Subject "Carcinogenesis"

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Open Access
CDC28 protein kinase regulatory subunit 1B (CKS1B) expression and genetic status analysis in oral squamous cell carcinoma
(Murcia: Universidad de Murcia, Facultad de Biología, 2011) Martín-Ezquerra, Gemma; Salgado, Rocio; Toll, Agustí; Baró, Teresa; Mojal, Sergi; Yébenes, Mireia; Garcia-Muret, María Pilar; Solé, Francesc; Alameda Quitllet, Francesc; Espinet, Blanca; Pujol, Ramón M.
CKS1B is a member of the highly conserved cyclin kinase subunit 1 (CKS1) protein family which interacts with cyclin-dependent kinases and plays a critical role in cell cycle progression. In oral squamous cell carcinoma (OSCC), as in other malignancies, CKS1B overexpression has been correlated with reduced survival. To our knowledge, no studies evaluating the genetic status of CKS1B gene in OSCC have been reported. Herein, genetic and protein status of CKS1B were analyzed by immunohistochemical (IHC) and fluorescence in situ hybridization (FISH) techniques in a series of primary OSCC (n=51) and lymph node OSCC metastases samples (n=14). The observed results were compared with those obtained in either inflammatory (oral lichen planus [OLP]) (n=13) and premalignant oral mucosal lesions (oral leukoplakia) (n=16). A significant CKS1B overexpression was observed in OSCC and lymph node metastases samples than in OLP and oral leukoplakia (mean 70% vs 35%, p<0.001). CKS1B overexpression correlated with p27 loss of expression (p=0.0013) and SKP2 overexpression (p<0.00). FISH study disclosed statistical differences in both gene amplifications and gains between samples corresponding to OSCC and metastases from those of OLP and leukoplakia (p<0.001). Amplifications were present in 53% of OSCC samples and 33% of lymph node metastases vs 14% of oral leukoplakia and 0% of OLP biopsy specimens (p=0.002). Polysomies of chromosome 1 were seen in 46% of OSCC, 33% of ganglionar metastases, 14% of oral leukoplakia and 10% of OLP (p=0.036). Correlation of CKS1B overexpression and gains (both polysomies and amplifications) determined by FISH was statistically significant (p<0.001). Our results indicate that a high CKS1B expression is a common finding in primary OSCC which correlates with p27 low expression and SKP2 overexpression. This phenomenon may be due either to numerical (chromosome 1 polysomy) or structural (amplifications) CKS1B genetic abnormalities. This phenotypical and cytogenetic profile is not observed in premalignant or inflammatory oral mucosal lesions.
Open Access
Concept maps in English of Molecular Toxicology del Grado en Bioquímica
(2024-04-16) Legaz Pérez, Isabel; Facultad de Ciencias Sociosanitarias
Open Access
Critical role of IkB kinase alpha in embryonic skin development and skin carcinogenesis
(Murcia : F. Hernández, 2009) Zhu, Feng; Park, Eunmi; Liu, Bigang; Xia, Xiaojun; Fischer, Susan M.; Hu, Yinling
IκB kinase alpha (IKKα), IKKß, and IKKγ/NEMO form the IKK complex, which is essential for NF-κB activation. However, genetic studies have shown that the role of IKKα is distinct from that of IKKß or IKKγ in the development of the mouse embryonic skin. Loss of IKKα has been shown to cause epidermal hyperplasia, prevent keratinocyte terminal differentiation, and impair the formation of the skin, resulting in the deaths of IKKα-deficient (Ikkα -/-) mice soon after birth. Recent experimental data from several laboratories have revealed that IKKα functions as a tumor suppressor in human squamous cell carcinomas (SCCs) of skin, lungs, and head and neck. Chemical carcinogenesis studies using mice have shown that reduction in IKKα expression increases the number and size of Ras-initiated skin tumors and promotes their progression, indicating that reduced IKKα expression provides a selective growth advantage that cooperates with Ras activity to promote skin carcinogenesis. In this review, we will summarize these findings from our and other studies on the role that IKKα plays in development of the mouse embryonic skin and skin carcinogenesis
Open Access
Down-regulated REIC expression in lung carcinogenesis: a molecular target for gene therapy
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Yang, Lei; Zhao, Shuang; Xia, Pu; Zheng, Hua Chuan
REIC (Reduced Expression in Immortalized Cells) gene is down-regulated in immortalized cells, compared with the normal parental counterparts. Its encoding protein could inhibit colony formation, tumor growth, and induce apoptosis. To investigate the roles of REIC expression in lung cancer, we examined REIC expression in lung cancer cells and tissues by RT-PCR or Western blot, and observed the effects of both recombinant REIC exposure and REIC overexpression on the aggressive phenotypes of lung cancer cells. It was found that the demethylation of REIC promoter by 5- Aza-dC could reserve its mRNA expression in lung cancer cells (P<0.05). There was a lower REIC mRNA expression in lung cancer than that in matched normal tissue (P<0.05). Recombinant REIC treatment enhanced the proliferation of lung cancer cells (P<0.05), but versa for REIC overexpression (P<0.05). Both recombinant REIC treatment and REIC overexpression induced apoptosis, and inhibited the migration and invasion of SQ-5 and KJ cells (P<0.05). Immunohistochemically, there was a positive correlation between REIC and Caspase-3 expression in lung cancer (P<0.05). According to Kaplan-Meier plotter, REIC mRNA overexpression was found to positively correlate with overall, progression-free and post- progression survival rates of lung cancer patients (P<0.05), even stratified by sex, histological subtyping, grading, TNM staging, chemotherapy, radiotherapy, or smoking. These findings suggested that down-regulated REIC expression might be involved in lung carcinogenesis due to its promoter methylation. Both recombinant REIC exposure and REIC overexpression might reverse the aggressive phenotypes of lung cancer cells. REIC may be employed as a potential target of gene therapy for lung cancer.
Open Access
Effect of N-Ethyl-N-Butyl-Nitrosamine on the esophageal mucosa of the rat. Histometric investigation of early tumor stages
(Murcia : F. Hernández, 1987) Sons, H.U.; Borchard, F.; Kaup, F.G.
80 male Wistar rats received an oral ad libitum application of N-ethyl-N-butyl-nitrosamine in a concentration of 0.18 g per litre of drinking water. The changes induced in the esophakeal mucosa and determined at three intervals (up to 48 days, up to 91 days, and up to 112 days after commencement of carcinogen exposure) were compared by microscopy with the results from a control group of 10 male Wistar rats of the same age. Several histomorphometric parameters were investigated with the aid of a Leitz ocular micrometer. The earliest localized changes found were an increase in the thickness of the epithelium and the horny layer, and an elongation of the papillary bodies and a widening of the parabasal cellular layer. Later - with a substantial increase in the rate of mitosis in all layers of the epithelium, there was a significant thickening of the non-papillomatous and papillomatous epithelium, an enlargement of the nuclei, especialli in the middle and upper layers of the epithelium and a thickening of the horny layer, parts of the latter being parakeratotic. The papillomatous changes corresponded in some cases to moderate epithelia1 dysplasias. As expected, no fully-developed invasive carcinomas occurred in the early period investigated. The histometric data permit the conclusion to be drawn that the lesions described are demonstrable not only at the exophytic-papillomatous epithelium but also in multifocally localized form at the flat, nonpapillomatous mucosa, and that they can definetely be regarded as the expression of an incipient field cancerification
Open Access
Elimination of transformed cells by normal cells: a novel concept for the control of carcinogenesis
(Murcia : F. Hernández, 1996) Bauer, G.
Control of transformed cells by neighbouring normal cells is known since the beginning of transformation studies in vitro. The classical explanation for this phenomenon is based on proliferation inhibition of transformed cells by normal cells. We extend this model by presenting data that show that TGF-B-treated normal cells can eliminate transformed cells by induction of apoptosis. Both the TGF-8-induced signal pathway in normal cells, leading to the production of a short-lived apoptosis-inducing factor, as well as the specific interaction of this factor with transformed cells depend on the action of reactive oxygen species. Sensitivity to induction of apoptosis seems to be a common feature associated with the transformed state, independent of the originally transforming principle. Therefore, tumor development should require either interference with the process of elimination or acquisition of resistance against it. We discuss experimental evidence for interfering substances, such as antioxidants, as well as for genetic systems that protect transformed cells from the negative effects of their cellular environment, such as Bcl-2 or papilloma viruses. These findings, as well as the general resistance of exvivo tumor cells against induction of apoptosis are in line with the novel model of control of tumor progression presented by us in this review.
Open Access
Expression of tropomyosins in lung cancer - a potential role in carcinogenesis and its utility in a histopathological diagnosis
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2016) Okudela, Koji; Mitsui, Hideaki; Woo, Tetsukan; Kojima, Yoko; Matsumura, Mai; Arai, Hiromasa; Suzuki, Takehisa; Umeda, Shigeaki; Saito, Yuichi; Tajiri, Michihiko; Masuda, Munetaka; Kameda, Yoichi; Ohashi, Kenichi
We herein analyzed the relationships between tropomyosin protein expression levels and clinicopathological factors in order to determine the significance of tropomyosins in lung cancers. Although neoplastic cells expressed different isoforms of tropomyosin, overall expression levels were lower than those in bronchial and alveolar epithelial cells. In adenocarcinomas, tropomyosin levels were markedly reduced in poorly differentiated or solid subtype carcinomas, suggesting that a loss in the expression of tropomyosins is involved in the progression of lung adenocarcinomas. The potential utility of the immunohistochemical expression of tropomyosins for a histopathological diagnosis was also investigated. The sensitivity and specificity of a loss in the expression of tropomyosins were 100% and 50%, respectively, which were superior to those for the strong expression of p53 (sensitivity 100% and specificity 44%), a conventional biomarker. An immunohistochemical examination of tropomyosins may assist in the histopathological detection of lung cancer cells in small biopsy specimens.
Open Access
FHL2: A scaffold protein of carcinogenesis, tumour-stroma interactions and treatment response
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2016) Verset, Laurine; Feys, Lynn; Trépant, Anne-Laure; De Wever, Olivier; Demetter, Pieter
Four-and-a-half LIM-domain protein 2 (FHL2) is a multifunctional scaffolding protein regulating signalling cascades and gene transcription. It shuttles between focal adhesions and the nucleus where it signals through direct interaction with a number of proteins including β-catenin. The multiplicity of molecular pathways affected by FHL2 suggests an important role in several physiological and pathological events. The function of FHL2 in cancer is particularly intriguing, since it may act as an oncoprotein or as a tumour suppressor in a tissue-dependent fashion. In this review we present the current knowledge on the role of FHL2 in carcinogenesis, with emphasis on the digestive tract. We discuss the overexpression of FHL2 in colorectal, gastric and pancreatic cancer, the downregulation in hepatocellular carcinoma and the role of FHL2 in epithelial-mesenchymal transition. We briefly look at the potential role of FHL2 in the tumoural microenvironment and discuss how FHL2 expression and function might influence cancer treatment. Before implementation of FHL2 as a biomarker by pathologists, antibody validation should, however, be carried out.
Open Access
Genomic imprinting and carcinogenesis
(Murcia : F. Hernández, 1998) Yun, K.
The Mendelian inheritance is based on the fundamental rule in which mammalian genes are expressed equally from two homologous biparental alleles. Recently a small number of genes have been identified to show an exception to this rule in that homologous alleles can function differently in somatic cells depending on whether they come from the mother or the father. This intriguing biological phenomenon is called as genomic imprinting which does not conform classical Mendelian inheritance and has potentially far reaching implications for genetics, evolution, developmental biology and pathology including cancer. The gene encoding insulin-like growth factor 2 (IGF2) harbors at llp15.5 and serves as paradigm for an imprinted gene. The lGF2 gene has been demonstrated to be imprinted with the paternal allele expressed and the maternal being silent which is evolutionally conserved between mice and human. Loss of imprinting (L01) of IGF2 has been demonstrated in a dozen of tumor types including Wilms tumor (WT) with a promise of many more to come. The LOT of IGF2 may induce increased or dcrcgulated IGF2 expression which could initiate the onset of WT. Thus the L01 of IGF2 may provide a novel mechanism of gene activation and play a role in the development of a wide range of tumors. This review also discusses other imprinted genes on llp15 which may have a role in WT or other diseases. Finally molecular mechanisms of genomic imprinting are discussed.
Open Access
Histological complexities of pancreatic lesions from transgenic mouse models are consistent with biological and morphological heterogeneity of human pancreatic cancer
(Murcia : F. Hernández, 2007) Liao, J.D.; Adsay, N.V.; Khannani, F.; Grignon, D.; Thakur, A.; Sarkar, F.H.
Although pancreatic cancer is the fourth leading cause of cancer death, it has received much less attention compared to other malignancies. There are several transgenic animal models available for studies of pancreatic carcinogenesis, but most of them do not recapitulate, histologically, human pancratic cancer. Here we review some detailed molecular complexity of human pancreatic cancer and their reflection in histomorphological complexities of pancreatic lesions developed in various transgenic mouse models with a special concern for studying the effects of chemotherapeutic and chemopreventive agents. These studies usually require a large number of animals that are at the same age and gender and should be either homozygote or heterozygote but not a mixture of both. Only single-transgene models can meet these special requirements, but many currently available models require a mouse to simultaneously bear several transgene alleles. Thus it is imperative to identify new gene promoters or enhancers that are specific for the ductal cells of the pancreas and are highly active in vivo so as to establish new single-transgene models that yield pancreatic ductal adenocarcinomas for chemotherapeutic and chemopreventive studies
Open Access
HuR, a key post-transcriptional regulator, and its implication in progression of breast cancer
(Murcia : F. Hernández, 2010) Yuan, Zhu; Sanders, Andrew J.; Ye, Lin; Jiang, Wen G.
HuR, an ubiquitously expressed member of the Hu family, selectively binds and stabilizes AREcontaining mRNAs encoding proto-oncogenes, cell cycle regulators, cytokines and growth factors. The mechanism of HuR stabilization on target mRNAs is believed to be mediated through competition with destabilizing ARE-BPs. HuR is mainly localized within the cell nucleus and the nucleo-cytoplasmic shuttling of HuR is generally assumed as the initial and critical step of its stabilizing effects. A number of signaling pathways are believed to be involved in HuR shuttling. Due to the pivotal role played by HuR in stabilizing the mRNA of key factors or cytokines involved in carcinogenesis and subsequent progression, its implication and therapeutic potential in cancer have been investigated intensively since its discovery in 1996. This review discusses the role of HuR in the stabilization of key mRNAs and it’s the nucleo-cytoplasmic shuttling. The review also covers the current knowledge of HuR’s role in carcinogenesis, particularly its involvement in breast cancer, and the feasibility of using HuR as a therapeutic target for the treatment of breast cancer.
Open Access
MicroRNA and ovarian cancer
(Murcia : F. Hernández, 2008) Corney, David C.; Nikitin, Alexander Yu.
Ovarian cancer remains a leading cause of morbidity and mortality, with little change in survival rates over the past 30 years. Research in the molecular biology underlying the disease demonstrates frequent mutation in the p53/Rb/p16 tumor suppressor pathways and activation of c-myc, K-ras and Akt oncogenic signaling. Recently, miRNAs have been demonstrated to play an important role in controlling proliferation, apoptosis and many other processes altered in the cancer state. In this review we discuss a number of recent publications that implicate a role for microRNAs in ovarian cancer and assess how this new field may improve our fundamental understanding of the disease and provide improved diagnostic and therapeutic approaches.
Open Access
NR4A1, 2, 3 an orphan nuclear hormone receptor family involved in cell apoptosis and carcinogenesis
(Murcia : F. Hernández, 2006) Li, Q.X.; Ke, N.; Sundaram, R.; Wong-Staal, F.
Three members of the NR4A1/Nur77/ NGFIB orphan nuclear hormone receptor subfamily (NR4A1, NR4A2, and NR4A3) belong to the steroid nuclear hormone receptor superfamily. They share similar structural features and have no known natural ligand. They constitute immediate early genes that are induced by serum, growth factors and receptor engagement and are thus implicated in cell mitogenic responses. These nuclear receptors are transcription factors that exert their functions through activation and subsequent induction of the downstream pathways. They have been shown to play a role in complex pathways of cell survival and apoptosis. Although the expression of these genes have been shown to be pro-survival, it has also been reported that NR4A1 expression can cause apoptosis. These two opposite effects apparently result from distinct mechanisms: either transcriptional activation of genes responsible for cell survival or cell apoptosis, or translocation into the cytoplasm where they target the mitochondria and cause cell apoptosis via Bcl- 2 binding. The latter mechanism constitutes a new paradigm of cellular apoptosis. In vitro functional studies using over-expression (gain of function) or gene inactivation (loss of function) type assays, combined with transgenic or knockout animal data in vivo, have revealed these effects and their physiological roles, including thymocyte development for NR4A1/3 and prosurvival in CNS for NR4A2. Recent studies have also suggested an important role of these receptors in cell transformation and tumorigenicity via both their antiapoptotic and pro-apoptotic functions. In particular, the recent identification of a functional ligand for NR4A1 suggests that these members could potentially serve as drug targets for disease indications such as cancer. While many aspects of these receptors have been previously reviewed, this article focuses on new experimentation and discovery of their apoptotic and carcinogenic roles, and discusses their potential roles as therapeutic targets.
Open Access
Overexpression of lactate dehydrogenase A in cholangiocarcinoma is correlated with poor prognosis
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Thonsri, Unchalee; Seubwai, Wunchana; Waraasawapati, Sakda; Sawanyawisuth, Kanlayanee; Vaeteewoottacharn, Kulthida; Boonmars, Thidarat; Cha’on, Ubon
Lactate dehydrogenase A (LDHA), a key metabolic enzyme, plays a crucial role in the final step of anaerobic glycolysis. Overexpression of LDHA is observed in many human malignancies in association with tumor progression. The purpose of this study was to investigate LDHA expression pattern during carcinogenesis, its clinico-pathological association, and evaluate the prognostic value of LDHA in CCA patients. LDHA expression was investigated using immunohistochemistry technique in both hamster- (n=60) and human-CCA tissues (n=82). Plasma LDH from healthy control (n=40) and CCA patients (n=29) were determined using an enzymatic based assay. The association of LDHA expression with clinicopathological findings and prognostic value were evaluated by statistical analysis. In the CCA hamster model, an increase of LDHA expression was associated with the progression of CCA-genesis. Higher LDHA overexpression was associated with shorter survival of CCA patients. Multivariate analysis indicated that LDHA expression including histological type were independent prognostic risk factor of patient’s survival. However, there was no difference in plasma LDH level between CCA patients and healthy controls. LDHA expression is involved in cholangio-carcinogenesis. Overexpression of LDHA can be a marker of poor prognosis in CCA patients and it might be a potential target for CCA treatment.
Open Access
Prostate stem cells and cancer
(Murcia : F. Hernández, 2007) Nikitin, Alexander Y.; Matoso, A.; Roy-Burman, P.
Properties shared by neoplastic and stem cells indicate a possibility that somatic stem cells or transit-amplifying cells that have reacquired stem cell properties, particularly the ability for self-renewal, represent favorable targets for malignant transformation. In this review we discuss significance of the stem cell model for understanding prostate cancer pathogenesis and describe relevant studies in animals. It is proposed that dissemination of rare cancer stem cells may lead to metastatic disease and that resistance of such cells to multiple drugs and androgen ablation make them responsible for failure of current treatments. Thus further understanding of the cancer stem cell biology is needed for development of efficient rationally designed therapy permitting better targeting and better treatment outcomes for patients with prostate neoplasms
Open Access
The clinicopathological significance of REIC expression in colorectal carcinomas
(F. Hernandez y JuanF. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología., 2012) Wang, Wei; Zhu, Wan; Xu, Xiao-yan; Nie, Xiao-cui; Yang, Xue; Xing, Ya-nan; Yu, Miao; Liu, Yun-peng; Takano, Yasuo; Zheng, Hua-chuan
REIC is down-regulated in immortalized cell lines compared with the parental normal counterparts, and could inhibit colony formation, tumor growth and induce apoptosis. Here, its expression was examined by immunohistochemistry on tissue microarray containing colorectal non-neoplastic mucosa (NNM), adenoma and adenocarcinoma. Colorectal carcinoma tissue and cell lines were studied for REIC expression or its secretory level by Western blot, RT-PCR or enzyme-linked immunosorbent assay (ELISA). The results demonstrated that REIC was differentially expressed in Colo201, Colo205, DLD-1, HCT-15, HCT-116, HT-29, KM-12, SW480, SW620, and WiDr with its secretion concentration less than 300 pg/mL. Carcinomas showed statistically lower REIC expression than matched NNM with no difference for protein content. Immunohistochemically, REIC expression was significantly decreased from NNM, adenoma to adenocarcinoma (p<0.05). REIC expression was negatively correlated with depth of invasion, TNM staging, dedifferentiation, Capase-3 and nuclear inhibitor of growth 5 (ING5) expression (p<0.05), while not with age, sex, tumor size, lymphatic or venous invasion, or lymph node metastasis (p>0.05). Kaplan-Meier analysis indicated that REIC expression was not associated with the prognosis of colorectal carcinomas (p>0.05). Cox’s analysis demonstrated that lymphatic and venous invasion, lymph node metastasis, and UICC staging were independent prognostic factors for carcinoma (p<0.05). Our study indicated that down- regulated REIC expression might play an important role in colorectal adenoma-adenocarcinoma sequence and subsequent progression. Aberrant REIC expression might be employed as a good marker of pathogenesis and development of colorectal carcinomas.
Open Access
Tumor heterogeneity: morphological, molecular and clinical implications
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2000) Lleonart, M. E.; Martin-Duque, P.; Sanchez-Prieto, R.; Moreno, A.; Ramon y Cajal, S.
Malignant tumors are characterized by their great heterogeneity and variability. There are hundreds of different types of malignant tumors that harbour many oncogenic alterations. The tumor heterogeneity has important morphological, molecular and clinical implications. Except for some hematopoietic and lymphoproliferative processes and small cell infant tumors, there are not specific molecular alterations for most human tumors. In this review we summarize the most important aspects of carcinogenesis and chemoradiosensitivity of malignant cells. In this regard, some oncogenes such as neu , ras and bcl-2 have been associated with cellular resistance to treatment with anticancer agents. The knowledge of oncogenic alterations involved in each tumor can be important to correlate the morphological features, the genetic background, the prognosis and the clinical response to treatment with anticancer agents. Based on the molecular background of the tumor there are new cancer gene therapy protocols. For example using adenovirus Ela in tumors with overexpression of neu oncogene, inhibitors of tirosine kinase specific for the PDGF receptor in glioma, inhibitors of farnesil transferase to prevent ras activity in tumors with mutations in the ras gene.

Browsing by Subject "Carcinogenesis"

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