Publications by authors named "Elzbieta Pluciennik"

42 Publications

Fragile Gene Guides /-Dependent Actions Against Tumor Progression in Grade II Bladder Cancer.

Front Oncol 2021 25;11:621060. Epub 2021 Feb 25.

Department of Molecular Carcinogenesis, Medical University of Lodz, Łódź, Poland.

Introduction: The presence of common fragile sites is associated with no-accidental chromosomal instability which occurs prior to carcinogenesis. The gene spans the second most active fragile site: FRA16D. Chromosomal breakage at this site is more common in bladder cancer patients who are tobacco smokers which suggests the importance of gene loss regarding bladder carcinogenesis. Tryptophan domains of WWOX are known to recognize motifs of other proteins such as AP-2α and AP-2γ allowing protein-protein interactions. While the roles of both AP-2 transcription factors are important for bladder carcinogenesis, their nature is different. Based on the literature, AP-2γ appears to be oncogenic, whereas AP-2α mainly exhibits tumor suppressor character. Presumably, the interaction between WWOX and both transcription factors regulates thousands of genes, hence the aim of the present study was to determine WWOX, AP-2α, and AP-2γ function in modulating biological processes of bladder cancer.

Methods: RT-112 cell line (grade II bladder cancer) was subjected to two stable lentiviral transductions. Overall, this resulted in six variants to investigate distinct WWOX, AP-2α, or AP-2γ function as well as WWOX in collaboration with a particular transcription factor. Cellular models were examined with immunocytochemical staining and in terms of differences in biological processes using assays investigating cell viability, proliferation, apoptosis, adhesion, clonogenicity, migration, activity of metalloproteinases and 3D culture growth.

Results: WWOX overexpression increased apoptosis but decreased cell viability, migration and large spatial colonies. AP-2α overexpression decreased tumor cell viability, migratory potential, matrix metalloproteinase-2 activity and clonogenicity. AP-2γ overexpression decreased matrix metalloproteinase-2 activity but increased wound healing, adhesion, clonogenicity and spatial colony formation. WWOX and AP-2α overexpression induced apoptosis but decreased cell viability, adhesion, matrix metalloproteinase-2 activity, overall number of cultured colonies and migration rate. WWOX and AP-2γ overexpression decreased tumor cell viability, proliferation potential, adhesion, clonogenicity and the ability to create spatial structures, but also increased apoptosis or migration rate.

Conclusion: Co-overexpression of WWOX with AP-2α or WWOX with AP-2γ resulted in a net anti-tumor effect. However, considering this research findings and the difference between AP-2α and AP-2γ, we suggest that this similarity is due to a divergent behavior of WWOX.
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http://dx.doi.org/10.3389/fonc.2021.621060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947623PMC
February 2021

In vitro and in silico assessment of the effect of WWOX expression on invasiveness pathways associated with AP-2 transcription factors in bladder cancer.

BMC Urol 2021 Mar 10;21(1):36. Epub 2021 Mar 10.

Department of Molecular Carcinogenesis, Medical University of Lodz, 90-752, Lodz, Poland.

Background: WW Domain Containing Oxidoreductase (WWOX) belongs to the unusual tumor suppressors, whose molecular function is not fully understood in bladder cancer, especially regarding interaction with Activator Protein 2 (AP-2) α/γ transcription factors. Thus, using lentiviral systems we created an in vitro model overexpressing or downregulating WWOX in CAL-29 cell line to assess invasiveness pathways. Surprisingly, while WWOX overexpression was accompanied with increased expression of both AP-2 factors, its downregulation only affected AP-2α level but not AP-2γ which remained high.

Methods: Using cellular models and unpaired t-test or Wilcoxon test, we investigated significant changes in biological processes: clonogenicity, extracellular matrix adhesion, metalloproteinases activity, 3D culture growth, proliferation, mitochondrial redox potential and invasiveness. Relative gene expression acquired through Real-Time qPCR has been analyzed by Welch's t-test. Additionally, using oncoprint analysis we distinguished groups for bioinformatics analyzes in order to perform a follow-up of in vitro experiments.

Results: Downregulation of WWOX in bladder cancer cell line intensified ability of single cell to grow into colony, mitochondrial redox potential and proliferation rate. Moreover, these cells shown elevated pro-MMP-2/9 activity but reduced adhesion to collagen I or laminin I, as well as distinct 3D culture growth. Through global in silico profiling we determined that WWOX alters disease-free survival of bladder cancer patients and modulates vital processes through AP-2 downstream effectors.

Conclusions: Our research indicates that WWOX possesses tumor suppressor properties in bladder cancer but consecutive examination is required to entirely understand the contribution of AP-2γ or AP-2α.
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http://dx.doi.org/10.1186/s12894-021-00806-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944886PMC
March 2021

MicroRNAs: Their Role in Metastasis, Angiogenesis, and the Potential for Biomarker Utility in Bladder Carcinomas.

Cancers (Basel) 2021 Feb 20;13(4). Epub 2021 Feb 20.

Department of Molecular Carcinogenesis, Medical University of Lodz, Zeligowskiego 7/9, 90-752 Lodz, Poland.

Angiogenesis is the process of generating new capillaries from pre-existing blood vessels with a vital role in tumor growth and metastasis. MicroRNAs (miRNAs) are noncoding RNAs that exert post-transcriptional control of protein regulation. They participate in the development and progression of several cancers including bladder cancer (BLCA). In cancer tissue, changes in microRNA expression exhibit tissue specificity with high levels of stability and detectability. miRNAs are less vulnerable to degradation, making them novel targets for therapeutic approaches. A suitable means of targeting aberrant activated signal transduction pathways in carcinogenesis of BLCA is possibly through altering the expression of key miRNAs that regulate them, exerting a strong effect on signal transduction. Precaution must be taken, as the complexity of miRNA regulation might result in targeting several downstream tumor suppressors or oncogenes, enhancing the effect further. Since exosomes contain both mRNA and miRNA, they could therefore possibly be more effective in targeting a recipient cell if they deliver a specific miRNA to modify the recipient cell protein production and gene expression. In this review, we discuss the molecules that have been shown to play a significant role in BLCA tumor development. We also discuss the roles of various miRNAs in BLCA angiogenesis and metastasis. Advances in the management of metastatic BLCA have been limited; miRNA mimics and molecules targeted at miRNAs (anti-miRs) as well as exosomes could serve as therapeutic modalities or as diagnostic biomarkers.
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http://dx.doi.org/10.3390/cancers13040891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924383PMC
February 2021

Zinc(II) Complexes of Amino Acids as New Active Ingredients for Anti-Acne Dermatological Preparations.

Int J Mol Sci 2021 Feb 6;22(4). Epub 2021 Feb 6.

Department of Cosmetic Raw Materials Chemistry, Faculty of Pharmacy, Medical University of Lodz, Muszyńskiego 1, 90-151 Łódź, Poland.

Zinc compounds have a number of beneficial properties for the skin, including antimicrobial, sebostatic and demulcent activities. The aim of the study was to develop new anti-acne preparations containing zinc-amino acid complexes as active ingredients. Firstly, the cytotoxicity of the zinc complexes was evaluated against human skin fibroblasts (1BR.3.N cell line) and human epidermal keratinocyte cell lines, and their antimicrobial activity was determined against . Then, zinc complexes of glycine and histidine were selected to create original gel formulations. The stability (by measuring pH, density and viscosity), microbiological purity (referring to PN-EN ISO standards) and efficacy of the preservative system (according to Ph. Eur. 10 methodology) for the preparations were evaluated. Skin tolerance was determined in a group of 25 healthy volunteers by the patch test. The preparations containing zinc(II) complexes with glycine and histidine as active substances can be topically used in the treatment of acne skin due to their high antibacterial activity against and low cytotoxicity for the skin cells. Dermatological recipes have been appropriately composed; no irritation or allergy was observed, and the preparations showed high microbiological purity and physicochemical stability.
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http://dx.doi.org/10.3390/ijms22041641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915519PMC
February 2021

Identification of a novel association for the WWOX/HIF1A axis with gestational diabetes mellitus (GDM).

PeerJ 2021 14;9:e10604. Epub 2021 Jan 14.

Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland.

Background: Although the WW-domain-containing oxidoreductase (WWOX)/Hypoxia-inducible factor 1 (HIF1) pathway is a well-known regulator of cellular glucose and energy metabolism in pathophysiological processes, its role in gestational diabetes mellitus (GDM), remains elusive. We undertook this study to determine the effect of WWOX/HIF1A signaling on the expression of glucose metabolism genes in GDM patients.

Methods: Leukocytes were obtained from 135 pregnant women with ( = 98) or without ( = 37) GDM and, in turn, 3 months ( = 8) and 1 year ( = 12) postpartum. Quantitative RT-PCR was performed to determine gene expression profiles of the WWOX/HIF1A-related genes, including those involved in glucose transport (), glycolytic pathway (), Wnt pathway (), and inflammatory response ().

Results: GDM patients displayed a significant downregulation of with simultaneous upregulation of which resulted in approximately six times reduction in ratio. As a consequence, induced genes () were found to be overexpressed in GDM compared to normal pregnancy and negative correlate with ratio. The postpartum expression was higher than during GDM, but its level was comparable to that observed in normal pregnancy.

Conclusions: The obtained results suggest a significant contribution of the gene to glucose metabolism in patients with gestational diabetes. Decreased expression in GDM compared to normal pregnancy, and in particular reduction of ratio, indicate that WWOX modulates HIF1α activity in normal tissues as described in the tumor. The effect of HIF1α excessive activation is to increase the expression of genes encoding proteins directly involved in the glycolysis which may lead to pathological changes in glucose metabolism observed in gestational diabetes.
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http://dx.doi.org/10.7717/peerj.10604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811782PMC
January 2021

Functional genomics of AP-2α and AP-2γ in cancers: in silico study.

BMC Med Genomics 2020 11 19;13(1):174. Epub 2020 Nov 19.

Department of Molecular Carcinogenesis, Medical University of Lodz, 90-752, Lodz, Poland.

Background: Among all causes of death, cancer is the most prevalent and is only outpaced by cardiovascular diseases. Molecular theory of carcinogenesis states that apoptosis and proliferation are regulated by groups of tumor suppressors or oncogenes. Transcription factors are example of proteins comprising representatives of both cancer-related groups. Exemplary family of transcription factors which exhibits dualism of function is Activating enhancer-binding Protein 2 (AP-2). Scientific reports concerning their function in carcinogenesis depend on particular family member and/or tumor type which proves the issue to be unsolved. Therefore, the present study examines role of the best-described AP-2 representatives, AP-2α and AP-2γ, through ontological analysis of their target genes and investigation what processes are differentially regulated in 21 cancers using samples deposited in Genomic Data Analysis Center (GDAC) Firehose.

Methods: Expression data with clinical annotation was collected from TCGA-dedicated repository GDAC Firehose. Transcription factor targets were obtained from Gene Transcription Regulation Database (GTRD), TRANScription FACtor database (TRANSFAC) and Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining (TRRUST). Monocle3 R package was used for global samples profiling while Protein ANalysis THrough Evolutionary Relationships (PANTHER) tool was used to perform gene ontology analysis.

Results: With RNA-seq data and Monocle3 or PANTHER tools we outlined differences in many processes and signaling pathways, separating tumor from normal tissues or tumors from each other. Unexpectedly, a number of alterations in basal-like breast cancer were identified that distinguished it from other subtypes, which could bring future clinical benefits.

Conclusions: Our findings indicate that while the AP-2α/γ role remains ambiguous, their activity is based on processes that underlie the cancer hallmarks and their expression could have potential in diagnosis of selected tumors.
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http://dx.doi.org/10.1186/s12920-020-00823-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678100PMC
November 2020

Identification and accumulation of phenolic compounds in the leaves and bark of Salix alba (L.) and their biological potential.

Biomolecules 2020 09 29;10(10). Epub 2020 Sep 29.

Department of Cosmetic Raw Materials Chemistry, Faculty of Pharmacy, Medical University of Lodz, Muszyńskiego 1, 90-151 Łódź.

The study examines the phenolic compounds in hydromethanolic extracts of (L.) leaves and bark as well as their antioxidant activity and cytotoxic potential. UPLC-PDA-Q/TOF-MS analysis showed a total of 29 phenolic compounds in leaves and 34 in bark. Total phenolic compound content was 5575.96 mg/100 g of dry weight (DW) in leaves and 2330.31 mg/100 g DW in bark. The compounds were identified as derivatives of phenolic acids (seven in leaves and five in bark), flavanols and procyanidins (eight in leaves and 26 in bark) and flavonols (14 in leaves and three in bark). Both extracts exhibited strong antioxidant potential, assessed by radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS), but the bark extract was even stronger than the ascorbic acid used as a standard. The cytotoxicity of both extracts was evaluated against human skin fibroblasts and human epidermal keratinocytes cell lines using the Presto Blue cell viability assay. The keratinocytes were more resistant to tested extracts than fibroblasts. The leaf and bark extracts at concentrations which exhibited antioxidant activity were also not toxic against the keratinocyte cell line. Thus, extracts, especially the leaf extract, offer promise as a nontoxic natural antioxidant, in cosmetic products or herbal medicines, and as a source of bioactive secondary metabolites.
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http://dx.doi.org/10.3390/biom10101391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600001PMC
September 2020

The Anticancer Properties of Silibinin: Its Molecular Mechanism and Therapeutic Effect in Breast Cancer.

Anticancer Agents Med Chem 2020 ;20(15):1787-1796

Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland.

Background: Silibinin (SB), the main component of Silymarin (SM), is a natural substance obtained from the seeds of the milk thistle. SM contains up to 70% of SB as two isoforms: A and B. It has an antioxidant and anti-inflammatory effect on hepatocytes and is known to inhibit cell proliferation, induce apoptosis, and curb angiogenesis. SB has demonstrated activity against many cancers, such as skin, liver, lung, bladder, and breast carcinomas.

Methods: This review presents current knowledge of the use of SM in breast cancer, this being one of the most common types of cancer in women. It describes selected molecular mechanisms of the action of SM; for example, although SB influences both Estrogen Receptors (ER), α and β, it has opposite effects on the two. Its action on ERα influences the PI3K/AKT/mTOR and RAS/ERK signaling pathways, while by up-regulating ERβ, it increases the numbers of apoptotic cells. In addition, ERα is involved in SB-induced autophagy, while ERβ is not. Interestingly, SB also inhibits metastasis by suppressing TGF-β2 expression, thus suppressing Epithelial to Mesenchymal Transition (EMT). It also influences migration and invasive potential via the Jak2/STAT3 pathway.

Results: SB may be a promising enhancement of BC treatment: when combined with chemotherapeutic drugs such as carboplatin, cisplatin, and doxorubicin, the combination exerts a synergistic effect against cancer cells. This may be of value when treating aggressive types of mammary carcinoma.

Conclusion: Summarizing, SB inhibits proliferation, induces apoptosis, and restrains metastasis via several mechanisms. It is possible to combine SB with different anticancer drugs, an approach that represents a promising therapeutic strategy for patients suffering from BC.
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http://dx.doi.org/10.2174/1871520620666191220142741DOI Listing
January 2020

The Gene Influences Cellular Pathways in the Neuronal Differentiation of Human Neural Progenitor Cells.

Front Cell Neurosci 2019 30;13:391. Epub 2019 Aug 30.

Department of Molecular Carcinogenesis, Medical University of Łódź, Łódź, Poland.

The brain is the most functionally organized structure of all organs. It manages behavior, perception and higher cognitive functions. The gene is non-classical tumor suppressor gene, which has been shown to have an impact on proliferation, apoptosis and migration processes. Moreover, genetic aberrations in induce severe neuropathological phenotypes in humans and rodents. The aim of the present study was to investigate in detail the impact of on human neural progenitor cell (hNPC) maintenance and how depletion of disturbs signaling pathways playing a pivotal role in neuronal differentiation and central nervous system (CNS) organogenesis. hNPC with a silenced gene exhibited lowered mitochondrial redox potential, enhanced adhesion to fibronectin and extracellular matrix protein mixture, downregulation of MMP2/9 expression and impaired 3D growth. Global transcriptome analysis using cap analysis of gene expression (CAGE) found that downregulation significantly changes the expression of multiple genes engaged in cytoskeleton organization, adhesion, cell signaling and chromatin remodeling. The massive changes in gene expression caused by silencing may strongly affect the differentiation and migration of neurons in organogenesis, brain injury, cancerogenesis or neurodifferentiation. gene appears to be an important regulator of neural tissue architecture and function.
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http://dx.doi.org/10.3389/fncel.2019.00391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730490PMC
August 2019

Exosomes as carriers transporting long non‑coding RNAs: Molecular characteristics and their function in cancer (Review).

Mol Med Rep 2019 Aug 5;20(2):851-862. Epub 2019 Jun 5.

Department of Molecular Carcinogenesis, Medical University of Łódź, 90‑752 Łódź, Poland.

Long non‑coding RNAs (lncRNAs) comprise a sizeable class of non‑coding RNAs with a length of over 200 base pairs. Little is known about their biological function, although over 20,000 lncRNAs have been annotated in the human genome. Through a diverse range of mechanisms, their primary function is in the regulation of the transcription of protein‑coding genes. lncRNA transcriptional activation can result from a group of nucleus‑retained and chromatin‑associated lncRNAs, which function as scaffolds in the cis/trans recruitment of transcription factors, co‑activators or chromatin remodelers, and/or promoter enhancers. Exosomes are released as extracellular vesicles and they are produced by endocytic pathways. Their synthesis is initiated by various processes including ceramide synthesis, release of intracellular Ca2+ or acid‑base balance disorders. Prior to vesicle creation, selective cargo loading occurs in the Endosomal Sorting Complex Required for Transport. Participation of endosomal sorting proteins such as tetraspanins or specific sumoylated proteins required for transport has been indicated in research. The endosomal‑sorting complex consists of four components, these induce the formation of multivesicular bodies and the induction of membrane deformation to form exosomes. Nanovesicles could be formed inside multivesicular bodies to allow transport outside the cell or digestion in lysosomes. The molecular content of exosomes is more heterogenic than its synthesis process, with different cargoes being examined inside vesicles with regard to the type or stage of cancers. This paper will review the importance of lncRNAs as crucial molecular content of exosomes, indicating its involvement in tumour suppression, pro‑tumorigenic events and the development of novel therapeutic approaches in the near future. Further studies of their mechanisms of function are essential, as well as overcoming several challenges to gain a clearer insight to the approaches for the best clinical application.
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http://dx.doi.org/10.3892/mmr.2019.10340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625196PMC
August 2019

A Novel Set of WNT Pathway Effectors as a Predictive Marker of Uterine Corpus Endometrial Carcinoma-Study Based on Weighted Co-expression Matrices.

Front Oncol 2019 10;9:360. Epub 2019 May 10.

Department of Molecular Carcinogenesis, Medical University of Łódz, Łódz, Poland.

Uterine corpus endometrial carcinomas (UCEC) are clinically divided into two subgroups-endometrioid endometrial carcinoma (EEC) or non-endometrioid endometrial carcinoma (NEEC). The first group shows relatively better prognosis. However, the discrimination seems to be insufficient due to the fact that in the mildest EEC are patients with poor treatment response and bad prognosis. Our aim was to examine the molecular background of such phenomenon and whether gene expression patterns might be of importance for the clinic. We focused our analysis on WNT pathway target genes since it is one of the main regulators of endometrial proliferation and differentiation. analysis of TCGA data, including Weighted Co-expression Network Analysis, Principle Component Analysis, and Multiple Factor Analysis, allows to select 28 genes that serve as a predictive markers for UCEC patients. Our study revealed that there is a subgroup of the endometrioid cases that molecularly resembles mixed/serous groups. This may explain the reason for existence of subgroup of patients, that although clinically diagnosed with the mildest endometrioid UCEC type, yet present failure in treatment and aggressive course of the disease. Our study suggests that worse outcome in these patients may be based on a disruption of proper WNT signalling pathway resulting in deregulation of its effector genes. Moreover, we showed that mixed group consisting of tumours containing both endometrioid and serous types of cells, has serous expression profile of WNT targets. The proposed gene set allows to predict progression of the disease trough dividing patients into groups of low or high grade with 70.8% sensitivity and 88.6% specificity (AUC = 0.837) as well as could predict patient prognosis associated with UCEC subtype with 70.1% sensitivity and 86.2% specificity (AUC = 0.855). Relatively small number of implicated genes makes it highly applicable and possibly clinically simple and useful tool.
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http://dx.doi.org/10.3389/fonc.2019.00360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524344PMC
May 2019

The biological characteristics of transcription factors AP-2α and AP-2γ and their importance in various types of cancers.

Biosci Rep 2019 03 15;39(3). Epub 2019 Mar 15.

Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland

The Activator Protein 2 (AP-2) transcription factor (TF) family is vital for the regulation of gene expression during early development as well as carcinogenesis process. The review focusses on the AP-2α and AP-2γ proteins and their dualistic regulation of gene expression in the process of carcinogenesis. Both AP-2α and AP-2γ influence a wide range of physiological or pathological processes by regulating different pathways and interacting with diverse molecules, i.e. other proteins, long non-coding RNAs (lncRNA) or miRNAs. This review summarizes the newest information about the biology of two, AP-2α and AP-2γ, TFs in the carcinogenesis process. We emphasize that these two proteins could have either oncogenic or suppressive characteristics depending on the type of cancer tissue or their interaction with specific molecules. They have also been found to contribute to resistance and sensitivity to chemotherapy in oncological patients. A better understanding of molecular network of AP-2 factors and other molecules may clarify the atypical molecular mechanisms occurring during carcinogenesis, and may assist in the recognition of new diagnostic biomarkers.
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http://dx.doi.org/10.1042/BSR20181928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418405PMC
March 2019

Placental Expression of NEMO Protein in Normal Pregnancy and Preeclampsia.

Dis Markers 2019 2;2019:8418379. Epub 2019 Jan 2.

Department of Medical Biotechnology, Medical University of Lodz, Zeligowskiego 7/9, Lodz, Poland.

Background: Preeclamptic pregnancies often present an intensified inflammatory state associated with the nuclear activity of NFB. NEMO is an essential regulator of nuclear factor kappa B (NFB) in cytoplasmic and nuclear cellular compartments. The aim of the present study is to examine the level and localization of the NEMO protein in preeclamptic and nonpreeclamptic placentas.

Methods: The study includes 97 preeclamptic cases and 88 controls. NEMO distribution was analyzed immunohistochemically. Its localization in the nuclear and cytoplasmic fractions, as well as in total homogenates of placental samples, was studied by western blot and ELISA.

Results: The western blot and ELISA results indicate a significant difference in NEMO concentration in the total and nuclear fractions between preeclamptic and control samples ( < 0.01 and < 0.001, respectively). In the cytoplasmic complement, similar levels of NEMO were found in preeclamptic and control placentas. In addition, immunohistochemical staining revealed that the NEMO protein is mainly localized in the syncytiotrophoblast layer, with controls demonstrating a stronger reaction with NEMO antibodies. This study also shows that the placental level of NEMO depends on the sex of the fetus.

Conclusions: The depletion of the NEMO protein in the cellular compartments of placental samples may activate one of the molecular pathways influencing the development of preeclampsia, especially in pregnancies with a female fetus. A reduction of the NEMO protein in the nuclear fraction of preeclamptic placentas may intensify the inflammatory state characteristic for preeclampsia and increase the level of apoptosis and necrosis within preeclamptic placentas.
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http://dx.doi.org/10.1155/2019/8418379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339720PMC
May 2019

Tumor Suppressor Gene in Breast Cancer, a Historical Perspective and Future Directions.

Front Oncol 2018 28;8:345. Epub 2018 Aug 28.

Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland.

The tumor suppressor gene is located at 16q23. 1-23.2, which covers the region of FRA16D-a common fragile sites. Deletions within the coding sequence are observed in up to 80% of breast cancer cases, which makes it one of the most common genetic alterations in this tumor type. The gene is known to play a role in breast cancer: increased expression of inhibits cell proliferation in suspension, reduces tumor growth rates in xenographic transplants, but also enhances cell migration through the basal membrane and contributes to morphological changes in 3D matrix-based cell cultures. The WWOX protein may act in several ways, as it has three functional domains-two WW domains, responsible for protein-protein interactions and an SDR domain (short dehydrogenase/reductase domain) which catalyzes conversions of low molecular weight ligands, most likely steroids. In epithelial cells, WWOX modulates gene transcription through interaction with p73, AP-2γ, and ERBB4 proteins. In steroid hormone-regulated tissues like mammary gland epithelium, the WWOX SDR domain acts as a steroid dehydrogenase. The relationship between WWOX and hormone receptors was shown in an animal model, where WWOX(C3H)+/-mice exhibited loss of both ER and PR receptors. Moreover, in breast cancer specimens, a positive correlation was observed between expression and ER status. On the other hand, decreased expression was associated with worse prognosis, namely higher relapse and mortality rates in BC patients. Recently, it was shown that genomic instability might be driven by the loss of WWOX expression. It was reported that plays role in DNA damage response (DDR) and DNA repair by regulating ATM activation through physical interaction. A genome caretaker function has also been proposed for , as it was found that WWOX sufficiency decreases homology directed repair (HDR) and supports non-homologous end-joining (NHEJ) repair as the dominant DSB repair pathway by Brca1-Wwox interaction. In breast cancer cells, was also found to modulate the expression of glycolysis pathway genes, through hypoxia-inducible transcription factor 1α (HIF1α) regulation. The paper presents the current state of knowledge regarding the WWOX tumor suppressor gene in breast cancer, as well as future research perspectives.
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http://dx.doi.org/10.3389/fonc.2018.00345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121138PMC
August 2018

Silencing of angiotensin receptor 1 interferes with angiotensin II oncogenic activity in endometrial cancer.

J Cell Biochem 2018 11 13;119(11):9110-9121. Epub 2018 Aug 13.

Department of Comparative Endocrinology, Faculty of Biomedical Sciences and Postgraduate Education, Medical University of Lodz, Lodz, Poland.

In mammalian cells, angiotensin II (AngII) binds to 2 distinct high-affinity plasma membrane receptors: angiotensin receptor 1 (AT1R) and angiotensin receptor 2 (AT2R). Healthy human endometrium from women of reproductive age expresses all of the components of the renin-angiotensin system. Many studies suggest that AngII, acting via AT1R, may have a role in the development and progression of cancer, which changes the expression of angiogenic factors, AngII and AT1R are correlated with the presence of endometrial cancer (EC). The aim of the current study was to identify the effects of AngII on the proliferation, cell cycle progression, apoptosis and mobility of ISHIKAWA, MFE296 and MFE280 EC cells with silenced AT1R. It also examines epithelial-mesenchymal transition markers by gene expression analysis. The obtained results suggest that the silencing of AT1R expression alters the migration and invasion ability of EC cells. However, this silencing is not sufficient to inhibit the effects of AngII on EC cells, suggesting that AngII plays a more complex role in the development of EC.
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http://dx.doi.org/10.1002/jcb.27174DOI Listing
November 2018

Regulation of mRNA gene expression of members of the NF-κB transcription factor gene family by angiotensin II and relaxin 2 in normal and cancer prostate cell lines.

Mol Med Rep 2017 Jun 26;15(6):4352-4359. Epub 2017 Apr 26.

Department of Comparative Endocrinology, Medical University of Lodz, Lodz 90‑752, Poland.

An increasing number of researchers are focusing on the influence of local peptide hormones such as angiotensin II (Ang II) and relaxin 2 (RLN2) in the regulation of inflammation and carcinogenesis. The interaction between the renin‑angiotensin system (RAS) and relaxin family peptide system (RFPS) is known to influence the proliferation, adhesion and migration of normal and cancer prostate cell lines. The aim of the present study was to evaluate changes in the expression of nuclear factor‑κB subunit 1 (NFKB1), nuclear factor‑κB subunit 2 (NFKB2), REL proto‑oncogene nuclear factor‑κB p65 subunit (REL), RELA proto‑oncogene nuclear factor‑κB subunit (RELA) and RELB proto‑oncogene nuclear factor‑κB subunit (RELB) mRNA caused by Ang II and RLN2. The members of NF‑kB family are involved in many processes associated with cancer development and metastasis. Reverse transcription‑quantitative polymerase chain reaction analysis identified that both peptide hormones have an influence on the relative expression of nuclear factor‑κB. Following treatment with either peptide, NFKB1 expression was downregulated in all prostate cancer cell lines (LNCaP, DU‑145 and PC3), but not in normal epithelial cells (PNT1A). Conversely, RELB mRNA was enhanced only in non‑cancerous prostate cells. RELA expression was strongly stimulated in the most aggressive cell line, whereas REL mRNA was unchanged. In many cases, the effect was strictly dependent on the cell line and/or the type of peptide: Ang II increased expression of both RELA and REL genes in the androgen‑dependent cell line while RLN2 enhanced NFKB2 and RELA mRNA in androgen‑independent cells (DU‑145). Further research is needed to understand the regulation of NF‑κB family members by key renin‑angiotensin system and RFPS peptides in prostate cancer cells; however, prostate carcinogenesis appears to be influenced by the balance between the cross‑regulation of nuclear factor‑κB (NF‑κB) and androgen receptor pathways by Ang II and relaxin 2.
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http://dx.doi.org/10.3892/mmr.2017.6514DOI Listing
June 2017

Angiotensin II promotes endometrial cancer cell survival.

Oncol Rep 2016 Aug 21;36(2):1101-10. Epub 2016 Jun 21.

Department of Comparative Endocrinology, Medical University of Lodz, Lodz 90-752, Poland.

Endometrial cancer (EC) is one of the most common female cancers. One of the key processes involved in EC development is uncontrolled proliferation stimulated by local factors such as angiotensin. The aim of the present study was to evaluate the influence of angiotensin II (Ang II) on human EC cells. Biological assays and gene expression analysis were performed on three cell lines: ISH, MFE-296 and MFE-280. Our results indicated that at the beginning of cancerogenesis Ang II induced abnormal proliferation at lower doses. We also showed that dose-dependent induction of proliferation was connected with changes in the expression of MKI67, CCND1 and CCNE1 genes in well- and poorly differentiated cancer cells. After Ang II treatment, poorly differentiated endometrial cancer cell line acquired a mesenchymal phenotype, which was characterized by induced expression of EMT-related genes (VIM, CD44, SNAI1, ZEB1 and ZEB2). Our study revealed that Ang II influences EC cells in terms of cancer-related processes, and is responsible for increased proliferation, reduction in apoptosis, increased mobility and modulation of adhesion potential. Its effect and effectiveness appear to be highly connected with the differentiation status of the cancerous cells, as Ang II appears to play a crucial role in the early and late stages of malignant transformation.
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http://dx.doi.org/10.3892/or.2016.4887DOI Listing
August 2016

A common effect of angiotensin II and relaxin 2 on the PNT1A normal prostate epithelial cell line.

J Physiol Biochem 2016 Sep 27;72(3):381-92. Epub 2016 Apr 27.

Department of Comparative Endocrinology, Medical University of Lodz, ul. Zeligowskiego 7/9, 90-752, Lodz, Poland.

The prostate gland is a part of the male reproductive tract which produces both angiotensin II (Ang II) and relaxin 2 (RLN2). The present study analyzes the effect of both these peptide hormones at concentration 10(-8)M on viability, proliferation, adhesion, migration, and invasion of normal prostate epithelial cells (PNT1A). Improved survival in two- and three-dimensional cell cultures was noted as well as visual changes in colony size and structure in Geltrex™. Stimulatory influence on cell viability of each peptide applied single was lower than in combination. Enhanced survival of PNT1A cells appears to be associated with increased BCL2/BAX messenger RNA (mRNA) expression ratio. Modulation of cell spreading and cell-extracellular matrix adhesion dynamics were also altered as an influence of tested hormone application. However, long-term Ang II and RLN2 effects may lead to an increase of normal prostate cell migration and invasion abilities. Moreover, gelatin zymography revealed that both gelatinases A and B were augmented by Ang II treatment, whereas RLN2 significantly stimulated only MMP-9 secretion. These results support the hypothesis that deregulation of locally secreted peptide hormones such as Ang II and RLN2 may take part in the development of certain cancers, including prostate cancer. Moreover, the observed ability of relaxin 2 to act as a regulator of mRNA expression levels not only LGR7 but also classic angiotensin receptors suggested that renin-angiotensin system and relaxin family peptide system are functionally linked.
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http://dx.doi.org/10.1007/s13105-016-0489-1DOI Listing
September 2016

Interaction between angiotensin II and relaxin 2 in the progress of growth and spread of prostate cancer cells.

Int J Oncol 2016 Jun 24;48(6):2619-28. Epub 2016 Mar 24.

Department of Comparative Endocrinology, Medical University of Lodz, 90-752 Lodz, Poland.

Deregulation of locally secreted hormones, such as angiotensin II (Ang II) and relaxin 2 (RLN2), has been linked to a higher risk of select cancers or a poor prognosis in patients. In this study, for the first time a common effect of Ang II and RLN2 in relation to various aspects of prostate cancer development and metastasis are presented. Four independent colorimetric assays were used to analyze cell viability and proliferation. The changes of cell adhesion to extracellular matrix proteins and invasion/aggressiveness ability of prostate cancer cells (LNCaP, PC3) before and after peptides treatment, were also investigated. The findings suggest that the both investigated systems, have an impact on cell growth/division or spread, to some degree via overlapping signal transduction pathways. Intermediate or sometimes poorer results were achieved by using a combination of both hormones than when each was used individually. It seems that Ang II and RLN2 can play a significant role in increasing the aggressiveness of prostate tumors by up-regulating BIRC5 expression and MMP-2 and MMP-9 secretion. In addition, we speculate that Ang II and RLN2 are involved in the transition from the androgen-dependent to the androgen-independent phenotype via modulation of the expression of androgen receptors.
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http://dx.doi.org/10.3892/ijo.2016.3458DOI Listing
June 2016

Finding NEMO in preeclampsia.

Am J Obstet Gynecol 2016 Apr 10;214(4):538.e1-538.e7. Epub 2015 Nov 10.

Department of Obstetrics and Gynecology, Polish Mother's Memorial Hospital-Research Institute in Lodz, Poland.

Background: The mechanism of preeclampsia and its way of inheritance are still a mystery. Biochemical and immunochemical studies reveal a substantial increase in tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 concentrations in the blood of women with preeclampsia. The level of these factors is regulated by nuclear facxtor-kappa B, whose activation in a classical pathway requires inhibitory kappa B kinase gamma (known as NEMO or IKBKG). Moreover, NEMO can schedule between cytoplasma and the nucleus. In the nucleus, IKBKG interacts with other proteins, and thus, it is implicated in the regulation of different gene expressions, which are related to cell cycle progression, proliferation, differentiation, and apoptosis.

Objective: This is the first study investigating the association between the level of NEMO gene expression and the presence of preeclampsia. We tested the hypothesis that the simultaneous increase in NEMO gene expression both in the mother and her fetus may be responsible for the preeclampsia development. Moreover, the relationships between clinical risk factors of preeclampsia and the levels of NEMO gene expression in blood, umbilical cord blood, and placentas were investigated.

Study Design: A total of 91 women (43 preeclamptic women and 48 controls) and their children were examined. Real-time reverse transcription-polymerase chain reaction was used to assess the amount total NEMO messenger ribonucleic acid (mRNA) content and the mRNA level of each NEMO transcript from exons 1A, 1B, and 1C in maternal blood, umbilical cord blood, and placentas. Univariate analyses and correlation tests were performed to examine the association between NEMO gene expression and preeclampsia.

Results: Newborn weight and height, maternal platelet number, and gestational age (week of delivery) were lower in the group of women with preeclampsia than controls. NEMO gene expression level was found to be almost 7 times higher in the group of women with preeclampsia than healthy controls. The correlation analysis found that a simultaneous increase in the expression level of total NEMO mRNA in maternal blood and the mRNA for total NEMO (Rs = 0.311, P < .05), transcripts 1A (Rs = 0.463, P < .01), 1B (Rs = 0.454, P < .01), and 1C (Rs = 0.563, P < .001) in fetal blood was observed in preeclamptic pregnancies. In addition, the mRNA levels for total NEMO and transcripts 1A, 1B, and 1C were lower in placentas derived from pregnancies complicated by preeclampsia.

Conclusion: Simultaneous increase of NEMO gene expression in maternal and fetal blood seems to be relevant for preeclampsia development. The results of our study also suggest that a decreased NEMO gene expression level in preeclamptic placentas may be the main reason for their intensified apoptosis.
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http://dx.doi.org/10.1016/j.ajog.2015.11.002DOI Listing
April 2016

The role of WWOX tumor suppressor gene in the regulation of EMT process via regulation of CDH1-ZEB1-VIM expression in endometrial cancer.

Int J Oncol 2015 16;46(6):2639-48. Epub 2015 Apr 16.

Department of Molecular Carcinogenesis, Medical University of Lodz, PL 90-752 Lodz, Poland.

This study defines the role of WWOX in the regulation of epithelial to mesenchymal transition. A group of 164 endometrial adenocarcinoma patients was studied as well as an ECC1 well-differentiated steroid-responsive endometrial cell line, which was transducted with WWOX cDNA by a retroviral system. The relationship between WWOX gene and EMT marker (CDH1, VIM, ZEB1, SNAI1) expression on mRNA (RT-qPCR) and protein levels (western blotting) was evaluated. The EMT processes were also analysed in vitro by adhesion of cells to extracellular matrix proteins, migration through a basement membrane, anchorage-independent growth and MMP activity assay. DNA microarrays (HumanOneArray™) were used to determine WWOX-dependent pathways in an ECC1 cell line. A positive correlation was observed between WWOX and ZEB1, and a negative correlation between CDH1 and VIM. WWOX expression was found to inversely correlate with the risk of recurrence of tumors in patients. However, in the WWOX-expressing ECC1 cell line, WWOX expression was found to be inversely related with VIM and positively with CDH1. The ECC1/WWOX cell line variant demonstrated increased migratory capacity, with increased expression of metalloproteinases MMP2/MMP9. However, these cells were not able to form colonies in suspension and revealed decreased adhesion to fibronectin and fibrinogen. Microarray analysis demonstrated that WWOX has an impact on the variety of cellular pathways including the cadherin and integrin signalling pathways. Our results suggest that the WWOX gene plays a role in the regulation of EMT processes in endometrial cancer by controlling the expression of proteins associated with cell motility, thus influencing tissue remodeling, with the suppression of mesenchymal markers.
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http://dx.doi.org/10.3892/ijo.2015.2964DOI Listing
February 2016

Alternating expression levels of tumor suppressor and cancer-related genes in patients with bladder cancer.

Oncol Lett 2014 Nov 22;8(5):2291-2297. Epub 2014 Aug 22.

Department of Molecular Cancerogenesis, Medical University of Lodz, Lodz 90-752, Poland.

The aim of the present study was to determine the roles of the tumor suppressor and cancer-related genes in bladder tumor carcinogenesis. Reverse transcription-quantitative polymerase chain reaction was used to analyze the status of promoter methylation (using MethylScreen™ technology) and loss of heterozygosity (LOH) in papillary urothelial cancer tissues. The associations between the expression levels of the following tumorigenesis-related genes were also assessed: The tumor suppressor gene the proliferation gene, the and apoptotic genes, the signal transduction gene, the vascular endothelial growth factor gene, and the and cell cycle genes. The results reveal a high frequency of LOH in intron 1 in the gene, as well as an association between reduced expression levels and increased promoter methylation. In addition, the present study demonstrates that in bladder tumors, apoptosis is inhibited by increased expression levels of the gene. A correlation between the proliferation indices of the and the genes was also revealed Furthermore, the expression levels of were identified to be positively associated with those of the gene.
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http://dx.doi.org/10.3892/ol.2014.2476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186597PMC
November 2014

[Proteins in cancer multidrug resistance].

Postepy Hig Med Dosw (Online) 2014 May 20;68:616-32. Epub 2014 May 20.

Zakład Kancerogenezy Molekularnej, Uniwersytet Medyczny w Łodzi.

Multidrug Resistance (MDR) is defined as insensitivity to administered medicines that are structurally unrelated and have different molecular targets. Cancers possess numerous mechanisms of drug resistance, involving various aspects of cell biology. A pivotal role in this phenomenon is played by proteins--enzymatic or structural parts of the cell. Membrane transporters, including the main members of ABC protein family--P-gp, MRP1 and BCRP, as well as LRP, which builds structure of vaults, determine the multidrug-resistant phenotype by decreasing drug concentration within the cell or modifying its distribution to intracellular compartments. The π isoform of protein enzyme--glutathione S-transferase (GSTP-1), is responsible for excessive intensity of detoxification of cytostatics. A common example of altered drug target site that does not respond to chemotherapy is topoisomerase II α (TopoIIa). Alterations of programmed cell death result from expression of metallothionein (MT)--inhibitor of the process, and cytokeratin 18 (CK18), which, if in high concentration, also prevents apoptosis of cells. Several methods of decreasing activity of these proteins have been developed, aiming to overcome MDR in cancer cells. However, for a variety of reasons, their clinical suitability is still very low, leading to continuous increase in death rate among patients. This paper presents current state of knowledge on the most important examples of proteins responsible for MDR of cancer cells and molecular mechanisms of their action.
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http://dx.doi.org/10.5604/17322693.1103268DOI Listing
May 2014

The correlation analysis of WWOX expression and cancer related genes in neuroblastoma- a real time RT-PCR study.

Acta Biochim Pol 2014 22;61(1):91-7. Epub 2014 Jan 22.

Department of Molecular Cancerogenesis, Medical University of Lodz, Łódź, Poland.

Neuroblastoma is one of the most common paediatric cancers, described as unpredictable due to diverse patterns of behaviour. WWOX is a tumour suppressor gene whose expression is reduced in many tumour types. Loss of its expression was shown to correlate with more aggressive disease stage and mortality rate. The aim of this study was to investigate the role of the WWOX tumour suppressor gene in neuroblastoma formation. We performed real-time RT-PCR to analyse levels of WWOX expression in 22 neuroblastic tumour samples in correlation with genes involved in cell cycle regulation (CCNE1, CCND1), proliferation (MKI67), apoptosis (BCL2, BIRC5, BAX) and signal transduction (EGFR, ERBB4). We also evaluated two potential mechanisms - promoter methylation (MethylScreen method) and loss of heterozygosity (LOH) status, which could be connected with regulation of WWOX gene expression. We found a positive correlation between WWOX gene and BCL2 and HER4 JM-a and negative with cyclin D1 and E1. Our observations are consistent with previous findings and emphasise the role of WWOX in cell cycle and apoptosis regulation. Moreover, strong positive association with HER4 JM-a in this tumour type may indicate a role for WWOX in neuroblastoma cell differentiation. The presented results indicate that LOH in locus D16S3096 (located in intron 8) may be involved in the regulation of WWOX mRNAexpression. However, no association between methylation status of WWOX promoter and its expression was observed.
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November 2014

The WWOX tumor suppressor gene in endometrial adenocarcinoma.

Int J Mol Med 2013 Dec 11;32(6):1458-64. Epub 2013 Oct 11.

Department of Molecular Cancerogenesis, Medical University of Lodz, PL 90-752 Lodz, Poland.

Endometrial cancer is a lethal malignancy, the causes of which remain to be determined. The aim of the present study, carried out on tumor samples from 79 patients, was to evaluate the role of the WWOX tumor suppressor gene in endometrial adenocarcinoma. The expression levels of WWOX and its protein content were assessed in normal endometrium and cancer samples. Quantitative PCR was used to assess the correlation between the expression levels of WWOX and the genes involved in the proliferation (MKI67), apoptosis (BAX, BCL2), signal transduction (EGFR), cell cycle (CCNE1, CCND1), cell adhesion (CDH1) and transcription regulation (TP73, NCOR1). The relationship between loss of hetero-zygosity (LOH) and WWOX mRNA levels was also investigated using high resolution melting. Results of the present study demonstrated a positive correlation of WWOX expression with BCL2 and CCND1 and a negative correlation with BAX, CDH1, NCOR1 and BCL2/BAX ratio. The results also showed that loss of heterozygosity at two analyzed loci of the WWOX gene is frequent in patients with endometrial cancer and that WWOX expression levels are lower in tumor samples than in normal tissue. In conclusion, WWOX may be involved in endometrial cancer.
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http://dx.doi.org/10.3892/ijmm.2013.1526DOI Listing
December 2013

Primary extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type in the central nervous system (MZL CNS) presented as traumatic subdural hematoma and subarachnoid bleeding - case report.

Clin Neuropathol 2013 Sep-Oct;32(5):384-92

The study describes a very rare case of primary extranodal marginal zone Bcell lymphoma of the central nervous system (MZL CNS) with an unusual clinical and radiological presentation mimicking subarachnoid bleeding and subdural hematoma (SDH) after head injury. The patient presented symptoms which had commenced 3 weeks earlier: a gradually-progressing headache associated with periodic right-sided cramp of the face muscles and numbness of the right upper limb. During urgent craniotomy for drainage of the presumed SDH, a tumor mass histopathologically and immunohistochemically matching marginal zone B-cell lymphoma was found. Molecular analysis confirmed monoclonal immunoglobulin heavy chain gene (IgH) rearrangement; the patient had previously suspected nodal lymphoma because of cervical lymphadenopathy, but histopathological, immunohistochemical and molecular examination excluded malignant lymphoma. The patient underwent successful radiotherapy, and achieved complete response. At present, no evidence of either systemic disease or lymph node enlargement has been found. The recognition of an indolent type of lymphoma in a rare anatomical localization is very important due to the proper management of the patient.
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http://dx.doi.org/10.5414/NP300579DOI Listing
November 2013

Correlation between VEGFR-2 receptor kinase domain-containing receptor (KDR) mRNA and angiotensin II receptor type 1 (AT1-R) mRNA in endometrial cancer.

Cytokine 2013 Feb 28;61(2):639-44. Epub 2012 Dec 28.

Department of Comparative Endocrinology, Medical University of Lodz, Poland.

Purpose: Angiogenesis, a multistep process that results in new blood vessel formation from preexisting vasculature is essential for both the growth of solid tumour and for metastasis. Stimulation of vascular endothelial growth factor receptor (VEGFR), a transmembrane glycoprotein, results in mitogenesis. Within this family of receptors, VEGFR 2/kinase-insert-domain containing receptor appears to be principally upregulated during tumorigenesis. The aim of this study was to determine the expression of VEGFR-2/kinase-insert-domain containing receptor (KDR) and its correlation with angiotensin receptor type 1 (AT1-R) and clinical factors in endometrial carcinoma.

Methods: The expression of KDR and AT1-R was studied in endometrial carcinoma and normal endometrium by Real-time RT-PCR and Western blot analysis in 136 samples. The expression profile was correlated with the clinicopathological characteristics of endometrial adenocarcinoma.

Results: We noted a significant correlation between the expression of KDR and AT1-R in tumour grade G1, G2 and G3 (R(s)=0.50; p=0.002, R(s)=0.69; p=0.0001, R(s)=0.52; p=0.005, respectively). In stage I and stage II carcinoma, a significant correlation was also found between the expression of KDR and AT1-R (R(s)=0.70, p=0.0001, R(s)=0.67; p=0.001, respectively). Moreover significant correlation was observed between both KDR and AT1-R in tissue with different myometrial invasion (R(s)=0.54, p=0.0001, R(s)=0.68; p=0.0001; respectively for tumours with invasion into the inner half and invasion into the outer half).

Conclusions: Basing on received correlation between AT1-R and KDR expression and previous results we speculate that angiotensin through AT1-R modulates KDR expression and thus have influence on local VEGF level. However, further studies are required to clarify the biological interaction between KDR, AT1-R and other hormonal regulators in endometrial carcinoma.
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http://dx.doi.org/10.1016/j.cyto.2012.11.017DOI Listing
February 2013

Genetic alterations of WWOX in Wilms' tumor are involved in its carcinogenesis.

Oncol Rep 2012 Oct 27;28(4):1417-22. Epub 2012 Jul 27.

Department of Molecular Cancerogenesis, Medical University of Lodz, 90-752 Lodz, Poland.

Loss of heterozygosity (LOH) in 16q appears in ~20-30% cases of Wilms' tumor. Within this region, known as common fragile site FRA16D, the WWOX tumor suppressor gene is located. Abnormalities of WWOX gene expression levels were observed in many tumor types and were associated with worse prognosis. The purpose of this study was to investigate the role of the WWOX tumor suppressor gene in Wilms' tumor samples. We evaluated the correlation between expression of WWOX and genes involved in proliferation (Ki67), apoptosis (BCL2, BAX), signal transduction (ERBB4, ERBB2, EGFR), cell cycle (CCNE1, CCND1), cell adhesion (CDH1) and transcription (TP73) using real-time RT-PCR in 23 tumor samples. We also analyzed the potential causes of WWOX gene expression reduction i.e., promoter methylation status (MethylScreen method) and loss of heterozygosity (LOH) status. We revealed a positive correlation between WWOX expression and BCL2, BCL2/BAX ratio, EGFR, ERBB4 isoform JM-a, TP73 and negative correlation with both cyclins. Loss of heterozygosity of the WWOX gene was observed only at intron 8, however, it had no influence on the reduction of its expression levels. Contrary to LOH, methylation of the region covering the 3' end of the promoter and part of exon 1 was associated with statistically significant reduction of WWOX gene expression levels. In the present study we reveal that in Wilms' tumors the WWOX expression levels are positively associated with the process of apoptosis, signal transduction through the ErbB4 pathway and EGFR and negatively with the regulation of the cell cycle (by cyclin E1 and D1). Moreover, our analysis indicates that in this type of tumor the expression of the WWOX gene can be regulated by an epigenetic mechanism--its promoter methylation.
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http://dx.doi.org/10.3892/or.2012.1940DOI Listing
October 2012

A comparison of the effects of Angiotensin IV on androgen-dependent and androgen-independent prostate cancer cell lines.

J Renin Angiotensin Aldosterone Syst 2013 Mar 7;14(1):74-81. Epub 2012 Jun 7.

Department of Comparative Endocrinology, Medical University of Lodz, Poland.

Introduction: Angiotensin IV is one of the biologically active peptides of the renin-angiotensin system. Limited data suggests that this hexapeptide could contribute to cancer development and/or progression.

Materials And Methods: Using the MTT reduction assay as an indicator of cell viability, and the bromodeoxyuridine incorporation assay as an indicator of cell proliferation, the influence of Angiotensin IV was evaluated on two human prostate cancer lines: androgen-dependent (LNCaP) and androgen-independent (DU-145). The potential effect of Angiotensin IV classic angiotensin receptors was examined by using the selective antagonists losartan and PD123319. Finally, the changes in expression levels of AT1 and AT2 receptors were compared, before and after angiotensin treatment.

Results: Angiotensin IV caused significant changes in cell viability and proliferation in LNCaP cells but not in DU-145. It was found that AT2 receptor blocker (PD123319) was able to diminish the suppressor effect of Angiotensin IV on bromodeoxyuridine incorporation into the DNA of androgen-dependent prostate cancer cells. Simultaneously, it was reported that Angiotensin IV is the factor that modulates the density of AT1 and AT2 receptors in prostate cancer cells.

Conclusions: These findings suggested that Angiotensin IV can modulate tumour cell proliferation in the early stage of androgen-dependent prostate cancer. The effect might be promoted by the change of the angiotensin receptor level.
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http://dx.doi.org/10.1177/1470320312447649DOI Listing
March 2013

Analysis of the expression of angiotensin II type 1 receptor and VEGF in endometrial adenocarcinoma with different clinicopathological characteristics.

Tumour Biol 2012 Jun 15;33(3):767-74. Epub 2011 Dec 15.

Department of Comparative Endocrinology, Medical University of Lodz, Lodz, Poland.

In Poland, endometrial carcinoma takes second place after breast cancer among all cancers in women and is considered the most common genital cancer. It has been repeatedly reported that angiotensin is involved in the development and invasion of some cancers including breast, ovarian, and pancreatic ones. It is suggested that angiotensin two and its receptors are actively involved in tumour biology in endometrial adenocarcinoma. In the present study, we identify a possible relationship between the expression of AT1-R, AT2-R, ERα, and VEGF and clinicopathological characteristics of primary endometrial adenocarcinoma. We determined the above components both at the mRNA (real-time RT-PCR) and protein levels (Western Blot assay). Our results indicate that in patients with grade G3 adenocarcinoma, the expression of AT1-R significantly decreased in comparison with G1 patients (p = 0.034), but the level of ERα was the highest in G2 and the lowest in G3. Moreover, the level of VEGF mRNA significantly increased between G2 and G3 (p = 0.034). We also noted a significant correlation between the expression of AT1-R and AT2-R in FIGO stage 1 (R (s) = 0.9636; p = 0.0001) and that of AT2-R and VEGF (R (s) = 0.5377; p = 0.005). In grade G1 and G2 carcinoma, a significant correlation was also found between the expression of AT1-R and AT2-R (R (s) = 0.9924; p = 0.0001; R (s) = 0.8717, p = 0.0005, respectively), but in grade G1, a negative correlation was observed between AT1-R and VEGF (R (s) = -0.8945, p = 0.0005). Further studies are required to clarify the biological function of the angiotensin receptor in regulating VEGF expression in endometrial carcinoma.
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http://dx.doi.org/10.1007/s13277-011-0292-0DOI Listing
June 2012