Carcinogenic Transformation Research Articles

Microfluid biosensor for detection of hpv in patient scraping samples: Determining E6 and E7 oncogenes

E6 and E7 oncogenes are pivotal in the carcinogenic transformation in HPV infections and efficient diagnostic methods can ensure the detection and differentiation of HPV genotype. This study describes the development and validation of an electrochemical, label-free genosensor coupled with a microfluidic system for detecting the E6 and E7 oncogenes in cervical scraping samples. The nanostructuring employed was based on a cysteine and graphene quantum dots layer that provides functional groups, surface area, and interesting electrochemical properties. Biorecognition tests with cervical scraping samples showed differentiation in the voltammetric response. Low-risk HPV exhibited a lower biorecognition response, reflected in ΔI% values of 82.33 % ± 0.29 for HPV06 and 80.65 % ± 0.68 for HPV11 at a dilution of 1:100. Meanwhile, high-risk, HPV16 and HPV18, demonstrated ΔI% values of 96.65 % ± 1.27 and 93 % ± 0.026, respectively, at the same dilution. Therefore, the biorecognition intensity followed the order: HPV16 >HPV18 >HPV06 >HPV11. The limit of detection and the limit of quantification of E6E7 microfluidic LOC−Genosensor was 26 fM, and 79.6 fM. Consequently, the E6E7 biosensor is a valuable alternative for clinical HPV diagnosis, capable of detecting the potential for oncogenic progression even in the early stages of infection.

An effective way for targeting EGFR-mediated carcinogenesis: an in vitro study

Introduction: EGFR-activating overexpression or somatic mutations are common in different human cancers. In this regard, the search for promising ways to control the carcinogenic transformation of tumor cells and the progression of malignant tumors expressing EGFR seems to be one of the most promising and developing areas of modern molecular pathology and pharmacology. Material and Methods: An antitumor activity of a novel compound, a pyridine carboxylic acid derivative LHT-17-19, was studied. The molecule was developed and synthesized at the Department of Chemistry, Drug Design and Technology of All-Russian Research Center for Biological Active Compounds Safety (Russia). The study was carried out in cell cultures of stomach cancer (Hs746T, AGS and MKN1) and patient-derived organoid (PDO) model of breast cancer (BC) expressing wild-type EGFR. Results: It was shown that LHT-17-19 induced concentration-dependent cytotoxicity of EGFR-expressing gastric cancer cells of all the aforementioned cultures. Pathomorphological, immunohistochemical and molecular validation of BC organoids derived from ductal breast carcinoma cells of a 68-year-old patient was done. PDOs were established as ER-negative, PR-negative, Her2/neu-negative, EGFR-positive with 35% of the Ki-67 expression index. In addition, the tumor cells translocation was resulted in a loss of ER expression and PDOs molecular pattern conversion towards a more aggressive triple negative type. PDOs incubation with 0.5-60.0 µM LHT-17-19 was accompanied not only by inhibition of their growth and proliferation, but also by significant cytoreduction. Conclusion: Thus, in two-dimensional and three-dimensional tumor cell cultures, the possibility of controlling the oncogenic expression of EGFR with the acridone compound 9-ammonium-3,3-dimethyl-3,4-dihydroacridine-1(2H)-OH L-2-hydroxybutanedivacate (LHT-17-19) was shown.

Utilization of Waste Materials for Making Plastic Bricks

Currently, due to urbanization, there has been a notable rise in the use of plastic in our daily lives, owing to its widespread utility and popularity. However, its non-biodegradable nature presents a significant drawback. One potential solution for recycling plastic waste involves creating plastic bricks by blending plastic with sand, offering a substitute for conventional bricks. The primary challenge lies in managing plastic waste, particularly as continued reuse of PET bottles carries the risk of carcinogenic transformation, with only a small percentage currently being recycled. To address this issue, PET bottles are meticulously cleaned and combined with fine aggregate (sand) at various ratios (3:7, 2:3, 1:1) to produce high-quality brick blocks with excellent thermal and acoustic insulation properties. This environmentally friendly approach tackles the non-biodegradability problem of plastics while reducing the overall cost of construction and pollution. The resulting bricks exhibit high compressive strength, minimal water absorption, and thermal resistance, rendering them suitable for diverse applications. Increasing the sand-to-plastic ratio enhances the strength of the bricks, ensuring durability with minimal water absorption and no efflorescence. This method shows promise in recycling plastic waste and mitigating its environmental impact. Furthermore, various tests including split tensile strength test, penetration test, and specific gravity were conducted to validate the efficacy of the approach. Key Word: PET (polyethylene terephthalate), compressive strength, water absorption, split tensile strength test, efflorescence, specific gravity test

Dysregulated Expression Patterns of Circular RNAs in Cancer: Uncovering Molecular Mechanisms and Biomarker Potential.

Circular RNAs (circRNAs) are stable, enclosed, non-coding RNA molecules with dynamic regulatory propensity. Their biogenesis involves a back-splicing process, forming a highly stable and operational RNA molecule. Dysregulated circRNA expression can drive carcinogenic and tumorigenic transformation through the orchestration of epigenetic modifications via extensive RNA and protein-binding domains. These multi-ranged functional capabilities have unveiled extensive identification of previously unknown molecular and cellular patterns of cancer cells. Reliable circRNA expression patterns can aid in early disease detection and provide criteria for genome-specific personalized medicine. Studies described in this review have revealed the novelty of circRNAs and their biological ss as prognostic and diagnostic biomarkers.

Abstract 4354: Long noncoding RNA DUXAP10 serves as a putative driver of carcinogenic transformation in anaplastic thyroid cancer

Abstract Anaplastic Thyroid Cancer (ATC) is the most aggressive thyroid cancer subset, with a <4% five-year survival rate. ATC is completely refractory to traditional therapy and newer immunotherapeutic options. Unlike other lethal cancers, ATC has a low mutational burden, warranting the need for a comprehensive study of differential gene expression patterns. Transcriptomic regulators known as long non-coding RNAs (lncRNA) have been described as pivotal orchestrators of gene expression and drivers of carcinogenic patterns. Thus, we present the role of novel lncRNAs in shaping the ATC genotype and phenotype. ​​Publicly available ATC vs. normal thyroid tissue transcriptomic datasets (Gene Expression Omnibus; GSE33630, GSE85457) were investigated to identify genomic transcripts that are differentially expressed in ATC samples using GEO2R. Bioinformatic analysis identified Double Homeobox A Pseudogene 10 (DUXAP10), as a highly upregulated lncRNA in ATC patient tissue samples in both databases (40-fold and 20-fold). Gene Expression Profiling Interactive Analysis statistically correlated high DUXAP10 expression with decreased survival in thyroid cancer patients. DUXAP10 expression was similarly upregulated in ATC cell line, T238, compared to immortalized “normal” thyroid epithelial cell line, Nthy-ori-3-1. Our T238-CRISPRi knockdown model of DUXAP10 was evaluated in vitro to assess consequences of overexpression. CRISPRi knockdown of DUXAP10 in T238 significantly reduced its migratory capabilities by 50%, invasion index by 30%, clonogenicity by 70%, cell viability by 67%, 60%, and 50% at 24, 48, and 72 hours, respectively, proliferation by 28%, 45%, and 36% at 24, 48, and 72 hours, respectively, and global transcription rate by 65%. Further, our DUXAP10-CRISPRi knockdown exhibited a downregulation of N-Cadherin and mediators of beta-catenin signaling- confirming a role in regulatory cross-talk of central carcinogenic pathways. We are currently evaluating proteins and miRNAs bound to and “sponged” by DUXAP10 in vitro utilizing RNA-centric methodology. These data reveal the novelty of DUXAP10, and that its over-expression may increase the negative consequences of ATC metastasis. Thus, we have identified DUXAP10 as a putative determinant for ATC diagnosis, prognosis, and therapeutic targeting. Citation Format: Nicole R. DeSouza, Michelle Carnazza, Danielle Quaranto, Tara Jarboe, Kaci Kopec, Robert Suriano, Kate Nielsen, Augustine Moscatello, Humayun Islam, Jan Geliebter, Raj K. Tiwari. Long noncoding RNA DUXAP10 serves as a putative driver of carcinogenic transformation in anaplastic thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4354.

An Insight Into the Role of Alpha-Fetoprotein (AFP) in the Development and Progression of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the primary malignancy of hepatocytes and the second most common cause of cancer-related mortality across the globe. Despite significant advancements in screening, diagnosis, and treatment modalities for HCC, the mortality-to-incidence ratio remain unacceptably high. A recent study indicates that a minor population of HCCs are AFP negative or express the normal range of AFP levels. Although it is a gold standard and a more reliable biomarker in the advanced stage of HCC and poorly differentiated tumors, it does not serve as a suitable means for screening HCC. AFP plays a significant role in the development and progression of HCC and understanding its role is crucial. By examining the molecular mechanisms involved in AFP-mediated tumorigenesis, we can better understand HCC pathogenesis and identify potential therapeutic targets. This article details the role of alpha-fetoprotein (AFP) in the carcinogenic transformation of hepatocytes. The article also focuses on information about the structure, biosynthesis, and regulation of AFP at the gene level. Additionally, it discusses the immune evasion, metastasis, and control of gene expression that AFP mediates during HCC.

Interactome of Long Non-Coding RNAs: Transcriptomic Expression Patterns and Shaping Cancer Cell Phenotypes.

RNA biology has gained extensive recognition in the last two decades due to the identification of novel transcriptomic elements and molecular functions. Cancer arises, in part, due to the accumulation of mutations that greatly contribute to genomic instability. However, the identification of differential gene expression patterns of wild-type loci has exceeded the boundaries of mutational study and has significantly contributed to the identification of molecular mechanisms that drive carcinogenic transformation. Non-coding RNA molecules have provided a novel avenue of exploration, providing additional routes for evaluating genomic and epigenomic regulation. Of particular focus, long non-coding RNA molecule expression has been demonstrated to govern and direct cellular activity, thus evidencing a correlation between aberrant long non-coding RNA expression and the pathological transformation of cells. lncRNA classification, structure, function, and therapeutic utilization have expanded cancer studies and molecular targeting, and understanding the lncRNA interactome aids in defining the unique transcriptomic signatures of cancer cell phenotypes.

Bromelain mitigates liver fibrosis via targeting hepatic stellate cells in vitro and in vivo

Various therapeutic approaches are conducted for regression of liver fibrosis and prevent possible further carcinogenic transformation. This study was aimed to assess the prospective therapeutic potential of bromelain against thioacetamide (TAA)-induced liver fibrosis using in-vitro and in vivo approaches. In vitro study, HSC-T6 cell line was used to evaluate the effect of bromelain on HSC-T6 cell viability and apoptosis. In vivo, Rats were treated by TAA for 6 weeks for induction of hepatic fibrosis followed by post treatment by different doses of bromelain and silymarin for further 4 weeks to assess the regression of hepatic fibrosis. The in-vitro findings indicated that bromelain hindered the proliferation of HSCs in concentration dependent manner compared with the untreated cells. The in vivo study revealed that treatment of TAA fibrotic rats with different doses of bromelain and silymarin induced a significant restoration in liver function biomarkers, attenuation of oxidative stress, upregulation of total antioxidant capacity and thereby decline of fibrotic biomarkers and improving histopathological and immunohistochemical changes. In conclusion, This study indicates that bromelain can regress TAA induced hepatic fibrosis in rats via inhibiting HSCs activation, α-SMA expression and the ECM deposition in hepatic tissue in addition to its antioxidants pathway, these findings prove the promising therapeutic potential of bromelain as a novel therapeutic approach for chronic hepatic fibrotic diseases.

DNA Methylation-Mediated Overexpression of CXCL1 in Helicobacter pylori-Induced Gastric Cancer: In Silico- and In Vitro-Based Identification of a Potential Biomarker for Carcinogenesis.

Given the high global prevalence and mortality associated with gastric cancer, and its known causal link with Helicobacter pylori infection, it is important to have a biomarker to identify malignant transformation at early stages. Previously, we, and others, have reported that H. pylori-induced epigenetic changes could mediate carcinogenic transformation of the gastric cells. Also, CXCL1 secreted by gastric cancer cells was reported as a key diagnostic and prognostic biomarker for the pathogenic progression of gastric cancer. In this study, for the first time, we aimed to investigate the role of H. pylori-induced DNA methylation-based epigenetic regulation of CXCL1. In silico analysis of publicly available datasets and in vitro experiments were performed. Our results showed that CXCL1 is highly expressed in both gastric cancer tissues and gastric cancer cells infected with H. pylori. Further, we showed and confirmed that H. pylori-mediated overexpression of CXCL1 is due to hypomethylation of its promoter region. Since epigenetic events such as DNA methylation happen early in the sequence; H. pylori-induced CXCL1 hypomethylation could likely be detected at an early stage of gastric cancer development. Epigenetic modifications, such as CXCL1 hypomethylation, are reversible and could potentially be a therapeutic target using demethylation drugs.

Interleukin-1 receptor associated kinase 1 (IRAK1) is epigenetically activated in luminal epithelial cells in prostate cancer.

The use of immune adjuvants such as toll-like receptor (TLR) agonists reflects a novel strategy in prostate cancer (PCa) therapy. However, interleukin-1 receptor associated kinase 1 (IRAK1), a central effector of TLR signaling, has been shown to be responsible for resistance to radiation-induced tumor cell death. In order to better understand the function and epigenetic regulation of IRAK1 in PCa, we performed in vitro cell culture experiments together with integrative bioinformatic studies using the latest single-cell RNA-sequencing data of human PCa and normal prostate (NOR), and data from The Cancer Genome Atlas. We focused on key effectors of TLR signaling, the Myddosome-complex components IRAK1, IRAK4 and MYD88 (myeloid differentiation primary response 88), and TRAF6 (tumor-necrosis-factor receptor associated factor 6). In PCa, IRAK1-mRNA was specifically enriched in luminal epithelial cells, representing 57% of all cells, whereas IRAK4 and MYD88 were predominantly expressed in leukocytes, and TRAF6, in endothelial cells. Compared to NOR, only IRAK1 was significantly overexpressed in PCa (Benjamini-Hochberg adjusted p<2x10-8), whereas the expression of IRAK4, MYD88, and TRAF6 was unchanged in PCa, and IRAK1-expression was inversely correlated with a specific differentially methylated region (IRAK1-DMR) within a predicted promoter region enriched for H3K27ac (Spearman correlation r<-0.36; Fisher’s test, p<10-10). Transcription factors with high binding affinities in IRAK1-DMR were significantly enriched for canonical pathways associated with viral infection and carcinogenic transformation in the Kyoto Encyclopedia of Gene and Genomes analysis. DU145 cells, exhibiting hypermethylated IRAK1-DMR and low IRAK1-expression, reacted with 4-fold increased IRAK1-expression upon combined treatment with 5-aza-2-deoxycytidine and trichostatin A, and were unresponsive to infection with the uropathogenic Escherichia coli strain UTI89. In contrast, PC3 and LNCaP cells, exhibiting hypomethylated IRAK1-DMR and high endogenous IRAK1-mRNA levels, responded with strong activation of IRAK1-expression to UTI89 infection. In summary, exclusive overexpression of IRAK1 was observed in luminal epithelial cells in PCa, suggesting it has a role in addition to Myddosome-dependent TLR signaling. Our data show that the endogenous epigenetic status of PCa cells within IRAK1-DMR is decisive for IRAK1 expression and should be considered as a predictive marker when selective IRAK1-targeting therapies are considered.

Eriodictyol inhibits breast carcinogenesis by targeting circ_0007503 and repressing PI3K/Akt pathway

BackgroundEriodictyol in citrus fruits, Eriodictyon californicum and several Chinese herbal medicines shows great promise for chronic disease prevention, including cancers. However, its role in chemopreventive activities against breast carcinogenesis is unknown. PurposeIn the present study, we investigated the chemopreventive effect and the underlying mechanism of eriodictyol on carcinogens-induced breast carcinogenesis in vivo and in vitro. MethodsThe carcinogenic transformation in MCF10A cells was induced by the environmental carcinogens in vitro. The chemopreventive effect in vivo was evaluated by using the experimental model of 1-methyl-1-nitrosourea (MNU)-induced mammary tumorigenesis in rats. The activation of the PI3K/Akt pathway was detected by western blot assay; the levels of circular RNAs (circRNAs) were measured by qRT-PCR. ResultsFirst, eriodictyol significantly reduces cells viability and induces apoptosis in breast cancer cells in a dose-dependent manner in vitro (P < 0.05). Next, eriodictyol could effectively suppress environmental carcinogens-induced acquisition of carcinogenic properties in human breast epithelial cell MCF10A (P < 0.05). In vivo, eriodictyol administration reduces the incidence of mammary tumor by 50% in carcinogen-treated female rats (P < 0.05). Further study revealed that eriodictyol represses the PI3K/Akt signaling pathway and down-regulates the level of circ_0007503 in breast cancer cells and in breast carcinogenesis (P < 0.01). When the effect of eriodictyol on circ_0007503 was blocked by transfection of a circ_0007503 over-expression plasmid, the cytotoxic effects and the suppression of the PI3K/Akt pathway of eriodictyol in breast cancer cells were significantly reduced (P < 0.05). ConclusionOur data indicated that eriodictyol could effectively suppress breast carcinogenesis in vitro and in vivoThe mechanism may be attributed to targeting circ_0007503 and inhibiting PI3K/Akt pathway.

Macrophages play a role in inflammatory transformation of colorectal cancer.

Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide, and it is also a typical inflammatory cancer. The function of macrophages is very important in the tissue immune microenvironment during inflammatory and carcinogenic transformation. Here, we evaluated the function and mechanism of macrophages in intestinal physiology and in different pathological stages. Furthermore, the role of macrophages in the immune microenvironment of CRC and the influence of the intestinal population and hypoxic environment on macrophage function are summarized. In addition, in the era of tumor immunotherapy, CRC currently has a limited response rate to immune checkpoint inhibitors, and we summarize potential therapeutic strategies for targeting tumor-associated macrophages.

Abstract 2413: POLE gene mutations in African Americans colorectal cancer

Abstract Background: Most focus in genetic instability in colon carcinogenic transformation was on DNA Mismatch Repair (MMR) genes alterations as they relate to the microsatellite instability phenotype. However, POLE gene mutations can also be instrumental in triggering genetic instability, at even higher magnitude of genome mutation rate. Aim: To assess POLE gene mutations in African Americans with colorectal cancer (CRC). Methods: Data from Whole exome sequencing of 12 CRC African American tumors was searched to scan POLE gene mutations. All detected mutations were checked in tumors and matched normal. The detected mutations were validated in a second set of samples that were sequenced using POLE gene targeted sequencing. Detected and validated mutations were checked in available databases such as COSMIC and dbSNP to determine novel mutations in our population that is at high risk of aggressive CRC. Results: Six out of 12 patients (50%) displayed mutations in POLE gene. There were 41 detected mutations, 11 are novel mutations and 15 are amino-acid changing. Nine of these were non-synonymous and predicted to have deleterious effects. All these mutations were validated using targeted sequencing. In comparison to DNA MMR, POLE gene has four folds more mutations than MSH2gne (10 mutations and MSH6 (11 mutations and two fold more than MSH3 gene (20 mutations) in the same set of 12 cancer/matched normals. The POLE mutations heterozygous/homozygous status was overall similar in normal and matched normal. However, most of the mutations were homozygous. Conclusion: POLE gene mutations are increasingly recognized as another important element in genetic instability. Our data shows that mutations affecting this gene are likely more significant than those affecting DNA MMR genes. Moreover, POLE mutations might be more consequential, especially those affecting its exonuclease domain of polymerase epsilon, proofreading catalytic subunit. Microsatellite-stable, hypermutated CRCs might need to be explored for POLE gene mutations to track the origin of high mutation rates. Citation Format: Hassan Brim, Babak Shokrani, Hamed Azimi, Sudhir Varma, Edward Lee, Hassan Ashktorab. POLE gene mutations in African Americans colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2413.

Categorizing the characteristics of human carcinogens: a need for specificity

The International Agency for Research on Cancer (IARC) has recently proposed employing "ten key characteristics of human carcinogens" (TKCs) to determine the potential of agents for harmful effects. The TKCs seem likely to confuse the unsatisfactory correlation from testing regimes that have ignored the differences evident when cellular changes are compared in short and long-lived species, with their very different stem cell and somatic cell phylogenies. The proposed characteristics are so broad that their use will lead to an increase in the current unacceptably high rate of false positives. It could be an informative experiment to take well-established approved therapeutics with well-known human safety profiles and test them against this new TKC paradigm. Cancers are initiated and driven by heritable and transient changes in gene expression, expand clonally, and progress via additional associated acquired mutations and epigenetic alterations that provide cells with an evolutionary advantage. The genotoxicity testing protocols currently employed and required by regulation, emphasize testing for the mutational potential of the test agent. Two-year, chronic rodent cancer bioassays are intended to test for the entire spectrum of carcinogenic transformation. The use of cytotoxic doses causing increased, sustained cell proliferation that facilitates accumulated genetic damage leads to a high false-positive rate of tumor induction. Current cancer hazard assessment protocols and weight-of-the-evidence analysis of agent-specific cancer risk align poorly with the pathogenesis of human carcinoma and so need modernization and improvement in ways suggested here.

Helicobacter pylori and colorectal neoplasms: a concise review.

Helicobacter pylori is the main etiological agent of all malignant tumors caused by an infectious disease. It is a major, at times dominant, factor in the pathogenesis of a large spectrum of diseases such as acute and chronic gastritis, gastric and duodenal ulcers, gastric carcinoma, and lymphoma. Epidemiological and experimental studies suggest that H. pylori chronic infection may be related to different extragastric diseases, including colorectal neoplasms. This concise review aims to explore the association of H. pylori infection with colorectal cancer and adenoma, including the recent epidemiological findings, the diagnostic methods employed to detect H. pylori and virulent factors, and the potentially involved mechanisms. Furthermore, is attempted to establish the current data integration for causal inference using the Bradford-Hill causality criteria. The weak, although global, strength of the epidemiological positive association between H. pylori infection and colonic neoplasms associated to new mechanisms postulated to explain this interaction, including intestinal dysbiosis, should stimulate future studies. Prospective confirmatory studies to establish the role of H. pylori eradication in the process of carcinogenic transformation of the colonic epithelium may define its eventual role in the treatment and prevention of colonic neoplasms.

Aberrant FGFR4 signaling worsens nonalcoholic steatohepatitis in FGF21KO mice.

Background: Nonalcoholic steatohepatitis (NASH) is the most severe form of non-alcoholic fatty liver disease (NAFLD) and a potential precursor of hepatocellular carcinoma (HCC). In our previous studies, we found that endocrine fibroblast growth factor 21 (FGF21) played a key role in preventing the development of NASH, however, the FGF15/19 mediated-FGFR4 signaling worsened NASH and even contributed to the NASH-HCC transition. The aim of this study is to determine whether FGF15/FGFR4 signaling could alleviate or aggravate NASH in the FGF21KO mice.Methods: NASH models were established in FGF21KO mice fed with high fat methionine-choline deficient (HFMCD) diet to investigate FGF15/FGFR4 signaling during early stage NASH and advanced stage NASH. Human hepatocytes, HepG2 and Hep3B cells, were cultured with human enterocytes Caco-2 cells to mimic gut-liver circulation to investigate the potential mechanism of NASH development.Results: Significant increase of FGF15 production was found in the liver of the NASH-FGF21KO mice, however the increased FGF15 protein was unable to alleviate hepatic lipid accumulation. In contrast, up-regulated FGF15/19/FGFR4 signaling was found in the FGF21KO mice with increased NASH severity, as evident by hepatocyte injury/repair, fibrosis and potential malignant events. In in vitro studies, blockage of FGFR4 by BLU9931 treatment attenuated the lipid accumulation, up-regulated cyclin D1, and epithelial-mesenchymal transition (EMT) in the hepatocytes.Conclusion: The increased FGF15 in NASH-FGF21KO mice could not substitute for FGF21 to compensate its lipid metabolic benefits thereby to prevent NASH development. Up-regulated FGFR4 signaling in NASH-FGF21KO mice coupled to proliferation and EMT events which were widely accepted to be associated with carcinogenic transformation.

Роль транскрипционных факторов коктейля Яманаки (OCT4, sOX2, KLF4, c-Myc) в дифференцировке соматических клеток, их злокачественной трансформации и прогрессировании опухолей

The paper reviews the role of transcription factors that are part of the Yamanaka cocktail (OCT4, SOX2, KLF4, and c-Myc) in the mechanisms of tumor stem cell (TSC) differentiation (a pool of pluripotent cells), their participation in the malignant transformation of somatic cells, and in tumor progression. Their increased proliferative activity, which determines their malignant potential, was believed to be the main feature of tumor cells. Currently, there is more evidence supporting another concept that explains the continued tumor growth, metastasis, and resistance to therapy of most malignant tumors with a small, rest-ing, and rarely dividing population of pluripotent tumor cells. Year 2006 is considered to be the beginning of a new direction in developmental biology when Japanese researchers K. Takahashi and S. Yamanaka published the results of their studies on the properties of embryonic stem cells and experiments on direct reprogramming of somatic terminally differentiated cells.The research proved that four transcription factors were sufficient to maintain the pluripotent properties of cells, namely Oct4, SOX2, KLF4, and c-Myc, which were later called the Yamanaka cocktail. Such factors as SOX2and Oct4 are at the top of the hierarchy of transcription factors that regulate the pluripotent proper-ties of cells, their differentiation, and dedifferentiation. TSCs represent, albeit a complex, but very promising target for the development of innovative products for the diagnosis of and targeted therapy for neoplasms. From this point of view, the factors of pluripotency, which are parts of the Yamanaka cocktail, could be such promising targets, whose effect will probably be able to suppress or reduce the malignant potential of the most aggressive tumors and even prevent carcinogenic transformation in cases of precancerous pathology. Keywords: Yamanaka cocktail, OCT4, SOX2, KLF4, c-Myc, malignant transformation

Genomic retargeting of p53 and CTCF is associated with transcriptional changes during oncogenic HRas-induced transformation

Gene transcription is regulated by distant regulatory elements via combinatorial binding of transcription factors. It is increasingly recognized that alterations in chromatin state and transcription factor binding in these distant regulatory elements may have key roles in cancer development. Here we focused on the first stages of oncogene-induced carcinogenic transformation, and characterized the regulatory network underlying transcriptional changes associated with this process. Using Hi-C data, we observe spatial coupling between differentially expressed genes and their differentially accessible regulatory elements and reveal two candidate transcription factors, p53 and CTCF, as determinants of transcriptional alterations at the early stages of oncogenic HRas-induced transformation in human mammary epithelial cells. Strikingly, the malignant transcriptional reprograming is promoted by redistribution of chromatin binding of these factors without major variation in their expression level. Our results demonstrate that alterations in the regulatory landscape have a major role in driving oncogene-induced transcriptional reprogramming.

Context is key: Understanding the regulation, functional control, and activities of the p53 tumour suppressor.

The p53 tumour suppressor is considered one of the most critical genes in cancer biology. By upregulating apoptosis, cell cycle arrest, and DNA damage repair in normal cells, p53 prevents the propagation of cells with tumorigenic potential; therefore, mutations in p53 are associated with carcinogenic transformation and can be accompanied by the accumulation of a novel gain-of-function oncogenic protein, mutant p53. Although p53 is most often understood to utilize context-dependent post-translational modifications to achieve regulation of its many target genes, recent research has also sought to define other mechanisms of regulating p53 gene expression prior to translation and to understand how this alternative regulation of p53 may influence target gene expression and cellular outcome. This review attempts to summarize what is known about p53 regulation at the transcriptional, post-transcriptional, and post-translational levels while paying special attention to the ways in which context may influence p53 regulation and subsequent regulation of its target genes.

Analysis of \u03b2-catenin association with obesity in African Americans with premalignant and malignant colorectal lesions

BackgroundAfrican Americans (AA) are at high risk for Colorectal Cancer (CRC). Studies report a 30–60% increase in CRC risk with physical inactivity, obesity and metabolic syndrome. Activation of the WNT/β-catenin (CTNNB1) signaling pathway plays a critical role in colorectal carcinogenesis. Accumulating evidence also indicates a role of WNT-CTNNB1 signaling in obesity and metabolic diseases.AimTo examine the association between obesity, β-Catenin expression and colonic lesions in African Americans.MethodsWe reviewed the pathology records of 152 colorectal specimens from 2010 to 2012 (46 CRCs, 74 advanced adenomas and 32 normal colon tissues). Tissue Microarrays (TMA) were constructed from these samples. Immunohistochemistry (IHC) for CTNNB1 (β-Catenin; clone β-Catenin-1) was performed on the constructed TMAs. The IHC results were evaluated by 2 pathologists and the nuclear intensity staining was scored from 0 to 4. BMI, sex, age, location of the lesion and other demographic data were obtained.ResultsPositive nuclear staining in normal, advanced adenoma and CRC was 0, 24 and 41%, respectively (P < 0.001). CRC was asso ciated with positive status for nuclear CTNNB1 intensity (adjusted OR: 3.40, 95%CI = 1.42–8.15, P = 0.006 for positive nuclear staining) compared to non-CRC samples (Normal or advanced adenoma). Nuclear staining percentage has a fair diagnostic ability for CRC with an AUC of 0.63 (95%CI = 0.55–0.71).Overweight/obese patients (BMI > 25) did not show a significant difference in (p = 0.3) nuclear CTNNB1 staining (17% positive in normal weight vs. 27% positive in overweight/obese). The association between nuclear intensity and CRC was not different between normal and overweight patients (P for interaction = 0.6). The positive nuclear CTNNB1status in CRC stage III and IV (35% of all CRC) was not different from stage I and II (50% vs. 36%, respectively, P = 0.4).ConclusionIn our study, advanced adenoma and CRC were associated with activation of β-catenin in physically fit, overweight and obese patients. Thus, obesity and WNT/β-Catenin pathway seem to be independent in African American patients. WNT/β-Catenin signaling pathway has a potential to be used as an effector in colon carcinogenic transformation. Whether or not BMI is a modifier of this pathway needs to be investigated further.