Inactivation Of Tumor Suppressor Genes Research Articles

Cellular mechanisms of heterogeneity in NF2-mutant schwannoma

Schwannomas are common sporadic tumors and hallmarks of familial neurofibromatosis type 2 (NF2) that develop predominantly on cranial and spinal nerves. Virtually all schwannomas result from inactivation of the NF2 tumor suppressor gene with few, if any, cooperating mutations. Despite their genetic uniformity schwannomas exhibit remarkable clinical and therapeutic heterogeneity, which has impeded successful treatment. How heterogeneity develops in NF2-mutant schwannomas is unknown. We have found that loss of the membrane:cytoskeleton-associated NF2 tumor suppressor, merlin, yields unstable intrinsic polarity and enables Nf2−/− Schwann cells to adopt distinct programs of ErbB ligand production and polarized signaling, suggesting a self-generated model of schwannoma heterogeneity. We validated the heterogeneous distribution of biomarkers of these programs in human schwannoma and exploited the synchronous development of lesions in a mouse model to establish a quantitative pipeline for studying how schwannoma heterogeneity evolves. Our studies highlight the importance of intrinsic mechanisms of heterogeneity across human cancers.

SCD5 Regulation by VHL Affects Cell Proliferation and Lipid Homeostasis in ccRCC.

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cancer, and inactivation of the VHL tumor suppressor gene is found in almost all cases of hereditary and sporadic ccRCCs. CcRCC is associated with the reprogramming of fatty acid metabolism, and stearoyl-CoA desaturases (SCDs) are the main enzymes controlling fatty acid composition in cells. In this study, we report that mRNA and protein expression of the stearoyl-CoA desaturase SCD5 is downregulated in VHL-deficient cell lines. Similarly, in C. elegans vhl-1 mutants, FAT-7/SCD5 activity is repressed, supporting an evolutionary conservation. SCD5 regulation by VHL depends on HIF, and loss of SCD5 promotes cell proliferation and a metabolic shift towards ceramide production. In summary, we identify a novel regulatory function of VHL in relation to SCD5 and fatty acid metabolism, and propose a new mechanism of how loss of VHL may contribute to ccRCC tumor formation and progression.

Proteasomal pathway inhibition as a potential therapy for NF2-associated meningioma and schwannoma.

Neurofibromatosis 2 (NF2) is an inherited disorder caused by bi-allelic inactivation of the NF2 tumor suppressor gene. NF2-associated tumors, including schwannoma and meningioma, are resistant to chemotherapy, often recurring despite surgery and/or radiation, and have generally shown cytostatic response to signal transduction pathway inhibitors, highlighting the need for improved cytotoxic therapies. Leveraging data from our previous high-throughput drug screening in NF2 preclinical models, we identified a class of compounds targeting the ubiquitin-proteasome pathway (UPP), and undertook studies using candidate UPP inhibitors, ixazomib/MLN9708, pevonedistat/MLN4924, and TAK-243/MLN7243. Employing human primary and immortalized meningioma (MN) cell lines, CRISPR-modified Schwann cells (SCs), and mouse Nf2-/- SCs, we performed dose response testing, flow cytometry-based Annexin V and cell cycle analyses, and RNA-sequencing to identify potential underlying mechanisms of apoptosis. In vivo efficacy was also assessed in orthotopic NF2-deficient meningioma and schwannoma tumor models. Testing of three UPP inhibitors demonstrated potent reduction in cell viability and induction of apoptosis for ixazomib or TAK-243, but not pevonedistat. In vitro analyses revealed that ixazomib or TAK-243 downregulates expression of c-KIT and PDGFRα, as well as the E3 ubiquitin ligase SKP2 while upregulating genes associated with endoplasmic reticulum stress-mediated activation of the unfolded protein response (UPR). In vivo treatment of mouse models revealed delayed tumor growth, suggesting a therapeutic potential. This study demonstrates the efficacy of proteasomal pathway inhibitors in meningioma and schwannoma preclinical models and lays the groundwork for use of these drugs as a promising novel treatment strategy for NF2 patients.

Coronavirus disease 2019 vaccines: challenges of using global mass vaccination to achieve herd immunity.

Coronavirus disease 2019 vaccines: challenges of using global mass vaccination to achieve herd immunity.

Five-hub genes identify potential mechanisms for the progression of asthma to lung cancer.

Previous studies have shown that asthma is a risk factor for lung cancer, while the mechanisms involved remain unclear. We attempted to further explore the association between asthma and non-small cell lung cancer (NSCLC) via bioinformatics analysis. We obtained GSE143303 and GSE18842 from the GEO database. Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) groups were downloaded from the TCGA database. Based on the results of differentially expressed genes (DEGs) between asthma and NSCLC, we determined common DEGs by constructing a Venn diagram. Enrichment analysis was used to explore the common pathways of asthma and NSCLC. A protein-protein interaction (PPI) network was constructed to screen hub genes. KM survival analysis was performed to screen prognostic genes in the LUAD and LUSC groups. A Cox model was constructed based on hub genes and validated internally and externally. Tumor Immune Estimation Resource (TIMER) was used to evaluate the association of prognostic gene models with the tumor microenvironment (TME) and immune cell infiltration. Nomogram model was constructed by combining prognostic genes and clinical features. 114 common DEGs were obtained based on asthma and NSCLC data, and enrichment analysis showed that significant enrichment pathways mainly focused on inflammatory pathways. Screening of 5 hub genes as a key prognostic gene model for asthma progression to LUAD, and internal and external validation led to consistent conclusions. In addition, the risk score of the 5 hub genes could be used as a tool to assess the TME and immune cell infiltration. The nomogram model constructed by combining the 5 hub genes with clinical features was accurate for LUAD. Five-hub genes enrich our understanding of the potential mechanisms by which asthma contributes to the increased risk of lung cancer.

Hepatocellular carcinoma: molecular mechanism, targeted therapy, and biomarkers.

Hepatocellular carcinoma (HCC) is a common malignancy and one of the leading causes of cancer-related death. The biological process of HCC is complex, with multiple factors leading to the broken of the balance of inactivation and activation of tumor suppressor genes and oncogenes, the abnormal activation of molecular signaling pathways, the differentiation of HCC cells, and the regulation of angiogenesis. Due to the insidious onset of HCC, at the time of first diagnosis, less than 30% of HCC patients are candidates for radical treatment. Systematic antitumor therapy is the hope for the treatment of patients with middle-advanced HCC. Despite the emergence of new systemic therapies, survival rates for advanced HCC patients remain low. The complex pathogenesis of HCC has inspired researchers to explore a variety of biomolecular targeted therapeutics targeting specific targets. Correct understanding of the molecular mechanism of HCC occurrence is key to seeking effective targeted therapy. Research on biomarkers for HCC treatment is also advancing. Here, we explore the molecular mechanism that are associated with HCC development, summarize targeted therapies for HCC, and discuss potential biomarkers that may drive therapies.

The legacy is not just with you: an interview with Stephen Baylin.

The legacy is not just with you: an interview with Stephen Baylin.

Deep genomic analysis of malignant peripheral nerve sheath tumor cell lines challenges current malignant peripheral nerve sheath tumor diagnosis

Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas of the peripheral nervous system that develop either sporadically or in the context of neurofibromatosis type 1 (NF1). MPNST diagnosis can be challenging and treatment outcomes are poor. We present here a resource consisting of the genomic characterization of 9 widely used human MPNST cell lines for their use in translational research. NF1-related cell lines recapitulated primary MPNST copy number profiles, exhibited NF1, CDKN2A, and SUZ12/EED tumor suppressor gene (TSG) inactivation, and presented no gain-of-function mutations. In contrast, sporadic cell lines collectively displayed different TSG inactivation patterns and presented kinase-activating mutations, fusion genes, altered mutational frequencies and COSMIC signatures, and different methylome-based classifications. Cell lines re-classified as melanomas and other sarcomas exhibited a different drug-treatment response. Deep genomic analysis, methylome-based classification, and cell-identity marker expression, challenged the identity of common MPNST cell lines, opening an opportunity to revise MPNST differential diagnosis.

Mesothelioma-associated fibroblasts enhance proliferation and migration of pleural mesothelioma cells via c-Met/PI3K and WNT signaling but do not protect against cisplatin

BackgroundPleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Unlike many other cancers, PM is mostly characterized by inactivation of tumor suppressor genes. Its highly malignant nature in absence of tumor driving oncogene mutations indicates an extrinsic supply of stimulating signals by cells of the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are an abundant cell type of the TME and have been shown to drive the progression of several malignancies. The aim of the current study was to isolate and characterize patient-derived mesothelioma-associated fibroblasts (Meso-CAFs), and evaluate their impact on PM cells.MethodsMeso-CAFs were isolated from surgical specimens of PM patients and analyzed by array comparative genomic hybridization, next generation sequencing, transcriptomics and proteomics. Human PM cell lines were retrovirally transduced with GFP. The impact of Meso-CAFs on tumor cell growth, migration, as well as the response to small molecule inhibitors, cisplatin and pemetrexed treatment was investigated in 2D and 3D co-culture models by videomicroscopy and automated image analysis.ResultsMeso-CAFs show a normal diploid genotype without gene copy number aberrations typical for PM cells. They express CAF markers and lack PM marker expression. Their proteome and secretome profiles clearly differ from normal lung fibroblasts with particularly strong differences in actively secreted proteins. The presence of Meso-CAFs in co-culture resulted in significantly increased proliferation and migration of PM cells. A similar effect on PM cell growth and migration was induced by Meso-CAF-conditioned medium. Inhibition of c-Met with crizotinib, PI3K with LY-2940002 or WNT signaling with WNT-C59 significantly impaired the Meso-CAF-mediated growth stimulation of PM cells in co-culture at concentrations not affecting the PM cells alone. Meso-CAFs did not provide protection of PM cells against cisplatin but showed significant protection against the EGFR inhibitor erlotinib.ConclusionsOur study provides the first characterization of human patient-derived Meso-CAFs and demonstrates a strong impact of Meso-CAFs on PM cell growth and migration, two key characteristics of PM aggressiveness, indicating a major role of Meso-CAFs in driving PM progression. Moreover, we identify signaling pathways required for Meso-CAF-mediated growth stimulation. These data could be relevant for novel therapeutic strategies against PM.

Promoter methylation levels of RASSF1 and ATIC genes are associated with lung cancer in Iranian patients.

Epigenetic alterations like methylation of tumor suppressor genes or oncogenes, in respiratory epithelium have been associated with lung cancer. Hypermethylation of genes promoter is an epigenetic event, and is responsible to tumor suppressor genes inactivation as well as oncogenes activation. This study aimed to assess the role of methylation status in promoter of RASSF1 and ATIC genes their potential implication in the pathogenesis of lung tumor in Iranian patients. In this study, we collected 100 tissue samples (50lung cancer tissues and 50 adjacent non-cancerous lung tissues) from Iranian lung cancer patients. The genomic DNA was extracted, and methylation status of both RASSF1 andATIC genes was investigated by methylation-sensitive high-resolution melting (MS-HRM) assay technique and Real-Time PCR. Cancer Genome Atlas (TCGA) dataset wasalso analyzed for further validation of the gene's methylation. Methylation of RASSF1 gene promoter was significantly higher in lung tumor tissues. However, promoter methylation levels of ATIC gene was significantly lower in lung tumor tissues. These results were additionally confirmed by TCGA analysis. Promoter methylation of both RASSF1 and ATIC genes was significantly associated with lymph node metastasis, and clinical stage of lung cancer. Thereceiver operating characteristic (ROC) curve analysis indicated a high accuracy of promoter methylation in these genes as a diagnostic biomarker for lung cancer. Methylation levels of both RASSF1 and ATIC genes promoters were associated with lung cancer pathogenesis in Iranian population, and may be a suitable biomarker for diagnosis and prognosis of lung cancer in early stage of tumorigenesis.

The Real Mechanisms of Emodin Treating Lung Cancer Based on System Pharmacology

In the world nowadays, cancer gradually becomes the first problem to public health and seriously threatens human life due to the high mortality and recurrence. In modern medical theory, cancer is considered as a genetic disease presenting either oncogene activation (OCG) or tumor suppressor gene (TSG) inactivation. Many clinical observations showed that the existing standard chemotherapies which target oncogenes and their related molecules have little benefit in improving survival, prognosis, recurrence and metastasis despite tumor size shrinkage. Compared with these routine treatment methods, the traditional Chinese medicine (TCM) cancer therapy based on TCM theory, in which the cancer initiation is regarded as disorder of human body system, focuses on the events impacting the gene rather than the gene itself. In fact, it is necessary but not sufficient for cancer initiation and progression to activate OCG or inactivate TSG, which exhibit oncogene or tumor-suppressor property depending on the biological context. In TCM theory, lung and large intestine are external-internal relations of each other, which are physiologically related and pathologically affected each other. Hence, the use of a classical laxative medicine rhubarb for lung cancer treatment is in line with TCM theory. Emodin as the major component of rhubarb represents the multi-targeting therapeutic mechanisms of TCM in multiple disease treatment including anti-cancer. There are some reviews on microscopic and inner mechanisms of emodin in cancer treatment, our previous study confirmed lung cancer-preventing effect of lung cancer. Here, we summarize the real mechanisms of emodin treating lung cancer based on system pharmacology, mainly focusing on the resolution of intrinsic pathological inducers, which will provide a solid foundation to understand cancer pathogenesis and formulate cancer therapy. Keywords: Emodin, Lung cancer, Traditional Chinese medicine (TCM) theory

Genetic mutations in the molecular pathogenesis of gastrointestinal stromal tumor

Gastrointestinal stromal tumors are mesenchymal tumors which predominantly originate from the interstitial cells of Cajal in the intestinal lining. Around ~85% of malignant GISTs possess activating mutations in the tyrosine kinase receptors KIT or PDGFRA. The driver mutations in genes other than KIT or PDGFRA account for around 15% GISTs and belong to highly heterogeneous groups called wild-type GISTs. Around 20–40% of WT-GISTS are deficient for the succinate dehydrogenase complex (SDHA, SDHB, SDHC, SDHD). Mutations in SDH cause the accumulation of oncometabolite succinate that increases the level of HIF1α which enhances the transcription of several genes including IGF1, IGF2, and VEGF inducing the proliferation of the cancer cells. The remaining WT-GISTS are associated with mutations in BRAF, loss-of-function of NF1, hyperactivation FGFR, inactivation of tumor suppressor genes (p53 and dystrophin), and mutations in DNA damage response genes such as RAD51 and BRCA2 which results in the activation of the PI3K/mTOR or RAS/RAF/MAPK signaling cascade. Therefore, understanding the mutational status and molecular characterization of GIST plays a very crucial role in the overall management of GIST.

The impact of TP53 and PTEN tumor suppressor genes on response to different breast cancer treatment modalities

<p><strong>Introduction.</strong> Breast cancer (BC) is the most frequent type of malignancy and the leading cause of cancer related death among women worldwide. BC is exceptionally heterogeneous disease and therefore distinct treatment modalities are necessary to address these differences. The aim of our study was to investigate the impact of TP53 and PTEN tumor suppressor genes (TSGs) inactivation on BC response to different treatment modalities and their possible cooperation, on post-operative BC samples. </p> <p><strong>Methods. </strong>Patients were classified, based on applied adjuvant therapy, into four distinct groups: those that received hormonal therapy (HT) only, hormonal therapy combined with chemotherapy (HT/CHT), hormonal therapy combined with chemo and biological therapy (HT/CHT/H), and other systemic therapies that exclude HT. Functional inactivation of TP53 and PTEN TSG’s were studied by mutation, loss of heterozygosity (LOH) and hypermethylation analysis. </p> <p><strong>Results.</strong> Our results revealed that TP53 gene was altered in 63 out of 90 specimens (70%), while the frequency of PTEN alterations was slightly lower, 54 out of 90 (60%). Simultaneous inactivation was detected in 43 tested samples (48%) with significant association between two analyzed TSGs. Further, we found that TP53 status has significant influence on patients’ therapy response. Contrary to this, no significance was found between mutational status of PTEN and various treatment modalities. However, significant association was found between the type of applied therapy and simultaneous alterations of these two TSGs (p = 0.00001). </p> <p><strong>Conclusion.</strong> Patients with wtTP53 show significantly better therapy response regardless of the type of therapy, compared to carriers of altered TPp53 gene.</p>

Investigation of the effects of the royal jelly on genomic demethylation and tumor suppressor genes in human cancer cells.

Royal jelly is a gelatinous nutrient secretion produced by the mandibular glands of young worker honey bees and has a critical role in honey bee life. In the honey bee colonies, queen and worker honey bees have very different morphologies and behaviors due to their diet in the larval period, despite having the same genome. In comparison, queen bees formed from larvae that feed royal jelly exclusively, and worker bees formed from larvae that feed on much less royal jelly. DNA methylation has been shown to play a critical role in the development of queen and worker honeybees. Alterations in DNA methylation, one of the epigenetic mechanisms defined as hereditable nucleotide modifications that occur in gene expression without changes in the DNA sequence, are closely related to many diseases, especially cancer. Hypermethylation of CpG islands located in the promoter regions of genes causes gene silencing and tumor suppressor genes epigenetically have silenced in cancer. The inactivation of tumor suppressor genes disrupts nearly all cellular pathways in cancer. In contrast to genetic alterations, gene silencing by epigenetic modifications may potentially be reversed and used in cancer treatment. Royal jelly, which causes epigenetic changes in bee colonies, has the potential to cause a change in cancer cells. In our study, royal jelly's effects on DNA methyltransferase enzyme and gene methylation of RASSF1A tumor suppressor were investigated in human cancer cell lines (HeLa, HT29, and A549), and modifications in the gene expression profile of royal jelly were determined by next generation sequencing.

Abstract A051: Understanding the Arf-p53 axis in PDAC suppression

Abstract Understanding the gene regulatory networks that contribute to PDAC initiation and progression is critical for improving early detection and more effectively treating this disease. Activating mutations in KRAS are often accompanied by mutations in the TP53, CDKN2A, and SMAD4 tumor suppressor genes in ~72%, 30%, and 32% of PDAC cases (Raphael et al. 2017). Understanding the consequences of deletion of individual tumor suppressor genes can delineate specific genotype-phenotype correlations that can provide new clinical insights. Using a genetically engineered mouse PDAC model based on KrasG12D expression and tumor suppressor gene inactivation through Ptf1aCreER expression in adult acinar cells, we showed previously that p53 deletion or point mutation dramatically accelerates PDAC relative to mice with intact p53. To understand tumor evolution in mice with different p53 statuses, we analyzed the transcriptomic profiles of PDACs developing with intact or mutant p53 by spatial transcriptomics and both bulk and single cell RNA-sequencing. These experiments have provided insight into the pathways that become dysregulated as PDAC develops in the context of different p53 alleles. In addition, as oncogenic signals trigger p53 stabilization via the p19ARF (ARF) protein in some contexts, we sought to determine whether ARF acts upstream of p53 in PDAC suppression. Indeed, the frequent deletion of the CDKN2A locus, which encodes both the ARF and p16INK4A (p16) tumor suppressor genes, suggests the importance of both these genes in suppressing PDAC, but the specific role of ARF in PDAC suppression has not been tested. Using mouse models to definitively interrogate the importance of ARF in suppressing PDAC, we found that Arf inactivation promotes KrasG12D-driven PDAC, and with a latency similar to p53 inactivation. Interestingly, concurrent inactivation of both p53 and Arf accelerated oncogenic KRAS-driven PDAC development relative to p53 inactivation alone, suggesting a p53-independent role for ARF in PDAC suppression. Transcriptomic profiling of tumors from these mice revealed both p53-dependent and p53-independent programs of ARF-mediated tumor suppression, which provides insight into how tumors develop in the absence of ARF. Characterization of the immune and fibroblast components of the tumor microenvironment in tumors with intact tumor suppressors, p53 deficiency, Arf deficiency and combined p53;Arf deficiency reveals genotype-dependent differences, including different CAF profiles observed in tumors of different genotypes. Ongoing analysis of human PDAC will help to further parse the roles of ARF and p16 in human pancreatic cancer development. Together, these studies will help to illuminate how p53 and Arf inactivation contribute to cancer cell evolution and crosstalk with the tumor microenvironment during PDAC development, understanding with potential for improving clinical interventions in PDAC. Citation Format: Laura D. Attardi, Brittany M. Flowers, Kathryn Hanson, Abigail S. Mulligan, Sofia Ferreira, Sohinee Bhattacharyya, Hannes Vogel, Laura D. Wood, Mara Sherman. Understanding the Arf-p53 axis in PDAC suppression [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A051.

EPCO-11. GATEKEEPER INACTIVATION DRIVES TUMOR PROGRESSION TO GRADE IV ASTROCYTOMA

Abstract IDH-mutant low-grade diffuse astrocytomas frequently progress to grade IV astrocytomas with implications for patient prognosis. To better understand this process, we applied whole-genome and transcriptome sequencing to matched tumor samples collected before and after progression to grade IV astrocytomas from five patients. All tumors carried an IDH1 mutation. The number of chromosomal rearrangements was increased between 1.3 and 3.5-fold in the tumors upon progression, with the exception of one case, in which the increase was only 1.03-fold. This case exhibited a hypermutation signature caused by homozygous deletion of the MSH2 gene, which encodes a member of the DNA mismatch repair complex. The most common genomic alterations acquired at progression were homozygous deletions in the CDKN2A/ RB1 -pathway or hemizygous deletion of PTEN. Additionally, PDGFRA was amplified in two grade IV tumors, with concordantly increased expression. For one of these cases, a PDGFRA-amplified subclone is likely to be present already in the low-grade astrocytoma. We further detected intrachromosomal rearrangements closeby the genes NRG3 in the progressed tumors as well as in the The Cancer Genome Atlas (TCGA) cohort. The expression of NRG3 decreased with increasing grade in the TCGA cohort and the gene was frequently deleted. Lower NRG3 expression was associated with shorter survival in the TCGA cohort. Several miRNAs showed differential expression upon progression. For two miRNAs the predicted targets were associated with cell cycle regulation and we detected inverse correlation between miRNA and target mRNA expression. While progression seems to occur via different pathways, the predicted outcome for many of the alterations was the inactivation of tumor suppressor genes and further dysregulation of cell proliferation.

Long-term treatment of cancer-prone germline PTEN mutant micewith low-dose rapamycin extends lifespan and delays tumour development.

PTEN is one of the most commonly inactivated tumour suppressor genes in sporadic cancer. Germline heterozygous PTEN gene alterations also underlie PTEN hamartoma tumour syndrome (PHTS), a rare human cancer-predisposition condition. A key feature of systemic PTEN deregulation is the inability to adequately dampen PI3-kinase (PI3K)/mTORC1 signalling. PI3K/mTORC1 pathway inhibitors such as rapamycin are therefore expected to neutralise the impact of PTEN loss, rendering this a more druggable context compared with those of other tumour suppressor pathways such as loss of TP53. However, this has not been explored in cancer prevention in a model of germline cancer predisposition, such as PHTS. Clinical trials of short-term treatment with rapamycin have recently been initiated for PHTS, focusing on cognition and colon polyposis. Here, we administered a low dose of rapamycin from the age of 6 weeks onwards to mice with heterozygous germline Pten loss, a mouse model that recapitulates most characteristics of human PHTS. Rapamycin was well tolerated and led to a highly significant improvement of survival in both male and female mice. This was accompanied by a delay in, but not full blockade of, the development of a range of proliferative lesions, including gastro-intestinal and thyroid tumours and endometrial hyperplasia, with no impact on mammary and prostate tumours, and no effect on brain overgrowth. Our data indicate that rapamycin may have cancer prevention potential in human PHTS. This might also be the case for sporadic cancers in which genetic PI3K pathway activation is an early event in tumour development, such as endometrial cancer and some breast cancers. To the best of our knowledge, this is the first report of a long-term treatment of a germline cancer predisposition model with a PI3K/mTOR pathway inhibitor. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Molecular Characteristics of Bladder Tumor: Increased Gene Expression of MAGE-A6 and MAGE-A11 with Decreased MicroRNA-34a and MicroRNA-125b.

Bladder cancer is recognized as one of the top ten most common cancers worldwide. Activation of oncogenes, inactivation of tumor suppressor genes, and dysregulation of androgen signaling pathways are three major pathophysiological causes in the development of bladder tumors. Discovering potential biomarkers is required for the management and immunotherapy of bladder cancer. Melanoma-associated antigen (MAGE)-A6 and MAGE-A11 are two cancer-testis antigens that are potential coregulators of androgen receptors. MicroRNAs, especially miR-34a and miR-125b are two important tumor suppressors that play a critical role in regulating different signaling pathways and inhibiting tumor development. Twenty-nine surgical tissue biopsies were collected from patients with no preoperative chemotherapy or radiotherapy (26 males and, 3 females, mean age±SD: 62.4±13.3 years). Seventeen adjacent uninvolved tissues with no abnormalities upon histological examination were considered normal controls (14 males and, 3 females, mean age±SD: 64.2±7.4 years) . Quantitative PCR was performed to evaluate the gene expression level of MAGE-A6, MAGE-A11, miR-34a, and miR-125b in bladder cancer biopsies. MAGE-A6 and MAGE-A11 expressions were significantly increased in bladder tumors compared with normal tissues. However, the expression levels of miR-34a and miR-125b were significantly downregulated in bladder tumor tissues.Interestingly, the expression level of all these genes was significantly associated with tumor grade, pathological stage (pT), and muscular invasion. MAGE-A6 and MAGE-A11 can be considered potential markers for the diagnosis and immunotherapy of bladder tumors. Furthermore, the modulation of miR-34a and miR-125b gene expression in association with increased MAGE-A6 and MAGE-A11 genes could open a new horizon in the improvement of bladder cancer.

Expression of the methylcytosine dioxygenase ten-eleven translocation-2 and connexin 43 in inflammatory bowel disease and colorectal cancer.

Inflammatory bowel disease (IBD) constitutes a substantial risk factor for colorectal cancer. Connexin 43 (Cx43) is a protein that forms gap junction (GJ) complexes involved in intercellular communication, and its expression is altered under pathological conditions, such as IBD and cancer. Recent studies have implicated epigenetic processes modulating DNA methylation in the pathogenesis of diverse inflammatory and malignant diseases. The ten-eleven translocation-2 (TET-2) enzyme catalyzes the demethylation, hence, regulating the activity of various cancer-promoting and tumor-suppressor genes. To investigate Cx43 and TET-2 expression levels and presence of 5-hydroxymethylcytosine (5-hmC) marks under inflammatory conditions both in vitro and in vivo. TET-2 expression was evaluated in parental HT-29 cells and in HT-29 cells expressing low or high levels of Cx43, a putative tumor-suppressor gene whose expression varies in IBD and colorectal cancer, and which has been implicated in the inflammatory process and in tumor onset. The dextran sulfate sodium-induced colitis model was reproduced in BALB/c mice to evaluate the expression of TET-2 and Cx43 under inflammatory conditions in vivo. In addition, archived colon tissue sections from normal, IBD (ulcerative colitis), and sporadic colon adenocarcinoma patients were obtained and evaluated for the expression of TET-2 and Cx43. Expression levels were reported at the transcriptional level by quantitative real-time polymerase chain reaction, and at the translational level by Western blotting and immunofluorescence. Under inflammatory conditions, Cx43 and TET-2 expression levels increased compared to non-inflammatory conditions. TET-2 upregulation was more pronounced in Cx43-deficient cells. Moreover, colon tissue sections from normal, ulcerative colitis, and sporadic colon adenocarcinoma patients corroborated that Cx43 expression increased in IBD and decreased in adenocarcinoma, compared to tissues from non-IBD subjects. However, TET-2 expression and 5-hmC mark levels decreased in samples from patients with ulcerative colitis or cancer. Cx43 and TET-2 expression levels were also investigated in an experimental colitis mouse model. Interestingly, mice exposed to carbenoxolone (CBX), a GJ inhibitor, had upregulated TET-2 levels. Collectively, these results show that TET-2 levels and activity increased under inflammatory conditions, in cells downregulating gap junctional protein Cx43, and in colon tissues from mice exposed to CBX. These results suggest that TET-2 expression levels, as well as Cx43 expression levels, are modulated in models of intestinal inflammation. We hypothesize that TET-2 may demethylate genes involved in inflammation and tumorigenesis, such as Cx43, potentially contributing to intestinal inflammation and associated carcinogenesis.

Research on the influence of APOBEC family on the occurrence, diagnosis, and treatment of various tumors.

Apolipoprotein B mRNA-editing catalytic polypeptide (APOBEC) is a family of highly efficient cytidine deaminase enzymes. APOBECs have been proven to deaminate cytidine on single-stranded DNA or RNA. Inducing the deamination of cytosine on the target gene into uracil, which exerts a variety of physiological functions, plays an important role in innate immunity, adaptive immunity, and antiviral. As the research progresses, APOBECs have been confirmed to be highly expressed in a variety of tumors, causing abnormal mutations in host genes, leading to inactivation of tumor suppressor genes or activation of proto-oncogenes, and their role in tumor development and as diagnostic and treatment markers gradually be found. This article will review the mechanism of APOBECs and their impact on tumor occurrence, development, diagnosis, and treatment, and provide a theoretical basis for future tumor treatment.