Inhibition Of Tumor Suppressor Genes Research Articles

CARCINOGENICITY OF IONIZING RADIATION: A LITERATURE REVIEW

Relevance: According to WHO, malignant neoplasms rank second in population mortality structure due to a constantly increasing influence of technogenic factors that have a direct carcinogenic effect on the body and suppress defense mechanisms. Ionizing radiation plays a special role in the development of cancer. It is used in industry, agriculture, medicine, and scientific research as a diagnostic tool in modern healthcare and radiation therapy for cancer treatment. The consequences of radiation influence are not only the result of a direct effect on the body but also a delayed one through generations of parents and grandparents. According to the radiobiological hypothesis, any level of radiation, no matter how small, poses a risk of long-term consequences, including cancer, in exposed people and their descendants of the first two generations. That is, cancerous tumors are likely consequences of the influence of radiation. Despite various theories of the biological effect of low doses of ionizing radiation, most authors attach primary importance to DNA damage in the manifestation of genetic effects (the concept of non-threshold mutational action).
 The study aimed to highlight the role of ionizing radiation in tumorigenesis.
 Methods: Data from MEDLINE, Embase, Scopus, PubMed, Cochrane Central Register of Controlled Trials was analyzed to select and analyze relevant information over the past 10 years using the keywords: gamma irradiation, spontaneous oncogenesis, prevention of oncogenesis.
 Results: Radiation exposure may increase the risk of cancer development due to epigenetic changes leading to increased genomic instability (GI) and/or specific suppression of tumor suppressor genes. Changes in the TP53 gene network expression occur; the most significant genes as predictors of carcinogenesis are ST13, IER3, BRCAI, LRDD, and MRAS. Epigenetic changes also influence individual susceptibility to radiation-induced cancer. In addition to the mutagenic effects of ROS and AFN, there is also evidence that oxidative stress plays a fundamental role in epigenetic modifications.
 Conclusion: As a result of radiation exposure, damage occurs that causes genetic and epigenetic changes, leading to changes in the level of protein expression due to changes in the methylation of cytosine residues in DNA, modification of histones, and regulation of microRNA expression.

CARCINOGENICITY OF IONIZING RADIATION:
 A LITERATURE REVIEW

Relevance: According to WHO, malignant neoplasms rank second in population mortality structure due to a constantly increasing influence of
 technogenic factors that have a direct carcinogenic effect on the body and suppress defense mechanisms. Ionizing radiation plays a special role in
 the development of cancer. It is used in industry, agriculture, medicine, and scientific research as a diagnostic tool in modern healthcare and radiation therapy for cancer treatment. The consequences of radiation influence are not only the result of a direct effect on the body but also a delayed
 one through generations of parents and grandparents. According to the radiobiological hypothesis, any level of radiation, no matter how small,
 ОБЗОРЫ ЛИТЕРАТУРЫ
 Онкология и Радиология Казахстана, №4 (70) 2023 45
 poses a risk of long-term consequences, including cancer, in exposed people and their descendants of the first two generations. That is, cancerous
 tumors are likely consequences of the influence of radiation. Despite various theories of the biological effect of low doses of ionizing radiation,
 most authors attach primary importance to DNA damage in the manifestation of genetic effects (the concept of non-threshold mutational action).
 The study aimed to highlight the role of ionizing radiation in tumorigenesis.
 Methods: Data from MEDLINE, Embase, Scopus, PubMed, Cochrane Central Register of Controlled Trials was analyzed to select and analyze
 relevant information over the past 10 years using the keywords: gamma irradiation, spontaneous oncogenesis, prevention of oncogenesis,
 Results: Radiation exposure may increase the risk of cancer development due to epigenetic changes leading to increased genomic instability
 (GI) and/or specific suppression of tumor suppressor genes. Changes in the TP53 gene network expression occur; the most significant genes as
 predictors of carcinogenesis are ST13, IER3, BRCAI, LRDD, and MRAS. Epigenetic changes also influence individual susceptibility to radiation-induced cancer. In addition to the mutagenic effects of ROS and AFN, there is also evidence that oxidative stress plays a fundamental role in
 epigenetic modifications.
 Conclusion: As a result of radiation exposure, damage occurs that causes genetic and epigenetic changes, leading to changes in the level of
 protein expression due to changes in the methylation of cytosine residues in DNA, modification of histones, and regulation of microRNA expression.

Review on novel toxicological effects and personalized health hazard in workers exposed to low doses of benzene.

Several recent reports indicate health hazards for workers with below occupational limit exposure to benzene (BZ). Our updated review indicates that such low exposures induced traditional as well as novel toxicity/genotoxicity, e.g., increased mitochondria copy numbers, prolongation of telomeres, impairment of DNA damage repair response (DDRR), perturbations of expression in non-coding RNAs, and epigenetic changes. These abnormalities were associated with alterations of gene expression and cellular signaling pathways which affected hematopoietic cell development, expression of apoptosis, autophagy, etc. The overarching mechanisms for induction of health risk are impaired DDRR, inhibition of tumor suppressor genes, and changes of MDM2-p53 axis activities that contribute to perturbed control for cancer pathways. Evaluation of the unusual dose-responses to BZ exposure indicates cellular over-compensation and reprogramming to overcome toxicity and to promote survival. However, these abnormal mechanisms also promote the induction of leukemia. Further investigations indicate that the current exposure limits for workers to BZ are unacceptable. Based on these studies, the new exposure limits should be less than 0.07ppm rather than the current 1ppm. This review also emphasizes the need to conduct appropriate bioassays, and to provide more reliable decisions on health hazards as well as on exposure limits for workers. In addition, it is important to use scientific data to provide significantly improved risk assessment, i.e., shifting from a population- to an individual-based risk assessment.

Compound AC1Q3QWB upregulates CDKN1A and SOX17 by interrupting the HOTAIR—EZH2 interaction and enhances the efficacy of tazemetostat in endometrial cancer

Endometrial cancer (EC) is a common malignancy of the female reproductive system, with an escalating incidence. Recurrent/metastatic EC presents a poor prognosis. The interaction between the long non-coding RNA (lncRNA) HOTAIR and the polycomb repressive complex 2 (PRC2) induces abnormal silencing of tumor suppressor genes, exerting a pivotal role in tumorigenesis. We have previously discovered AC1Q3QWB (AQB), a small-molecule compound targeting HOTAIR-EZH2 interaction. In the present study, we unveil that AQB selectively hampers the interaction between HOTAIR and EZH2 within EC cells, thus reversing the epigenetic suppression of tumor suppressor genes. Furthermore, our findings demonstrate AQB's synergistic effect with tazemetostat (TAZ), an EZH2 inhibitor, significantly boosting the expression of CDKN1A and SOX17. This, in turn, induces cell cycle arrest and impedes EC cell proliferation, migration, and invasion. In vivo experiments further validate AQB's potential by enhancing TAZ's anti-tumor efficacy at lower doses. Our results advocate AQB, a recently discovered small-molecule inhibitor, as a promising agent against EC cells. When combined with TAZ, it offers a novel therapeutic strategy for EC treatment.

Mechanisms of Cancer-killing by Quercetin; A Review on Cell Death Mechanisms.

Cancer drug resistance has always been a serious issue regarding cancer research and therapy. Different cancers undergo different mutations, which may cause suppression of tumor suppressor genes, inhibition of apoptosis, stimulation of drug resistance mediators, and exhaustion of the immune system. The modulation of pro-death and survival-related mediators is an intriguing strategy for cancer therapy. Several nature-derived molecules, e.g., quercetin, have shown interesting properties against cancer through the modulation of apoptosis and autophagy mediators. Such molecules, e.g., quercetin, have been shown to stimulate apoptosis and other types of cell death pathways in cancers via the modulation of ROS metabolism. Quercetin may affect immune system function and trigger the expression and activity of tumor suppressor genes. Furthermore, it may suppress certain multidrug resistance mechanisms in cancer cells. This paper aims to review the effects of quercetin on various cell death mechanisms such as apoptosis, autophagic cell death, senescence, ferroptosis, and others.

Epigenetic Abnormalities in Chondrosarcoma.

In recent years, our understanding of the epigenetic mechanisms involved in tumor pathology has improved greatly. DNA and histone modifications, such as methylation, demethylation, acetylation, and deacetylation, can lead to the up-regulation of oncogenic genes, as well as the suppression of tumor suppressor genes. Gene expression can also be modified on a post-transcriptional level by microRNAs that contribute to carcinogenesis. The role of these modifications has been already described in many tumors, e.g., colorectal, breast, and prostate cancers. These mechanisms have also begun to be investigated in less common tumors, such as sarcomas. Chondrosarcoma (CS) is a rare type of tumor that belongs to sarcomas and is the second most common malignant bone tumor after osteosarcoma. Due to unknown pathogenesis and resistance to chemo- and radiotherapies of these tumors, there is a need to develop new potential therapies against CS. In this review, we summarize current knowledge on the influence of epigenetic alterations in the pathogenesis of CS by discussing potential candidates for future therapies. We also emphasize ongoing clinical trials that use drugs targeting epigenetic modifications in CS treatment.

Acromegaly and Colorectal Neoplasm: An Update.

Acromegaly is a systemic disease caused by excessive inappropriate secretion of GH and IGF-I levels, resulting in many systemic complications, including cardiovascular, respiratory, metabolic diseases, and a possible increased risk of some neoplasias. Although many studies on acromegaly and cancer remain uncertain, most data indicate that colorectal cancer (CRC) incidence is increased in this population. The exact mechanism involved in the role of GH-IGF-I axis in CRC has not been fully explained, yet it is associated with local and circulating effects of GH and IGF-I on the colon, promoting angiogenesis, cell proliferation, risk of mutation, inhibition of tumor-suppressor genes and apoptosis, thus facilitating a tumor microenvironment. Nevertheless, population-based studies present controversial findings on CRC incidence and mortality. All worldwide guidelines and expert consensuses agree with the need for colonoscopic screening and surveillance in acromegaly, although there is no consensus regarding the best period to do this. This review aims to analyze the existing data on CRC and acromegaly, exploring its pathophysiology, epidemiological studies and their limitations, colonic polyp characteristics, overall cancer and CRC incidences and mortality, risk factors for colon cancer pathophysiology, and recommendation guideline aspects.

PVT1 signals an androgen-dependent transcriptional repression program in prostate cancer cells and a set of the repressed genes predicts high-risk tumors

BackgroundAndrogen receptor (AR) and polycomb repressive complex 2 (PRC2) are known to co-occupy the loci of genes that are downregulated by androgen-stimulus. Long intergenic non-coding RNA (lincRNA) PVT1 is an overexpressed oncogene that is associated with AR in LNCaP prostate cancer cells, and with PRC2 in HeLa and many other types of cancer cells. The possible involvement of PVT1 in mediating androgen-induced gene expression downregulation in prostate cancer has not been explored.MethodsLNCaP cell line was used. Native RNA-binding-protein immunoprecipitation with anti-AR or anti-EZH2 was followed by RT-qPCR with primers for PVT1. Knockdown of PVT1 with specific GapmeRs (or a control with scrambled GapmeR) was followed by differentially expressed genes (DEGs) determination with Agilent microarrays and with Significance Analysis of Microarrays statistical test. DEGs were tested as a tumor risk classifier with a machine learning Random Forest algorithm run with gene expression data from all TCGA-PRAD (prostate adenocarcinoma) tumors as input. ChIP-qPCR was performed for histone marks at the promoter of one DEG.ResultsWe show that PVT1 knockdown in androgen-stimulated LNCaP cells caused statistically significant expression upregulation/downregulation of hundreds of genes. Interestingly, PVT1 knockdown caused upregulation of 160 genes that were repressed by androgen, including a significantly enriched set of tumor suppressor genes, and among them FAS, NOV/CCN3, BMF, HRK, IFIT2, AJUBA, DRAIC and TNFRSF21. A 121-gene-set (out of the 160) was able to correctly predict the classification of all 293 intermediate- and high-risk TCGA-PRAD tumors, with a mean ROC area under the curve AUC = 0.89 ± 0.04, pointing to the relevance of these genes in cancer aggressiveness. Native RIP-qPCR in LNCaP showed that PVT1 was associated with EZH2, a component of PRC2. PVT1 knockdown followed by ChIP-qPCR showed significant epigenetic remodeling at the enhancer and promoter regions of tumor suppressor gene NOV, one of the androgen-repressed genes that were upregulated upon PVT1 silencing.ConclusionsOverall, we provide first evidence that PVT1 was involved in signaling a genome-wide androgen-dependent transcriptional repressive program of tumor suppressor protein-coding genes in prostate cancer cells. Identification of transcriptional inhibition of tumor suppressor genes by PVT1 highlights the pathway to the investigation of mechanisms that lie behind the oncogenic role of PVT1 in cancer.DiTiwbuLh6zGF35UTdvYfAVideo

Перспективы диагностики эндометриоза с учетом роли генетических факторов в патогенезе заболевания

This paper discusses promising diagnostic modalities for endometriosis considering current ideas about the role of genetic factors in the pathogenesis of this condition. The hypotheses on pathogenesis and modern diagnostic approaches are addressed. The authors uncover the issues of genetic predisposition to endometriosis. The inhibition of tumor suppressor genes (CDKN2B, CDKN2 A, and ARF) and the activation of genes of early (embryonic) development of the female reproductive system (HOXA, HOXB, WNT4) lead to endometrial metaplasia. As a result, endometrial cells gain the ability to proliferate. The role of microRNA in the impaired regulation of the methylation of various genes associated with endometriosis is described. These factors specifically affect the course and clinical manifestations of endometriosis. Certain key proteins involved in the pathogenesis of endometriosis and whose synthesis is controlled by microRNA may be regarded as the diagnostic markers of endometriosis. Their in-depth study will identify novel therapeutic targets and promote the development of new non-hormonal treatment approaches to endometriosis. KEYWORDS: endometriosis, proliferation, endometrium, genes, polymorphism, diagnostic, epigenetics, microRNA. FOR CITATION: Ikhtiyarova G.A., Aslonova M.Zh., Kurbanova Z.Sh., Kalimatova D.M. Promising diagnostic tools for endometriosis given the pathogenic role of genetic factors. Russian Journal of Woman and Child Health. 2021;4(1):12–16. DOI: 10.32364/2618-8430- 2021-4-1-12-16.

Abstract PO-076: miR-181a initiates and perpetuates ovarian cancer transformation through inhibition of the tumor suppressors RB1 and stimulator of interferon genes (STING)

Abstract Genomic instability predisposes cells to malignant transformation, however the molecular mechanisms that allow for the propagation of cells with a high-degree of genomic instability remains unclear. Here we report that miR-181a is able to transform fallopian tube secretory epithelial cells (FTSECs, the precursor cell type for the majority of high-grade serous ovarian cancers) through the inhibition of RB1. Increased miR-181a expression simultaneously drives cell protective inhibition of the stimulator-of-interferon-genes (STING) in order to maintain a microenvironment conducive to the propagation of cells with a high-degree of genomic instability. We found that miR-181a inhibition of RB1 leads to profound nuclear defects, genomic instability, and nuclear rupture resulting in a persistence of genomic material in the cytoplasm. Normally, this persistence of genomic material in the cytoplasm induces a cell-intrinsic interferon response through STING to drive cell death. However, miR-181a directly downregulates STING and prevents interferon induction and cell death in the FTSECs. The most common mechanism by which oncogenic miRNAs promote tumorigenesis is through the direct inhibition of tumor suppressor genes. However, our studies highlight a new mechanism of oncomiR transformation through the combination of tumor suppressor gene and intrinsic interferon signaling inhibition that initiates and propagates tumor cell survival. Importantly, we found that miR-181a induction in ovarian patient tumors is tightly associated with decreased IFNγ response and downregulation of lymphocyte infiltration and leukocyte fraction. Our findings are the first to identify a miRNA, miR-181a, that can downregulate STING expression and suppress activation of cell-intrinsic innate immune signaling in precursor cells undergoing oncogenic transformation to create a survival advantage. Our studies support the notion that the induction of STING-mediated signaling in developing cancer cells could lead directly to cancer cell death, and that these effects can be inhibited by miR-181a. Given the recent interest in the development of STING agonists as a strategy to harness the immune system to treat cancer, this study introduces miR-181a as a novel patient selective biomarker as well as potential therapeutic target for HGSOC treatment. Citation Format: Matthew Knarr, Rita Avelar, Sreeja Sekhar, Lily Kwiatkowski, Michele Dziubinski, Jessica McAnulty, Stephanie Skala, Stefanie Avril, Ronny Drapkin, Analisa DiFeo. miR-181a initiates and perpetuates ovarian cancer transformation through inhibition of the tumor suppressors RB1 and stimulator of interferon genes (STING) [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-076.

LncRNA CRNDE facilitates epigenetic suppression of CELF2 and LATS2 to promote proliferation, migration and chemoresistance in hepatocellular carcinoma

Our study aimed to investigate the expression, functional significance, and related mechanism of long noncoding RNA CRNDE (colorectal neoplasia differentially expressed) in hepatocellular carcinoma (HCC) pathogenesis. The resulted revealed that CRNDE was significantly overexpressed in HCC tissues and cell lines, and was statistically correlated with poor clinical outcome. CRNDE knockdown markedly decreased HCC cell proliferation, migration, and chemoresistance. In addition, in vivo experiments confirmed the suppressive effect of CRNDE knockdown on HCC progression. Mechanically, CRNDE directly bound to EZH2 (enhancer of zeste homolog), SUZ12 (suppressor of zeste 12), SUV39H1, and mediated their inhibition of tumor suppressor genes, including CUGBP Elav-like family member 2 (CELF2) and large tumor suppressor 2 (LATS2). CELF2 exerted tumor suppressive effect in HCC and was involved in CRNDE-mediated oncogenic effect. In addition, the oncogenic effects of CRNDE on HCC proliferation, migration and tumorigenesis, as well as its inhibition of Hippo pathway were abolished by LATS2 overexpression. Together, our work demonstrated the importance of CRNDE in HCC progression and elucidated the underlying molecular mechanisms. These findings provided new insights into HCC pathogenesis and chemoresistance mediated by CRNDE.

MiR-216b/Smad3/BCL-2 Axis Is Involved in Smoking-Mediated Drug Resistance in Non-Small Cell Lung Cancer.

Epidemiologic studies have shown that vast majority of lung cancers (85–90%) are causally linked to tobacco smoking. Although much information has been gained about the effects of smoking on various signaling pathways, little is known about how deregulation of miRNAs leads to activation of oncogenes and inhibition of tumor suppressor genes in non-small cell lung cancer (NSCLC). Our previous study showed that smoking inhibits TGF-β-induced tumor suppressor functions through downregulation of Smad3 in lung cancer cells. In order to understand the upstream mechanism of downregulation of Smad3 by smoking, we performed miRNA microarray analyses after treating human lung adenocarcinoma A549 and immortalized peripheral lung epithelial HPL1A cells with cigarette smoke condensate (CSC). We identified miR-216b as being upregulated in CSC treated cells. MiR-216b overexpression decreases Smad3 protein expression by binding to its 3′-UTR, and attenuates transforming growth factor beta (TGF-β) signaling and target gene expression. MiR-216b increases B-cell lymphoma 2 (BCL-2) expression and promotes chemoresistance of NSCLC cells by decreasing apoptosis. Increased acetylation of histones H3 and H4 in miR-216b gene promoter plays a role in CSC induced miR-216b expression. Taken together, these results suggest that smoking-mediated upregulation of miR-216b increases NSCLC cell growth by downregulating Smad3 and inhibiting TGF-β-induced tumor suppressor function, and induces resistance to platinum-based therapy.

Abstract B02: miR-181a initiates and perpetuates oncogenic transformation through the regulation of innate immune signaling

Abstract Genomic instability predisposes cells to malignant transformation; however, the molecular mechanisms that allow for the propagation of cells with a high degree of genomic instability remain unclear. Here we report that miR-181a is able to transform fallopian tube secretory epithelial cells—the precursor cell type for the majority of high-grade serous ovarian cancers—through the inhibition of RB1 and simultaneously drives a cell-protective inhibition of the stimulator-of-interferon-genes (STING) in order to maintain a microenvironment conducive to the propagation of cells with a high-degree of genomic instability. We found that miR-181a inhibition of RB1 leads to profound nuclear defects, genomic instability, and nuclear rupture resulting in a persistence of genomic material in the cytoplasm. While normally, this persistence of genomic material in the cytoplasm induces interferon response through STING to drive cell death, miR-181a directly downregulates STING and prevents apoptosis. The most common mechanism by which oncogenic miRNAs promote tumorigenesis is through the direct inhibition of tumor suppressor genes; however, our studies highlight a new mechanism of oncomiR transformation through the combination of tumor suppressor gene inhibition and abrogation of immune surveillance that initiates and propagates tumor cell survival. Importantly, we found that miR-181a induction in human ovarian tumors is tightly associated with decreased IFNg response and downregulation of lymphocyte infiltration and leukocyte fraction. To date, DNA oncoviruses are the only known inhibitors of STING that allow for cellular transformation; thus, our findings are the first to identify a genetic factor, miR-181a, that can downregulate STING expression and impair signaling in cancer cells, creating a survival advantage. Our studies support the notion that the induction of STING-mediated signaling in cancer cells could lead directly to cancer cell death; however, these effects are abrogated by miR-181a. Given the recent interest in the development of STING agonists as a strategy to harness the immune system to treat cancer, this study introduces a novel patient-selective biomarker as well as potent therapeutic target for development of the most effective combination treatments. Citation Format: Matthew Knarr, Lily J. Kwiatkowski, Michele Dziubinski, Jessica McAnulty, Stephanie Skala, Stefanie Avril, Ronny Drapkin, Analisa DiFeo. miR-181a initiates and perpetuates oncogenic transformation through the regulation of innate immune signaling [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B02.

DNMT1 as a therapeutic target in pancreatic cancer: mechanisms and clinical implications.

Pancreatic cancer or pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating cancer types with a 5-year survival rate of only 9%. PDAC is one of the leading causes of cancer-related deaths in both genders. Epigenetic alterations may lead to the suppression of tumor suppressor genes, and DNA methylation is a predominant epigenetic modification. DNA methyltransferase 1 (DNMT1) is required for maintaining patterns of DNA methylation during cellular replication. Accumulating evidence has implicated the oncogenic roles of DNMT1 in various malignancies including PDACs. Herein, the expression profiles, oncogenic roles, regulators and inhibitors of DNMT1 in PDACs are presented and discussed. DNMT1 is overexpressed in PDAC cases compared with non-cancerous pancreatic ducts, and its expression gradually increases from pre-neoplastic lesions to PDACs. DNMT1 plays oncogenic roles in suppressing PDAC cell differentiation and in promoting their proliferation, migration and invasion, as well as in induction of the self-renewal capacity of PDAC cancer stem cells. These effects are achieved via promoter hypermethylation of tumor suppressor genes, including cyclin-dependent kinase inhibitors (e.g., p14, p15, p16, p21 and p27), suppressors of epithelial-mesenchymal transition (e.g., E-cadherin) and tumor suppressor miRNAs (e.g., miR-148a, miR-152 and miR-17-92 cluster). Pre-clinical investigations have shown the potency of novel non-nucleoside DNMT1 inhibitors against PDAC cells. Finally, phase I/II clinical trials of DNMT1 inhibitors (azacitidine, decitabine and guadecitabine) in PDAC patients are currently underway, where these inhibitors have the potential to sensitize PDACs to chemotherapy and immune checkpoint blockade therapy.

Intestinal microbiota and its association with colon cancer and red/processed meat consumption.

The human colon harbors a high number of microorganisms that were reported to play a crucial role in colorectal carcinogenesis. In the recent decade, molecular detection and metabolomic techniques have expanded our knowledge on the role of specific microbial species in promoting tumorigenesis. In this study, we reviewed the association between microbial dysbiosis and colorectal carcinoma (CRC). Various microbial species and their association with colorectal tumorigenesis and red/processed meat consumption have been reviewed. The literature demonstrated a significant abundance of Fusobacterium nucleatum, Streptococcus bovis/gallolyticus, Escherichia coli, and Bacteroides fragilis in patients with adenoma or adenocarcinoma compared to healthy individuals. The mechanisms in which each organism was postulated to promote colon carcinogenesis were collated and summarized in this review. These include the microorganisms' ability to adhere to colon cells; modulate the inhibition of tumor suppressor genes, the activations of oncogenes, and genotoxicity; and activate downstream targets responsible for angiogenesis. The role of these microorganisms in conjugation with meat components including N-nitroso compounds, heterocyclic amines, and heme was also evident in multiple studies. The outcome of this review supports the role of red meat consumption in modulating CRC progression and the possibility of gut microbiome influencing the relationship between CRC and diet. The study also demonstrates that microbiota analysis could potentially complement existing screening methods when detecting colonic lesions.

Enhanced E2F1 activity increases invasive and proliferative activity of breast cancer cells through non-coding RNA CDKN2B-AS1

Long non-coding RNAs have recently appeared as fundamental regulators of gene transcription in several biological processes, but only a few have known functional influences in the malignant transformation of breast cancer. CDKN2B-AS1 gene, also termed ANRIL, encoding a long non-coding RNA is located in the CDKN2B-CDKN2A gene cluster, loss of which is the most frequent alternation in several types of human malignancies. CDKN2B-AS1 is involved in the suppression of tumor suppressor genes (INK4a, ARF, and INK4b) and has been recognized as a direct target of E2F1. However, the roles of E2F1–CDKN2B-AS1 interaction in breast cancer have remained muchly mysterious. In this particular study, we reveal that both CDKN2B and CDKN2B-AS1 genes were differentially expressed in breast cancer cells in contrast to breast epithelial cells. Ectopic expression of E2F1 activated CDKN2B-AS1 but not CDKN2B expression. Lastly, overexpression of E2F1 improved the colony formation and migratory capacities of breast cancer cells. These results suggest that enhanced E2F1 activity increased invasive and proliferative activity of breast cancer but not breast epithelial cells possibly through up-regulating CDKN2B-AS1 transcript.

Novel approach to therapeutic targeting of castration-resistant prostate cancer

Development of resistance to anti-androgen therapy limits the usefulness of second-generation androgen receptor (AR) antagonists including enzalutamide and abiraterone in castration resistant prostate cancer (CRPC) patients. Recent genomic studies reveal that AR-regulated genes contribute to CRPC emergence. Several reasons for the development of resistance towards anti-androgens have been hypothesized, including intracellular testosterone production, androgen overexpression, somatic mutations of AR resulting in a gain of function, constitutive activation of AR splice variants, imbalance in AR regulators, and bypass of AR in CRPC progression. Recent findings suggest that epigenetic alterations are involved in the deregulation of AR signaling. Overexpression of enhancer of zeste homolog 2 (EZH2), the enzymatic member of the polycomb repressor complex PRC2, has emerged as a key activator of AR in CRPC. Studies indicate that overabundance of EZH2 in localized prostate tumors increases the risk of biochemical recurrence after surgery, as it activates AR by enhancing methylation, resulting in the suppression of tumor suppressor genes and activation of oncogenes. This apparent association between EZH2 and AR in activating target genes by cooperative recruitment might play a critical role in the emergence of CRPC. Our hypothesis is that combination treatment targeting EZH2 and AR may be a novel efficacious therapeutic regime for the treatment of castrate resistant prostate cancer, and we propose to investigate this possibility.

Current Immune-Related Molecular Approach in Combating Nasopharyngeal Cancer.

Nasopharyngeal cancer is a cancer closely related to Epstein-Barr virus (EBV) infection. EBV protein has been shown to be related to various oncogenic development. Suppression of tumor suppressor genes, upregulating molecules to prevent immune attack, downregulating pro-apoptotic proteins, and stimulating local immune suppressive environment are among some roles that EBV proteins can exert on host cells. All those factors combined together with underlying genetic susceptibility of host cells further increase the chance of nasopharyngeal cancer development. Approach targeting those carcinogenesis pathways has been tested with marginal benefit. A newer approach boosting immune cells to increase recognition of tumor antigen and promoting cytotoxic T cell attack has shown promising clinical benefit. Further combination of those immunotherapies with other modality, in particular radiotherapy, has resulted in amplification of cancer killing.

Biochemical overview of the recent findings on the correlation between viral hepatitis and its related hepatocellular carcinoma

Abstract As one of the most common primary liver cancers, hepatocellular carcinoma (HCC) usually occurs in the presence of inflammation. Compared to other risk factors such as alcohol abuse, aflatoxin, and obesity, virus-induced hepatitis can be effectively prevented by vaccines. For the past several decades, HCC has been believed to be closely related to viral infections although no comprehensive mechanism was established regarding the contribution of viral hepatitis toward HCC. Recent studies have shown that viral infection plays multiple roles in the process of carcinogenesis by causing an increase in genomic instability, cancer-promoting genetic mutations, signal pathway interruption, and tumor suppressor gene inhibition. Sorafenib has become a novel option for HCC patients, especially those who are in advanced disease stage for which conventional treatment methods are not recommended. Future studies should focus more on novel targeted drugs which can be adopted as alternatives to sorafenib or as second-line drugs after the failure of sorafenib

Prevention of pancreatic acinar cell carcinoma by Roux-en-Y Gastric Bypass Surgery

Roux-en-Y Gastric Bypass Surgery (RYGB) prevents the occurrence of pancreatic cell acinar carcinoma (ACC) in male and female Ngn3-Tsc1−/− mice. Ngn3 directed Cre deletion of Tsc1 gene induced the development of pancreatic ACC. The transgenic mice with sham surgery demonstrated a cancer incidence of 96.7 ± 3.35% and survival rate of 67.0 ± 1.4% at the age of 300 days. Metastasis to liver and kidney was observed in 69.7 ± 9.7% and 44.3 ± 8.01% of these animals, respectively. All animals with RYGB performed at the age of 16 weeks survived free of pancreatic ACC up to the age of 300 days. RYGB significantly attenuated the activation of mTORC1 signaling and inhibition of tumor suppressor genes: p21, p27, and p53 in pancreatic ACC. Our studies demonstrate that bariatric surgery may limit the occurrence and growth of pancreatic ACC through the suppression of mTORC1 signaling in pancreas. RYGB shows promise for intervention of both metabolic dysfunction and organ cancer.