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Cancer progression involves multiple genetic and epigenetic events, which involve gain-of-functions of oncogenes and loss-of-functions of tumor suppressor genes. Classical tumor suppressor genes are recessive in nature, anti-proliferative, and frequently found inactivated or mutated in cancers. However, extensive research over the last few years have elucidated that certain tumor suppressor genes do not conform to these standard definitions and might act as "double agents", playing contrasting roles in vivo in cells, where either due to haploinsufficiency, epigenetic hypermethylation, or due to involvement with multiple genetic and oncogenic events, they play an enhanced proliferative role and facilitate the pathogenesis of cancer. This review discusses and highlights some of these exceptions; the genetic events, cellular contexts, and mechanisms by which four important tumor suppressors-pRb, PTEN, FOXO, and PML display their oncogenic potentials and pro-survival traits in cancer.

The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family of cytoplasmic adaptor proteins regulate the signal transduction pathways of a variety of receptors, including the TNF-R superfamily, Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and cytokine receptors. TRAF-dependent signaling pathways participate in a diverse array of important cellular processes, including the survival, proliferation, differentiation, and activation of different cell types. Many of these TRAF-dependent signaling pathways have been implicated in cancer pathogenesis. Here we analyze the current evidence of genetic alterations of TRAF molecules available from The Cancer Genome Atlas (TCGA) and the Catalog of Somatic Mutations in Cancer (COSMIC) as well as the published literature, including copy number variations and mutation landscape of TRAFs in various human cancers. Such analyses reveal that both gain- and loss-of-function genetic alterations of different TRAF proteins are commonly present in a number of human cancers. These include pancreatic cancer, meningioma, breast cancer, prostate cancer, lung cancer, liver cancer, head and neck cancer, stomach cancer, colon cancer, bladder cancer, uterine cancer, melanoma, sarcoma, and B cell malignancies, among others. Furthermore, we summarize the key in vivo and in vitro evidence that demonstrates the causal roles of genetic alterations of TRAF proteins in tumorigenesis within different cell types and organs. Taken together, the information presented in this review provides a rationale for the development of therapeutic strategies to manipulate TRAF proteins or TRAF-dependent signaling pathways in different human cancers by precision medicine.

Planarians have been long known for their regenerative ability, which hinges on pluripotency. Recently, however, the planarian model has been successfully established for routine toxicological screens aimed to assess overproliferation, mutagenicity and tumorigenesis. In this study, we focused on planarian tumor suppressor genes (TSGs) and their role during chemically induced carcinogenic stress in Schmidtea mediterranea Combining in silico and proteomic screens with exposure to human carcinogen type 1A agent cadmium (Cd), we showed that many TSGs have a function in stem cells and that, in general, exposure to Cd accelerated the onset and increased the severity of the observed phenotype. This suggested that the interaction between environmental and genetic factors plays an important role in tumor development in S. mediterranea Therefore, we further focused on the synergistic effects of Cd exposure and p53 knockdown (KD) at the cellular and molecular levels. Cd also produced a specific proteomic landscape in homeostatic animals, with 172 proteins differentially expressed, 43 of which were downregulated. Several of these proteins have tumor suppressor function in human and other animals, namely Wilms Tumor 1 Associated Protein (WT1), Heat Shock Protein 90 (HSP90), Glioma Pathogenesis-Related Protein 1 (GLIPR1) and Matrix Metalloproteinase B (Smed-MMPB). Both Glipr1 and MmpB KD produced large outgrowths, epidermal lesions and epidermal blisters. The epidermal blisters that formed as a consequence of Smed-MmpB KD were populated by smedwi1 + cells, many of which were actively proliferating, while large outgrowths contained ectopically differentiated structures, such as photoreceptors, nervous tissue and a small pharynx. In conclusion, Smed-MmpB is a planarian TSG that prevents stem cell proliferation and differentiation outside the proper milieu ., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Malignant mesothelioma (MM), a rare and severe cancer, mainly caused as a result of past-asbestos exposure, is presently a public health concern. Current molecular studies aim to improve the outcome of the disease, providing efficient therapies based on the principles of precision medicine. To model the molecular profile of human malignant mesothelioma, animal models have been developed in rodents, wild type animals and genetically engineered mice harbouring mutations in tumour suppressor genes, especially selecting genes known to be inactivated in human malignant mesothelioma. Animals were either exposed or not exposed to asbestos or to other carcinogenic fibres, to understand the mechanism of action of fibres at the molecular level, and the role of the selected genes in mesothelial carcinogenesis. The aim of the manuscript was to compare mesothelioma models to human malignant mesothelioma and to specify the clue genes playing a role in mesothelial carcinogenesis. Collectively, MM models recapitulate the clinical features of human MM. At least two altered genes are needed to induce malignant mesothelioma in mice. Two pathways regulated by Cdkn2a and Trp53 seem independent key players in mesothelial carcinogenesis. Other genes and pathways appear as bona fide modulators of the neoplastic transformation.

Hepatocellular carcinoma (HCC) is one of the most common and aggressive cancers worldwide. HCC is the fifth common malignancy in the world and the second leading cause of cancer death in Asia. Long non-coding RNAs (lncRNAs) are RNAs with a length greater than 200 nucleotides that do not encode proteins. lncRNAs can regulate gene expression and protein synthesis in several ways by interacting with DNA, RNA and proteins in a sequence specific manner. They could regulate cellular and developmental processes through either gene inhibition or gene activation. Many studies have shown that dysregulation of lncRNAs is related to many human diseases such as cardiovascular diseases, genetic disorders, neurological diseases, immune mediated disorders and cancers. However, the study of lncRNAs is challenging as they are poorly conserved between species, their expression levels aren't as high as that of mRNAs and have great interpatient variations. The study of lncRNAs expression in cancers have been a breakthrough as it unveils potential biomarkers and drug targets for cancer therapy and helps understand the mechanism of pathogenesis. This review discusses many long non-coding RNAs and their contribution in HCC, their role in development, metastasis, and prognosis of HCC and how to regulate and target these lncRNAs as a therapeutic tool in HCC treatment in the future., Competing Interests: Conflict-of-interest statement: The authors have no conflict of interest to report.

Lysosomal-associated protein multispanning transmembrane 5 (LAPTM5) is a membrane protein that localizes to intracellular vesicles. It has been previously demonstrated that LAPTM5 expression level is decreased in neuroblastoma (NB) cells, and excessive accumulation of LAPTM5 was shown to induce lysosomal cell death in these cells. However, the pathological expression and role of LAPTM5 in other types of human cancers are largely unknown. Here, we found that LAPTM5 mRNA level is frequently decreased in various cancer cell lines, and its low expression in patients with esophageal squamous cell carcinoma (ESCC) and non-small cell lung cancer (NSCLC) was significantly correlated with poor prognosis. Furthermore, we showed that overexpression of LAPTM5 in several cancer cells induces lysosomal cell death due to lysosomal destabilization, indicated by leakage of lysosomal cathepsin D into the cytosol as well as impairment of autophagy. These findings suggest that the inactivation of LAPTM5 may contribute to tumorigenesis in a subset of human cancers., Competing Interests: There are no conflicts of interest to disclose.

More than 1.5 million people were diagnosed with skin cancer in 2012 in Germany-of which 318,000 were malignant melanoma. The number of malignant skin tumours has increased by 60% since 2005. Epithelial skin cancers are even more common. Since 2012, 1.3 million diagnoses have been documented. This incidence represents an increase of 79% within 7 years. The number of skin cancer patients treated in German hospitals has also increased. In 2014, 99,613 patients were treated as inpatients with the diagnosis of skin cancer; in 2000 there were 57,147 patients. This was the largest growth rate among all cancer treatments in hospitalised patients. The continuously changing age pyramid leads to an expected further growth of the incidence of skin tumours. In parallel the development of molecular knowledge in tumorigenesis is also rapid. A series of cell-specific mutations have been described in recent years for various skin tumours. Mutations are found mainly in genes engaging their translation products at key positions in regulatory cell metabolism or cell division. These include oncogenes, which have greatly increased activity due to targeted mutations or tumor suppressor genes and act under physiological conditions as negative regulators that are inactivated by mutations. These findings have led to the development of a series of new promising compounds for the treatment of skin tumours.

Cancer has been recognized for thousands of years. Egyptians believed that cancer occurred at the will of the gods. Hippocrates believed human disease resulted from an imbalance of the four humors: blood, phlegm, yellow bile, and black bile with cancer being caused by excess black bile. The lymph theory of cancer replaced the humoral theory and the blastema theory replaced the lymph theory. Rudolph Virchow was the first to recognize that cancer cells like all cells came from other cells and believed chronic irritation caused cancer. At the same time there was a belief that trauma caused cancer, though it never evolved after many experiments inducing trauma. The birth of virology occurred in 1892 when Dimitri Ivanofsky demonstrated that diseased tobacco plants remained infective after filtering their sap through a filter that trapped bacteria. Martinus Beijerinck would call the tiny infective agent a virus and both Dimitri Ivanofsky and Marinus Beijerinck would become the fathers of virology. Not to long thereafter, Payton Rous founded the field of tumor virology in 1911 with his discovery of a transmittable sarcoma of chickens by what would come to be called Rous sarcoma virus or RSV for short. The first identified human tumor virus was the Epstein-Barr virus (EBV), named after Tony Epstein and Yvonne Barr who visualized the virus particles in Burkitt's lymphoma cells by electron microscopy in 1965. Since that time, many viruses have been associated with carcinogenesis including the most studied, human papilloma virus associated with cervical carcinoma, many other anogenital carcinomas, and oropharyngeal carcinoma. The World Health Organization currently estimates that approximately 22% of worldwide cancers are attributable to infectious etiologies, of which viral etiologies is estimated at 15-20%. The field of tumor virology/viral carcinogenesis has not only identified viruses as etiologic agents of human cancers, but has also given molecular insights to all human cancers including the oncogene activation and tumor suppressor gene inactivation., (© 2016 Elsevier Inc. All rights reserved.)

Loss of 3p11-p14 is a frequent event in epithelial cancer and a candidate prognostic biomarker in cervical cancer. In addition to loss, promoter methylation can participate in gene silencing and promote tumor aggressiveness. We have performed a complete mapping of promoter methylation at 3p11-p14 in two independent cohorts of cervical cancer patients (n = 149, n = 121), using Illumina 450K methylation arrays. The aim was to investigate whether hyperm-ethylation was frequent and could contribute to gene silencing and disease aggressiveness either alone or combined with loss. By comparing the methylation level of individual CpG sites with corresponding data of normal cervical tissue, 26 out of 41 genes were found to be hypermethylated in both cohorts. The frequency of patients with hypermethylation of these genes was found to be higher at tumor stages of 3 and 4 than in stage 1 tumors. Seventeen of the 26 genes were transcriptionally downregulated in cancer compared to normal tissue, whereof 6 genes showed a significant correlation between methylation and expression. Integrated analysis of methylation, gene dosage, and expression of the 26 hypermethylated genes identified 3 regulation patterns encompassing 8 hypermethylated genes; a methylation driven pattern (C3orf14, GPR27, ZNF717), a gene dosage driven pattern (THOC7, PSMD6), and a combined methylation and gene dosage driven pattern (FHIT, ADAMTS9, LRIG1). In survival analysis, patients with both hypermethylation and loss of LRIG1 had a worse outcome compared to those harboring only hypermethylation or none of the events. C3orf14 emerged as a novel methylation regulated suppressor gene, for which knockdown was found to promote invasive growth in human papilloma virus (HPV)-transformed keratinocytes. In conclusion, hypermethylation at 3p11-p14 is common in cervical cancer and may exert a selection pressure during carcinogenesis alone or combined with loss. Information on both events could lead to improved prognostic markers.

Oxidative stress is a defense mechanism that occurs when there is an imbalance between the production of reactive metabolites and free radicals and the antioxidants’ ability to eliminate them. Reactive metabolites are free radicals referred to as oxidants or reactive oxygen species (ROS). Cells are harmed by this imbalance, which may influence the entire body. When the intra- and extracellular environmental circumstances in cells change, ROS is essential for stimulating the corresponding signaling pathways. All aspects of carcinogenesis, including prevention and treatment, are tightly associated with reactive species, particularly ROS. Numerous tumor suppressor genes and proto-oncogenes are deregulated by ROS, which also modify several cellular signaling pathways. However, most chemotherapy drugs and even radiation therapy dramatically raise the ROS concentrations in the tumor microenvironment. Antioxidants cause programmed cell death, which is used in cancer treatment; yet people receiving chemotherapy benefit from antioxidants. Nevertheless, the exact processes underlying this anticancer action remain unclear. Many studies carried out in laboratories and on animals revealed high concentrations of exogenic antioxidants, that inhibit the forms of free radical injury linked with the formation of cancer. There haven’t been many human clinical trials looking into the potential of dietary supplementation to reduce the risk of cancer development or death. Since there have been studies on the advantages and downsides of antioxidants in the treatment of cancer, several considerations need to be deemed before administering antioxidant supplements. In conclusion, little is known about the mechanism underlying antioxidant effect in cancer treatment. [ABSTRACT FROM AUTHOR]

Let-7b and miRNA-96 are among the dysregulated microRNAs in various diseases. Selected seventy-five male rats were divided into five equal treatment groups and were given 4-nitroquinoline 1-oxide (4-NQO) by drinking water (50 ppm) for five different drenching periods. To each treatment group, a control group of five males was also assigned. The oral pathological changes were microscopically evaluated thereafter. Histopathological changes indicating dysplasia or frank carcinoma were observed in the fifth treatment group only. Let-7b and miRNA-96 expressions in the tongue tissue and serum were quantified using quantitative reverse transcription PCR (qRT-PCR). The fifth treatment group only showed signs of severe and well differentiated squamous cell carcinoma in percentages of 40% and 26.7%, respectively. Let-7b expression appeared to be statistically non-significantly different when up and downregulation were compared in tissue and serum samples (p=.3; p=.08). For miRNA-96, it seemed that no statistically significant difference (p=.08) was attained when tissue samples were studied, while the difference was statistically significant (p=.04) when serum samples were considered. Let-7b can be considered a good biomarker for oral squamous cell carcinoma (OSCC) in tissue and body fluid as well, while miRNA-96 demonstrated a controversial result as far as the tissue type was considered and, thus, can play the role of an oncogene (OG) or a tumor suppressor gene (TS). [ABSTRACT FROM AUTHOR]

Purpose: HtrA1, HtrA2, HtrA3 and HtrA4 appear to be involved in the development of pathologies such as cancer. This systematic review reports the results of a literature search performed to compare the expression of HtrA family genes and proteins in cancer versus non-cancer tissues and cell lines, assess relationships between HtrA expression and cancer clinical features in cancer, and analyse the molecular mechanism, by which HtrA family affects cancer. Methods: The literature search was conducted according to the PRISMA statement among four databases (PubMed, Web of Science, Embase and Scopus). Results: A total of 38 articles met the inclusion criteria and involved the expression of HtrA family members and concerned the effect of HtrA expression on cancer and metastasis development or on the factor that influences it. Additionally, 31 reports were retrieved manually. Most articles highlighted that HtrA1 and HtrA3 exhibited tumour suppressor activity, while HtrA2 was associated with tumour growth and metastasis. There were too few studies to clearly define the role of the HtrA4 protease in tumours. Conclusion: Although the expression of serine proteases of the HtrA family was dependent on tumour type, stage and the presence of metastases, most articles indicated that HtrA1 and HtrA3 expression in tumours was downregulated compared with healthy tissue or cell lines. The expression of HtrA2 was completely study dependent. The limited number of studies on HtrA4 expression made it impossible to draw conclusions about differences in expression between healthy and tumour tissue. The conclusions drawn from the study suggest that HtrA1 and HtrA3 act as tumour suppressors. [ABSTRACT FROM AUTHOR]

Viral integration within the host genome plays a pivotal role in carcinogenesis. Various disruptive mechanisms are involved, leading to genomic instability, mutations, and DNA damage. With next-generation sequencing (NGS), we can now precisely identify viral and host genomic breakpoints and chimeric sequences, which are useful for integration site analysis. In this study, we evaluated a commercial hybrid capture NGS panel specifically designed for detecting three key viruses: HPV, HBV, and HIV-1. We also tested workflows for Viral Hybrid Capture (VHC) and Viral Integration Site (VIS) analysis, leveraging customized viral databases in CLC Microbial Genomics. By analyzing sequenced data from virally infected cancer cell lines (including SiHa, HeLa, CaSki, C-33A, DoTc2, 2A3, SCC154 for HPV; 3B2, SNU-182 for HBV; and ACH-2 for HIV-1), we precisely pinpointed viral integration sites. The workflow also highlighted disrupted and neighboring human genes that may play a crucial role in tumor development. Our results included informative virus–host read mappings, genomic breakpoints, and integration circular plots. These visual representations enhance our understanding of the integration process. In conclusion, our seamless end-to-end workflow bridges the gap in understanding viral contributions to cancer development, paving the way for improved diagnostics and treatment strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Endometrial cancer has emerged as the main gynecological malignant tumour in developed countries. The development of molecular techniques allows the precise profiling of each case. This affects the selection of a therapy and the patient's prognosis. Long non-coding RNAs, which influence tumour development, are a novelty in endometrial cancer. They can both stimulate and inhibit the progression of the disease. Their number is constantly growing, and the mechanisms of action are not fully discovered. Some of them may become targets for new molecular therapies in the future. Endometrial cancer is one of the most common malignant tumours in women. The development of this tumour is associated with several genetic disorders, many of which are still unknown. One type of RNA molecules currently being intensively studied in many types of cancer are long non-coding RNAs (lncRNAs). LncRNA-coding genes occupy a large fraction of the human genome. LncRNAs regulate many aspects of cell development, metabolism, and other physiological processes. Diverse types of lncRNA can function as a tumour suppressor or an oncogene that can alter migration, invasion, cell proliferation, apoptosis, and immune system response. Recent studies suggest that selected lncRNAs are important in an endometrial cancer course. Our article describes over 70 lncRNAs involved in the development of endometrial cancer, which were studied via in vivo and in vitro research. It was proved that lncRNAs could both promote and inhibit the development of endometrial cancer. In the future, lncRNAs may become an important therapeutic target. The aim of this study is to review the role of lncRNAs in the development of carcinoma of uterine body. [ABSTRACT FROM AUTHOR]

Simple Summary: The current theories of carcinogenesis are the result of a long succession of thoughts and beliefs since antiquity. From the humor theory that interpreted cancer as an excess of black bile to the three notions of initiation, promotion, and progression and the most recent definitions of hallmarks of cancer, we reviewed and discussed each of these steps to better understand the state of the art of carcinogenesis. While cancer is one of the most documented diseases, how normal cells become cancerous is still debated. To address this question, in the first part of this review, we investigated the long succession of theories of carcinogenesis since antiquity. Initiated by Hippocrates, Aristotle, and Galen, the humoral theory interpreted cancer as an excess of acid, the black bile. The discovery of the circulation of blood by Harvey in 1628 destroyed the basis of the humoral theory but revived the spontaneous generation hypothesis which was also promoted by Aristotle. In 1859, the theory of microbes promoted by Pasteur demonstrated the irrelevance of this last theory and contributed to the emergence of the germ cancer theory, opposed to the cellular theory of cancer, in which cancer was supposed to be caused by microbes or transformed cells, respectively. These theories were progressively refined by the notions of initiation, promotion, and progression thanks to advances in mutagenesis and cellular proliferation. In the second part of this review, recent discoveries and paradigms in carcinogenesis, notably the role of the protein ATM, a major actor of the stress response involved in both mutagenesis and cellular proliferation, were discussed to better understand the current state of the art of carcinogenesis. [ABSTRACT FROM AUTHOR]

The src homology 2 domain-containing inositol 5-phosphatases SHIP1 and SHIP2 are two proteins involved in intracellular signaling pathways and have been linked to the pathogenesis of several diseases. Both protein paralogs are well known for their involvement in the formation of various kinds of cancer. SHIP1, which is expressed predominantly in hematopoietic cells, has been implicated as a tumor suppressor in leukemogenesis especially in myeloid leukemia, whereas SHIP2, which is expressed ubiquitously, has been implicated as an oncogene in a wider variety of cancer types and is suggested to be involved in the process of metastasis of carcinoma cells. However, there are numerous other diseases, such as inflammatory diseases as well as allergic responses, Alzheimer's disease, and stroke, in which SHIP1 can play a role. Moreover, SHIP2 overexpression was shown to correlate with opsismodysplasia and Alzheimer's disease, as well as metabolic diseases. The SHIP1-inhibitor 3-α-aminocholestane (3AC), and SHIP1-activators, such as AQX-435 and AQX-1125, and SHIP2-inhibitors, such as K161 and AS1949490, have been developed and partly tested in clinical trials, which indicates the importance of the SHIP-paralogs as possible targets in the therapy of those diseases. The aim of this article is to provide an overview of the current knowledge about the involvement of SHIP proteins in the pathogenesis of cancer and other human diseases and to create awareness that SHIP1 and SHIP2 are more than just tumor suppressors and oncogenes. [ABSTRACT FROM AUTHOR]

Humans have generally evolved some adaptations to protect against UV and different levels of background ionizing radiation. Similarly, elephants and whales have evolved adaptations to protect against cancer, such as multiple copies of the tumor suppressor gene p53, due to their large size and long lifespan. The difference in cancer protection strategies between humans and elephants/whales depends on genetics, lifestyle, environmental exposures, and evolutionary pressures. In this paper, we discuss how the differences in evolutionary adaptations between humans and elephants could explain why elephants have evolved a protective mechanism against cancer, whereas humans have not. Humans living in regions with high levels of background radiation, e.g. in Ramsar, Iran where exposure rates exceed those on the surface of Mars, seem to have developed some kind of protection against the ionizing radiation. However, humans in general have not developed cancer-fighting adaptations, so they instead rely on medical technologies and interventions. The difference in cancer protection strategies between humans and elephants/whales depends on genetics, lifestyle, environmental exposures, and evolutionary pressures. In this paper, we discuss how the differences in evolutionary adaptations between humans and elephants could explain why elephants have evolved a protective mechanism against cancer, whereas humans have not. Studying elephant adaptations may provide insights into new cancer prevention and treatment strategies for humans, but further research is required to fully understand the evolutionary disparities. [ABSTRACT FROM AUTHOR]

Mutated genes may lead to cancer development in numerous tissues. While more than 600 cancer-causing genes are known today, some of the most widespread mutations are connected to the RAS gene; RAS mutations are found in approximately 25% of all human tumors. Specifically, KRAS mutations are involved in the three most lethal cancers in the U.S., namely pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, and lung adenocarcinoma. These cancers are among the most difficult to treat, and they are frequently excluded from chemotherapeutic attacks as hopeless cases. The mutated KRAS proteins have specific three-dimensional conformations, which perturb functional interaction with the GAP protein on the GAP–RAS complex surface, leading to a signaling cascade and uncontrolled cell growth. Here, we describe a gluing docking method for finding small molecules that bind to both the GAP and the mutated KRAS molecules. These small molecules glue together the GAP and the mutated KRAS molecules and may serve as new cancer drugs for the most lethal, most difficult-to-treat, carcinomas. As a proof of concept, we identify two new, drug-like small molecules with the new method; these compounds specifically inhibit the growth of the PANC-1 cell line with KRAS mutation G12D in vitro and in vivo. Importantly, the two new compounds show significantly lower IC50 and higher specificity against the G12D KRAS mutant human pancreatic cancer cell line PANC-1, as compared to the recently described selective G12D KRAS inhibitor MRTX-1133. [ABSTRACT FROM AUTHOR]

methyltransferase gene (DNA) methylation is a key process in epigenetic modification. This transformation leads to genomic instability that creates an impact on gene expression. DNA methylation is also involved in several mutations of tumour suppressor genes (TSGs) or proto‐oncogenes, resulting in cancer (hypermethylation and hypomethylation). Hypermethylation of promoter segments in TSGs causes transcriptional silencing, whereas hypomethylation of regulatory sequence activates proto‐oncogenes and retrotransposons. DNA methylation regulated by DNA methyltransferases is one of the essential epigenetic mechanisms that controls the cell cycle, cell proliferation, differentiation, apoptosis and transformation in eukaryotes, leading to genetic instability of tumour cells. Recent scientific research has highlighted that DNA methylation is a vital cancer biomarker source of several parts of body fluids that allow primary‐stage cancer cell detection during clinical screening. Nowadays, epigenetic biomarkers have been introduced as a decision maker with the potential to improve cancer prognosis. DNA methylation profiling helps to determine cancer at the deep genetic level, and create high impactful cancer screening approach in the future. [ABSTRACT FROM AUTHOR]

In carcinogenesis, tumor cells acquire certain cancer hallmarks based on the changes at various molecular levels. This review discusses abnormalities in cancer cells at the genetic and epigenetic levels. Genetic alterations are considered in the example of seven cancers, including lung, breast, prostate, colorectal, renal, cervical, and ovary cancers. Genetic changes disrupt the functioning of both oncogenes and tumor suppressor genes and occur as deletions, amplifications, chromosomal aberrations and chromosomal loci, thousands of somatic mutations and the appearance of oncogenic fusion transcripts etc. Epigenetic aberrations are also multifaceted. These include hypermethylation and hypomethylation of gene promoters, histone modifications, changes in non-coding RNA expression profiles etc. Genetic and epigenetic disorders are tumor-specific and common for many cancer types. The development of modern large-scale methods for detecting genetic and epigenetic alterations makes it possible to detect simultaneously these aberrations and molecular profiles of different cancer types. Many of these alterations could be the targets for cancer diagnosis and the development of effective treatments. [ABSTRACT FROM AUTHOR]

Macroautophagy/autophagy acts as an anti-tumor mechanism in early cancer stages but promotes growth in established tumors. Similarly, miRNAs function as tumor suppressors or oncogenes, depending on their target genes. This reciprocal relationship between autophagy and miRNAs is a well-studied area, primarily focused on how miRNAs regulate autophagy-related genes. Our research provides innovative insights into how autophagy selectively controls miRNAs. For instance, MIR224 is preferentially degraded within autophagosomes, leading to the upregulation of SMAD4 and suppressing hepatocellular carcinoma (HCC) tumorigenesis. Conversely, autophagy positively regulates MIR449A by degrading EP300/p300 to activate FOXO1 and facilitate MIR449A transcription in colorectal cancer (CRC). In conclusion, our findings reveal the role of autophagy in maintaining the cellular balance of two miRNAs to mitigate tumorigenic stresses and highlight that autophagy-regulated miRNA profiles may serve as diagnostic and therapeutic markers for cancer development. [ABSTRACT FROM AUTHOR]

Signal transducers and activators of transcription or STAT are proteins that consist of various transcription factors that are responsible for activating genes regarding cell proliferation, differentiation, and apoptosis. They commonly activate several cytokine, growth, or hormone factors via the JAK-STAT signaling pathway by tyrosine phosphorylation which are responsible for giving rise to numerous immune responses. Mutations within the Janus-Kinases (JAKs) or the STATs can set off the commencement of various malfunctions of the immune system of the body; carcinogenesis being an inevitable outcome. STATs are known to act as both oncogenes and tumor suppressor genes which makes it a hot topic of investigation. Various STATs related mechanisms are currently being investigated to analyze its potential of serving as a therapeutic base for numerous immune diseases and cancer; a deeper understanding of the molecular mechanisms involved in the signaling pathways can contribute to the same. This review will throw light upon each STAT member in causing cancer malignancies by affecting subsequent signaling pathways and its genetic and epigenetic associations as well as various inhibitors that could be used to target these pathways thereby devising new treatment options. The review will also focus upon the therapeutic advances made in cancers that most commonly affect people and discuss how STAT genes are identified as prognostic markers. [ABSTRACT FROM AUTHOR]

Simple Summary: Glutaminase GLS2 is an enzyme that metabolizes glutamine, one of the main sources of energy and building blocks in tumor cells. In some types of cancer, this enzyme is overexpressed and fuels malignancy; however, there are some types of cancer in which GLS2 plays a role opposite to that of a tumor suppressor. The mechanisms behind the GLS2-mediated inhibition of tumorigenesis are complex and context-dependent. In this review, we report both the pro- and anti-tumorigenic properties of this protein. In rapidly proliferating cancer cells, glutamine is a major source of energy and building blocks. Increased glutamine uptake and enhanced glutaminolysis are key metabolic features of many cancers. Glutamine is metabolized by glutaminase (GA), which is encoded by two genes: GLS and GLS2. In contrast to isoforms arising from the GLS gene, which clearly act as oncoproteins, the role of GLS2 products in tumorigenesis is far from well understood. While in some cancer types GLS2 is overexpressed and drives cancer development, in some other types it is downregulated and behaves as a tumor suppressor gene. In this review, we describe the essential functions and regulatory mechanisms of human GLS2 and the cellular compartments in which GLS2 has been localized. Furthermore, we present the context-dependent oncogenic and tumor-suppressor properties of GLS2, and delve into the mechanisms underlying these phenomena. [ABSTRACT FROM AUTHOR]

Here we contrast several carcinogenesis models. The somatic-mutation-theory posits mutations as main causes of malignancy. However, inconsistencies led to alternative explanations. For example, the tissue-organization-field-theory considers disrupted tissue-architecture as main cause. Both models can be reconciled using systems-biology-approaches, according to which tumors hover in states of self-organized criticality between order and chaos, are emergent results of multiple deviations and are subject to general laws of nature: inevitable variation(mutation) explainable by increased entropy(second-law-of-thermodynamics) or indeterminate decoherence upon measurement of superposed quantum systems(quantum mechanics), followed by Darwinian-selection. Genomic expression is regulated by epigenetics. Both systems cooperate. So cancer is neither just a mutational nor an epigenetic problem. Rather, epigenetics links environmental cues to endogenous genetics engendering a regulatory machinery that encompasses specific cancer-metabolic-networks. Interestingly, mutations occur at all levels of this machinery (oncogenes/tumor-suppressors, epigenetic-modifiers, structure-genes, metabolic-genes). Therefore, in most cases, DNA mutations may be the initial and crucial cancer-promoting triggers. [ABSTRACT FROM AUTHOR]

DNA methylation is the most important epigenetic element that activates the inhibition of gene transcription and is included in the pathogenesis of all types of malignancies. Remarkably, the effectors of DNA methylation are DNMTs (DNA methyltransferases) that catalyze de novo or keep methylation of hemimethylated DNA after the DNA replication process. DNA methylation structures in cancer are altered, with three procedures by which DNA methylation helps cancer development which are including direct mutagenesis, hypomethylation of the cancer genome, and also focal hypermethylation of the promoters of TSGs (tumor suppressor genes). Conspicuously, DNA methylation, nucleosome remodeling, RNA-mediated targeting, and histone modification balance modulate many biological activities that are essential and indispensable to the genesis of cancer and also can impact many epigenetic changes including DNA methylation and histone modifications as well as adjusting of non-coding miRNAs expression in prevention and treatment of many cancers. Epigenetics points to heritable modifications in gene expression that do not comprise alterations in the DNA sequence. The nucleosome is the basic unit of chromatin, consisting of 147 base pairs (bp) of DNA bound around a histone octamer comprised of one H3/H4 tetramer and two H2A/H2B dimers. DNA methylation is preferentially distributed over nucleosome regions and is less increased over flanking nucleosome-depleted DNA, implying a connection between nucleosome positioning and DNA methylation. In carcinogenesis, aberrations in the epigenome may also include in the progression of drug resistance. In this report, we report the rudimentary notes behind these epigenetic signaling pathways and emphasize the proofs recommending that their misregulation can conclude in cancer. These findings in conjunction with the promising preclinical and clinical consequences observed with epigenetic drugs against chromatin regulators, confirm the important role of epigenetics in cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer with heterogeneous molecular pathogenesis. Oral lichen planus (OLP) is demonstrated potentially can transfer to OSCC malignant lesions. Unfortunately, there are no definitive prognostic and predictive biomarkers for the clinical management of OSCC patients. The present research is the first study that compared an oral premalignant lesion such as OLP to malignant lesions like OSCC for NOTCH1 expression levels to better understand its oncogenic or tumor suppressive role. Materials and Methods: In this cross-sectional study, mRNA expression of NOTCH1 was evaluated by quantitative polymerase chain reaction in 65 tissue-embedded Paraffin-Block samples, including 32 OSCC and 33 OLP. Furthermore, we collected demographic information and pathological data, including tumor stage and grade. The association between NOTCH1 and GAPDH gene expressions was determined by Chi-squared, Spearman, and Mann-Whitney tests. A P < 0.05 was considered statistically significant for all statistical analyses. Results: Comparison of OSCC and OLP groups showed a statistically significant difference between the quantitative expression of the NOTCH1 gene (P < 0.001). Qualitative gene expression was divided into low expression and high expression. Both study groups demonstrated a statistically significant gene expression difference (P < 0.001). There was a statistically significant difference between age and NOTCH1 expression in the OLP group (P = 0.036). There was no correlation between NOTCH1 expression and age, gender, tumor grade, and stage. Conclusion: Since the OSCC is a malignant lesion and the OLP showed the possible nature of malignancy transformation, we can consider the NOTCH1 as a biomarker for the assessment of the tumorigenesis process with a definition of a standard threshold for potentially malignant lesions and malignant OSCC tumors. [ABSTRACT FROM AUTHOR]

Laryngeal cancer is a very common tumor in the upper aero-digestive tract. Understanding its biological mechanisms has garnered significant interest in recent years. The development of laryngeal squamous cell carcinoma (LSCC) follows a multistep process starting from precursor lesions in the epithelium. Various risk factors have been associated with laryngeal tumors, including smoking, alcohol consumption, opium use, as well as infections with HPV and EBV viruses, among others. Cancer development involves multiple steps, and genetic alterations play a crucial role. Tumor suppressor genes can be inactivated, and proto-oncogenes may become activated through mechanisms like deletions, point mutations, promoter methylation, and gene amplification. Epigenetic modifications, driven by miRNAs, have been proven to contribute to LSCC development. Despite advances in molecular medicine, there are still aspects of laryngeal cancer that remain poorly understood, and the underlying biological mechanisms have not been fully elucidated. In this narrative review, we examined the literature to analyze and summarize the main steps of carcinogenesis and the risk factors associated with laryngeal cancer. [ABSTRACT FROM AUTHOR]

Context.--Despite their stromal origin, follicular dendritic cells (FDCs) share many functions with hematopoietic system cells. FDC neoplasms are currently classified by the World Health Organization along with those of a histiocytic nature. However, the molecular alterations driving oncogenesis in FDC sarcomas (FDCSs) are beginning to be unveiled and do not seem to concur with those described in histiocytic neoplasms, namely MAPK pathway activation. Objective.--To identify molecular alterations driving tumorigenesis in FDCS. Design.--We investigated the role of MYC and TP53 in FDC-derived tumor oncogenesis and assessed comprehensively the status of the MAPK pathway in 16 FDCSs, 6 inflammatory pseudotumor (IPT)--like FDCSs, and 8 IPTs. Results.--MYC structural alterations (both amplifications and rearrangements) were identified in 5 of 14 FDCSs (35.7%), all associated with MYC overexpression. TP53 mutations were identified in 4 of 14 FDCSs (28.6%), all of which displayed intense and diffuse p53 expression. None of these alterations were identified in any IPT-like FDCSs or in IPT cases. No MAPK pathway gene alterations were identified in any of the cases studied. Conclusions.--The presence of MYC and TP53 alterations and the lack of association with Epstein-Barr virus segregate classical FDCS from IPT-like FDCS, pointing at different oncogenic mechanisms in both entities. Our results suggest a possible oncogenic role of MYC and TP53 alterations in FDCS. The absence of MAPK pathway alterations confirms the lack of a significant role of this pathway in the oncogenesis of FDC-derived neoplasms. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is the leading cause of death worldwide and it is estimated that approximately one in six deaths globally are due to cancer. Understanding the causes of cancer is critical for prevention, early detection, treatment optimization, public health planning, and to make informed decisions to reduce the burden of cancer on individuals and society. Transcription factors via multiple pathways have been shown to exert significant influence over gene expression programs and cellular processes involved in cancer progression. Understanding the role of transcription factors during these processes can provide critical insights into the underlying molecular mechanism and help develop therapeutic interventions. This review summarizes the possible pathways via which the transcription factor BEND3 may serve as a driver for cancer development. BEND3 is a transcription factor that plays a critical role in the regulation of gene expression in mammals. While there is limited research on the role of BEND3 as a tumor suppressor or an oncogene and its potential role in cancer therapy is still emerging, several studies suggest that it may be involved in both the processes. Its interaction and regulation with multiple other factors via p21 have already been reported to play a significant role in cancer development, which serves as an indication of its potential role in oncogenesis. Its interaction with chromatin modifiers such as NuRD and NoRC and its role in the recruitment of polycomb repressive complex 2 (PRC2) are some of the additional events indicative of its potential role in cancer development. Moreover, a few recent studies indicate BEND3 as a potential target for cancer therapy. Since the specific mechanisms by which BEND3 may contribute to cancer progression are not yet fully elucidated, in this review, we have discussed the possible pathways BEND3 may take to serve as an oncogenic driver or suppressor. [ABSTRACT FROM AUTHOR]

The reintegration of excised signal joints resulting from human V(D)J recombination was described as a potent source of genomic instability in human lymphoid cancers. However, such molecular events have not been recurrently reported in clinical patient lymphoma/leukemia samples. Using a specifically designed NGS-capture pipeline, we here demonstrated the reintegration of T-cell receptor excision circles (TRECs) in 20/1533 (1.3%) patients with T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). Remarkably, the reintegration of TREC recurrently targeted the tumor suppressor gene, ZFP36L2, in 17/20 samples. Thus, our data identified a new and hardly detectable mechanism of gene deregulation in lymphoid cancers providing new insights in human oncogenesis. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the leading cause of cancer deaths in women. The current management of patients with breast cancer needs improvement in two aspects: risk estimation, which forms the basis for treatment, and effective therapies. In our research, we discovered taxifolin to inhibit breast cancer via increasing the expression of 36 genes. These genes, as a group, effectively predict the death probability in patients with breast cancer. Importantly, aggressive breast cancers are frequently associated with increases in the 1q21.3 DNA region, which is home to the HNRN, KPRP, CRCT1, and FLG2 genes. These four genes can inhibit breast cancer, and their expressions are induced by taxifolin, revealing a novel mechanism by which taxifolin suppresses breast cancer. This study thus advances our ability in relation to the risk estimation and treatment of breast cancer. Through using taxifolin as a nutritional supplement, our research reveals an intriguing application of taxifolin in the clinical management of patients with breast cancer. Taxifolin inhibits breast cancer (BC) via novel mechanisms. In a syngeneic mouse BC model, taxifolin suppressed 4T-1 cell-derived allografts. RNA-seq of 4T-1 tumors identified 36 differentially expressed genes (DEGs) upregulated by taxifolin. Among their human homologues, 19, 7, and 2 genes were downregulated in BCs, high-proliferative BCs, and BCs with high-fatality risks, respectively. Three genes were established as tumor suppressors and eight were novel to BC, including HNRN, KPRP, CRCT1, and FLG2. These four genes exhibit tumor suppressive actions and reside in 1q21.3, a locus amplified in 70% recurrent BCs, revealing a unique vulnerability of primary and recurrent BCs with 1q21.3 amplification with respect to taxifolin. Furthermore, the 36 DEGs formed a multiple gene panel (DEG36) that effectively stratified the fatality risk in luminal, HER2+, and triple-negative (TN) equivalent BCs in two large cohorts: the METABRIC and TCGA datasets. 4T-1 cells model human TNBC cells. The DEG36 most robustly predicted the poor prognosis of TNBCs and associated it with the infiltration of CD8+ T, NK, macrophages, and Th2 cells. Of note, taxifolin increased the CD8+ T cell content in 4T-1 tumors. The DEG36 is a novel and effective prognostic biomarker of BCs, particularly TNBCs, and can be used to assess the BC-associated immunosuppressive microenvironment. [ABSTRACT FROM AUTHOR]

Background: Uterine Cervical Carcinoma (UCC) is the most prevalent gynecological malignancy globally, with a rising incidence in recent years. Accumulating evidence indicates that specific viral infections, including human papillomavirus (HPV), Epstein-Barr virus (EBV), Hepatitis B and C viruses (HBV and HCV), and human herpesvirus (HHV), may contribute to UCC development and progression. Understanding the complex interplay between viral infections and UCC risk is crucial for developing novel preventative and therapeutic interventions. Methods: This comprehensive review investigates the association between viral infections and UCC risk by examining the roles of various viral pathogens in UCC etiology and pathogenesis, and possible molecular mechanisms. Additionally, we evaluate current diagnostic methods and potential therapeutic strategies targeting viral infections for UCC prevention or treatment. Results: The prevention of UCC has been significantly advanced by the emergence of self-sampling for HPV testing as a crucial tool, allowing for early detection and intervention. However, an essential challenge in UCC prevention lies in understanding how HPV and other viral coinfections, including EBV, HBV, HCV, HHV, HIV, or their concurrent presence, may potentially contribute to UCC development. The molecular mechanisms implicated in the association between viral infections and cervical cancer development include: (1) interference of viral oncogenes with cellular regulatory proteins, resulting in uncontrolled cell proliferation and malignant transformation; (2) inactivation of tumor suppressor genes by viral proteins; (3) evasion of host immune responses by viruses; (4) induction of a persistent inflammatory response, contributing to a tumor-promoting microenvironment; (5) epigenetic modifications that lead to aberrant gene expression; (6) stimulation of angiogenesis by viruses; and (7) activation of telomerase by viral proteins, leading to cellular immortalization. Additionally, viral coinfections can also enhance oncogenic potential through synergistic interactions between viral oncoproteins, employ immune evasion strategies, contribute to chronic inflammation, modulate host cellular signaling pathways, and induce epigenetic alterations, ultimately leading to cervical carcinogenesis. Conclusion: Recognizing the implications of viral oncogenes in UCC etiology and pathogenesis is vital for addressing the escalating burden of UCC. Developing innovative preventative and therapeutic interventions requires a thorough understanding of the intricate relationship between viral infections and UCC risk. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinase-9 (MMP-9) is one of the widely studied enzymes of the extracellular matrix which can degrade various matrix biomolecules. The gene coding for this enzyme has been found to be associated with various multifactorial diseases, including cancer. More specifically, the expression of MMP-9 and polymorphisms of its gene have been found to be correlated with the formation and the invasiveness of different types of cancer. Hence, the latter gene can potentially be used both as a clinical genetic marker and a possible target in anticancer therapy. The present minireview explores the role of the MMP-9 gene in the process of tumor formation, growth, and metastasis and presents an overview of the polymorphisms of the gene associated with cancer as well as its regulation mechanisms, to provide an insight into the potential clinical applications. Nevertheless, further clinical trials and research are still required to reach more valuable conclusions for the clinical implications of the recent findings. [ABSTRACT FROM AUTHOR]

Background: Despite the association of ferroptosis with various tumors, the specific mechanism by which it influences colon adenocarcinoma (COAD) microenvironmental equilibrium remains elusive. This study aims to elucidate how ferroptosis affects COAD microenvironmental homeostasis and its potential impact on COAD research. Objective: By employing genetic screening and single-cell analysis of tumor data, we investigated the role of ferroptosis genes in COAD microenvironmental homeostasis. The genes were correlated with immune cell infiltration in tissue samples and patient outcomes. Methods: Ferroptosis-associated genes were initially identified through the FerrDb database. Utilizing the tidyverse and Seurat packages, genes with substantial expression differences were extracted, and clustering analysis was performed on the single-cell data. A Venn diagram depicted shared differential genes for ferroptosis and tumors. To screen key ferroptosis genes, further enrichment analysis and immune cell infiltration analysis were conducted. Lastly, human COAD cell lines were employed to overexpress CDGSH iron sulfur domain 2 (CISD2) through cellular assays to validate its function in COAD. Results: Following screening of The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, 414 COAD patient samples and 341 normal samples were included. Through the FerrDb database, 259 ferroptosis genes were identified. Clustering the single-cell data revealed 911 tumor marker genes, of which 18 were ferroptosis genes. Analysis of variance (ANOVA) and univariate regression analysis determined that only CISD2 was statistically significantly associated with clinical outcomes. Additionally, CISD2 was found to positively correlate with activated memory T cells and negatively correlate with regulatory T cells (Tregs) and plasma cells in COAD, as well as being significantly associated with several immune-related and cancer-related pathways. CISD2 expression was elevated in most tumors, likely due to cell cycle regulation and immune system activation. Moreover, CISD2 upregulation inhibited COAD cell proliferation and enhanced 5-fluorouracil (5-FU) sensitivity. Our findings indicate, for the first time, that CISD2 governs the cell cycle and stimulates the immune system to impede COAD progression. Conclusion: By modulating the cell cycle and mediating immune infiltration, CISD2 may inhibit COAD development by influencing tumor immune microenvironment equilibrium, providing valuable insights into the relevance and potential impact of the research results on the COAD research field. [ABSTRACT FROM AUTHOR]

Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by the presence of multiple polyps in the gastrointestinal tract and a wide range of systemic extra-intestinal manifestations. Patients affected will inevitably undergo abdominal surgery due to the malignant transformation of one or more adenomas. The pathogenesis of the disease is based on a loss of function mutation in adenomatous polyposis coli (APC), a tumor-suppressor gene, inherited following a Mendelian pattern. This gene is a key component of multiple cell functions that cooperate for homeostasis; when mutated, it contributes to the progression of colorectal adenoma into cancer. Recent studies have demonstrated that several additional mechanisms may influence this process, such as alterations in gut microbiota composition and mucosal barrier immunity, interaction with the immune microenvironment and inflammation, the hormone estrogen, and other signaling pathways. These factors represent promising targets of future therapies and chemoprevention, aiming to alter the progressive nature of the disease and improve the quality of life of families affected. Therefore, we performed a narrative review about the current knowledge of the aforementioned pathways involved in colorectal cancer pathogenesis in FAP, exploring the genetic and environmental factors that may contribute to the development of CRC in FAP. [ABSTRACT FROM AUTHOR]

Simple Summary: Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive blood cancer with poor survival rates, particularly for patients with advanced-stage and relapsed disease. Emerging research on the genetic and molecular causes of ENKTL have revealed new potential treatment strategies. In this review, we summarize how research on the biological causes of ENKTL has translated to new targets for the treatment of ENKTL, as well as the identification of new bi-omarkers which may predict prognosis and responses to specific anti-cancer therapies and enable a personalized medicine approach towards ENKTL therapy. Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive extranodal non-Hodgkin lymphoma (NHL) with poor outcomes, particularly in advanced-stage and relapsed/refractory disease. Emerging research on molecular drivers of ENKTL lymphomagenesis by next-generation and whole genome sequencing has revealed diverse genomic mutations in multiple signaling pathways, with the identification of multiple putative targets for novel therapeutic agents. In this review, we summarize the biological underpinnings of newly-understood therapeutic targets in ENKTL with a focus on translational implications, including epigenetic and histone regulatory aberrations, activation of cell proliferation signaling pathways, suppression of apoptosis and tumor suppressor genes, changes in the tumor microenvironment, and EBV-mediated oncogenesis. In addition, we highlight prognostic and predictive biomarkers which may enable a personalized medicine approach toward ENKTL therapy. [ABSTRACT FROM AUTHOR]

Nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4) has been implicated in keratinocyte development and several types of cancer. A well-defined role for NFATC4 in cutaneous squamous cell carcinoma (CSCC) has not yet been established. In this study, NFATC4 gene function in CSCC development was examined. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to measure the mRNA expression of NFATC4 in CSCC tissues and controls. A431 and Colo16 cell proliferation, invasion, and apoptosis were measured by CCK-8 assay, transwell invasion, and flow cytometry, respectively, after an NFATC4 expression lentivirus infection. Animal models were applied to validate the function of the NFATC4 gene. (1) CSCC tissues showed a significant decrease in NFATC4 expression compared to controls. (2) Overexpression of NFATc4 suppresses A431 and Colo16 cell proliferation and invasion but promotes cell apoptosis. (3) Mouse models overexpressing NFATC4 showed reduced tumourigenesis. It was suggested that NFATC4 might be a tumour suppressor gene in CSCC. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is the fifth leading cause of cancer-associated death worldwide, accounting for 768,793 related deaths and 1,089,103 new cases in 2020. Despite diagnostic advances, GC is often detected in late stages. Through a systematic literature search, this study focuses on the associations between the Iroquois gene family and GC. Accumulating evidence indicates that Iroquois genes are involved in the regulation of various physiological and pathological processes, including cancer. To date, information about Iroquois genes in GC is very limited. In recent years, the expression and function of Iroquois genes examined in different models have suggested that they play important roles in cell and cancer biology, since they were identified to be related to important signaling pathways, such as wingless, hedgehog, mitogen-activated proteins, fibroblast growth factor, TGFβ, and the PI3K/Akt and NF-kB pathways. In cancer, depending on the tumor, Iroquois genes can act as oncogenes or tumor suppressor genes. However, in GC, they seem to mostly act as tumor suppressor genes and can be regulated by several mechanisms, including methylation, microRNAs and important GC-related pathogens. In this review, we provide an up-to-date review of the current knowledge regarding Iroquois family genes in GC. [ABSTRACT FROM AUTHOR]

Sebaceous carcinomas of the human ocular adnexa commonly exhibit pagetoid spread, mutations in tumor-suppressor genes, and protooncogene copy number gain. Sebaceous carcinomas are rarely reported in other species, and while the Meibomian gland (MG) represents the most common ocular adnexal structure of the canine eyelid to develop neoplasia, most are clinically and histologically benign. The objective of this study was to compare molecular features of canine MG carcinomas and adenomas. Two retrospectively identified MG carcinomas were subject to immunohistochemistry and qPCR. When compared with normal glands, MYC was upregulated in benign and malignant MG neoplasms. Aberrant p53 expression was restricted to the nuclei of intraepithelial neoplastic cells in MG carcinomas. Adipophilin expression was diminished in MG neoplasms compared with the normal MG. Our findings, if confirmed in a larger cohort of cases, could suggest that MG oncogenesis in a dog may exhibit similar molecular features as their human counterparts. [ABSTRACT FROM AUTHOR]

Simple Summary: Synovial sarcoma (SyS) is a rare malignant tumor mainly occurring in children, adolescents, and young adults. SyS displays the pathognomonic t(X;18) translocation resulting in the SS18-SSX fusion protein being able to interact with both the BAF enhancer complexes and polycomb repressor complexes, and either activate or repress gene transcription, resulting in genome-wide epigenetic deregulation and altered gene expression. This review analyzes the different experimental in vivo models for SyS research: (I) conditional transgenic mouse models expressing the SS18-SSX fusion protein that, alone or combined with some of the few other recurrent alterations (gains in BCL2, Wnt-β-catenin signaling, FGFR family, or loss of PTEN and SMARCB1), spontaneously develop SyS; (II) SyS patient-derived xenografts (PDX) established in immunodeficient mice; (III) SyS cell lines and cell line-derived xenografts. SyS preclinical models are greatly contributing to the disclosure of additional vulnerabilities and to the development of new therapeutic approaches for SyS. Synovial sarcomas (SyS) are rare malignant tumors predominantly affecting children, adolescents, and young adults. The genetic hallmark of SyS is the t(X;18) translocation encoding the SS18-SSX fusion gene. The fusion protein interacts with both the BAF enhancer and polycomb repressor complexes, and either activates or represses target gene transcription, resulting in genome-wide epigenetic perturbations and altered gene expression. Several experimental in in vivo models, including conditional transgenic mouse models expressing the SS18-SSX fusion protein and spontaneously developing SyS, are available. In addition, patient-derived xenografts have been estab-lished in immunodeficient mice, faithfully reproducing the complex clinical heterogeneity. This review focuses on the main molecular features of SyS and the related preclinical in vivo and in vitro models. We will analyze the different conditional SyS mouse models that, after combination with some of the few other recurrent alterations, such as gains in BCL2, Wnt-β-catenin signaling, FGFR family, or loss of PTEN and SMARCB1, have provided additional insight into the mechanisms of synovial sarcomagenesis. The recent advancements in the understanding of SyS biology and improvements in preclinical modeling pave the way to the development of new epigenetic drugs and immunotherapeutic approaches conducive to new treatment options. [ABSTRACT FROM AUTHOR]

Simple Summary: Mutations in the tumor suppressor p53 (p53) occur in ~50% of human cancers, the majority of which are missense mutations. Mutations in p53 not only impair the tumor suppressive function, but also confer missense mutant p53 (mutp53) with oncogenic activities independent of wild-type p53 (wtp53). Since p53 mutations are cancer-specific, several approaches targeting them have been taken to develop novel cancer therapies, including restoration or stabilization of wtp53 conformation from mutp53, rescue of p53 nonsense mutations, depletion of mutp53 proteins, and induction of p53 synthetic lethality or targeting of vulnerabilities imposed by p53 deficiencies (activated retrotransposons) or mutations (enhanced YAP/TAZ). Here, we summarize clinically available investigational and FDA-approved drugs that target p53 mutations for their mechanisms of action and activities to suppress cancer progression. Mutations in the tumor suppressor p53 (p53) promote cancer progression. This is mainly due to loss of function (LOS) as a tumor suppressor, dominant-negative (DN) activities of missense mutant p53 (mutp53) over wild-type p53 (wtp53), and wtp53-independent oncogenic activities of missense mutp53 by interacting with other tumor suppressors or oncogenes (gain of function: GOF). Since p53 mutations occur in ~50% of human cancers and rarely occur in normal tissues, p53 mutations are cancer-specific and ideal therapeutic targets. Approaches to target p53 mutations include (1) restoration or stabilization of wtp53 conformation from missense mutp53, (2) rescue of p53 nonsense mutations, (3) depletion or degradation of mutp53 proteins, and (4) induction of p53 synthetic lethality or targeting of vulnerabilities imposed by p53 mutations (enhanced YAP/TAZ activities) or deletions (hyperactivated retrotransposons). This review article focuses on clinically available FDA-approved drugs and drugs in clinical trials that target p53 mutations and summarizes their mechanisms of action and activities to suppress cancer progression. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common malignancies worldwide; it is the fourth leading cause of cancer-related deaths. CRC arises due to mutations that can affect oncogenes, tumour suppressor genes and DNA repair genes. The lack of novel diagnostic and therapeutic targets and the development of chemoresistance are some of the major issues when dealing with CRC. The overexpression of ATP-binding cassette (ABC) transporters is considered one facilitating mechanism for chemoresistance. Furthermore, ABC transporters have additional roles in cancer development beyond multidrug resistance. In CRC, lipid dysregulation has a key role in tumour development and progression, as cancer cells rely on lipids for energy and rapid cell proliferation. ABC subfamily A (ABCA) contains the largest members of ABC proteins, mainly known for their role in lipid transport, mostly membrane lipids such as cholesterol and phospholipids. Although the exact mechanism of action of these members is not confirmed, their expression is usually correlated with tumour progression and therapy resistance, probably due to their role in lipid homeostasis. CRC shows alteration in the expression of ABCA transporters, which is usually linked to poor prognosis and overall survival. Therefore, as lipid transporters, their role in CRC is investigated, and their diagnostic and prognostic potential is evaluated. This minireview presents evidence from various studies suggesting that ABCA transporters might have an active role in CRC and can be utilized as potential diagnostic and therapeutic targets. [ABSTRACT FROM AUTHOR]

Simple Summary: The deubiquitinase-mediated cleavage of ubiquitin chains from substrate proteins plays a crucial role in regulating protein degradation, activities, interactions, and localization. The dysregulation of multiple deubiquitinases has been implicated in various human diseases, especially cancer. More importantly, many small molecules targeting oncogenic deubiquitinases have been discovered, some of which have exhibited promising anti-cancer effects and entered clinical trials. Gastric cancer remains one of the most common and fatal malignancies. In this review, we aim to summarize the multifaceted roles of deubiquitinases in gastric tumorigenesis. We also present the upstream regulation of specific deubiquitinases and the research progress of several deubiquitinase-associated small molecules for gastric cancer therapy. Together, this review will improve our understanding of the biological role of deubiquitinases as well as the therapeutic potential of targeting deubiquitinases in gastric cancer. Gastric cancers (GCs) are malignant tumors with a high incidence that threaten global public health. Despite advances in GC diagnosis and treatment, the prognosis remains poor. Therefore, the mechanisms underlying GC progression need to be identified to develop prognostic biomarkers and therapeutic targets. Ubiquitination, a post-translational modification that regulates the stability, activity, localization, and interactions of target proteins, can be reversed by deubiquitinases (DUBs), which can remove ubiquitin monomers or polymers from modified proteins. The dysfunction of DUBs has been closely linked to tumorigenesis in various cancer types, and targeting certain DUBs may provide a potential option for cancer therapy. Multiple DUBs have been demonstrated to function as oncogenes or tumor suppressors in GC. In this review, we summarize the DUBs involved in GC and their associated upstream regulation and downstream mechanisms and present the benefits of targeting DUBs for GC treatment, which could provide new insights for GC diagnosis and therapy. [ABSTRACT FROM AUTHOR]

In tumourigenesis, oncogenes or dysregulated tumour suppressor genes alter the canonical translation machinery leading to a reprogramming of the translatome that, in turn, promotes the translation of selected mRNAs encoding proteins involved in proliferation and metastasis. It is therefore unsurprising that abnormal expression levels and activities of eukaryotic initiation factors (eIFs), elongation factors (eEFs) or termination factors (eRFs) are associated with poor outcome for patients with a wide range of cancers. In this review we discuss how RNA binding proteins (RBPs) within the canonical translation factor machinery are dysregulated in cancers and how targeting such proteins is leading to new therapeutic avenues. [ABSTRACT FROM AUTHOR]

Simple Summary: Epigenetic events, which comprise post-translational modifications of histone tails or DNA methylation, control gene expression by altering chromatin structure without change in the DNA sequence. Histone tails modifications are driven by specific cellular enzymes such as histone methyltransferases or histone acetylases, which play a key role in regulating diverse biological processes. Their alteration may have consequences on growth and tumorigenesis. Epigenetic regulations, that comprise histone modifications and DNA methylation, are essential to processes as diverse as development and cancer. Among the histone post-translational modifications, lysine methylation represents one of the most important dynamic marks. Here, we focused on methyltransferases of the nuclear binding SET domain 1 (NSD) family, that catalyze the mono- and di-methylation of histone H3 lysine 36. We review the loss of function mutations of NSD1 in humans that are the main cause of SOTOS syndrome, a disease associated with an increased risk of developing cancer. We then report the role of NSD1 in triggering tumor suppressive or promoter functions according to the tissue context and we discuss the role of NSD1 in melanoma. Finally, we examine the ongoing efforts to target NSD1 signaling in cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: It has been proposed that highly expressed HDAC1 (histone deacetylases 1) removes the acetyl group from the histones at the promoter regions of tumor suppressor genes to block their expression in tumors. We here revealed the underlying mechanism that HDAC1 differentially regulates the expression of oncogenes and tumor suppressors. In detail, we found that HDAC1 is unable to occupy the promoters of oncogenes but maintains its occupancy with the tumor suppressors due to its interaction with an oncoprotein, CREPT (cell cycle-related and expression-elevated protein in tumor). Histone deacetylases 1 (HDAC1), an enzyme that functions to remove acetyl molecules from ε-NH3 groups of lysine in histones, eliminates the histone acetylation at the promoter regions of tumor suppressor genes to block their expression during tumorigenesis. However, it remains unclear why HDAC1 fails to impair oncogene expression. Here we report that HDAC1 is unable to occupy at the promoters of oncogenes but maintains its occupancy with the tumor suppressors due to its interaction with CREPT (cell cycle-related and expression-elevated protein in tumor, also named RPRD1B), an oncoprotein highly expressed in tumors. We observed that CREPT competed with HDAC1 for binding to oncogene (such as CCND1, CLDN1, VEGFA, PPARD and BMP4) promoters but not the tumor suppressor gene (such as p21 and p27) promoters by a chromatin immunoprecipitation (ChIP) qPCR experiment. Using immunoprecipitation experiments, we deciphered that CREPT specifically occupied at the oncogene promoter via TCF4, a transcription factor activated by Wnt signaling. In addition, we performed a real-time quantitative PCR (qRT-PCR) analysis on cells that stably over-expressed CREPT and/or HDAC1, and we propose that HDAC1 inhibits CREPT to activate oncogene expression under Wnt signaling activation. Our findings revealed that HDAC1 functions differentially on tumor suppressors and oncogenes due to its interaction with the oncoprotein CREPT. [ABSTRACT FROM AUTHOR]

Introduction: The PTEN (phosphatase and tensin homologue deleted on chromosome 10) gene is one of the most commonly mutated suppressor genes in malignant tumours. PTEN protein counteracts the process of carcinogenesis by inhibition of many kinases promoting cell proliferation. Aim of the research: A review and analysis of detected PTEN gene mutations in malignant tumours and identification of the most commonly mutated sites in the PTEN gene. Material and methods: The systematic review included 70 publications. Results: Mutations in the PTEN gene were found in 18% of cases. The largest number of mutations were observed in endometrial cancer - 49% of examined patients. Mutations most frequently occurred in exon 5 (49% of examined cases), followed by exon 8 (15% of cases) and exon 7 (13% of cases). Conclusions: The identification of mutations in the PTEN gene in malignant tumours is of great clinical importance - targeted treatment with temsirolimus and everolimus is available for patients. [ABSTRACT FROM AUTHOR]

SWI/SNF chromatin remodeling complexes play a key role in gene transcription as epigenetic regulators and are typically considered to act as tumor suppressors in cancers. Compared to other cancer-related components of the SWI/SNF complex, research on SMARCC2, a component of the initial BAF core, has been relatively limited. This study aimed to elucidate the role of SMARCC2 in breast cancer by employing various in vitro and in vivo methods including cell proliferation assays, mammosphere formation, and xenograft models, complemented by RNA-seq, ATAC-seq, and ChIP analyses. The results showed that SMARCC2 silencing surprisingly led to the suppression of breast tumorigenesis, indicating a pro-tumorigenic function for SMARCC2 in breast cancer, which contrasts with the roles of other SWI/SNF subunits. In addition, SMARCC2 depletion reduces cancer stem cell features of breast cancer cells. Mechanistic study showed that SMARCC2 silencing downregulated the oncogenic Ras-PI3K signaling pathway, likely by directly regulating the chromatin accessibility of the enhancers of the key genes such as PIK3CB. Together, these results expand our understanding of the SWI/SNF complex's role in cancer development and identify SMARCC2 as a promising new target for breast cancer therapies. • SMARCC2 silencing attenuates cancer phenotypes in breast cancer. • SMARCC2 depletion reduces cancer stem cell features of breast cancer cells. • SMARCC2 regulates the Ras-PI3K signaling pathway in breast cancer. • SMARCC2 regulates chromatin accessibility of the Ras-PI3K pathway genes. [ABSTRACT FROM AUTHOR]

Increasing evidence of association between kidney stone disease (KSD) and renal cell carcinoma (RCC) has been reported. Nevertheless, mechanism underlying such association remained unknown. Herein, we investigated the effects of calcium oxalate monohydrate (COM), a major crystalline component causing KSD, on induction of carcinogenic features in non-cancerous renal cells. COM crystals induced morphological changes from epithelial to fibroblast-like spindle shape. Additionally, COM increased spindle index and mesenchymal markers (fibronectin and vimentin) but declined epithelial markers (E-cadherin and zonula occludens-1). Moreover, COM down-regulated ARID1A, a tumor suppressor gene recently reported to be reversely associated with RCC, at both mRNA and protein levels. COM also down-regulated other RCC-related tumor suppressor genes, PTEN and VHL, but up-regulated oncogene TPX2. Finally, COM enhanced invading capability, cell-aggregate formation, chemoresistance to cisplatin, and secretion of an angiogenic factor (VEGF). These data indicate that COM crystals trigger epithelial-mesenchymal transition (EMT) and several carcinogenic features in the non-cancerous renal cells. These mechanisms may explain and strengthen the association between KSD and RCC. [ABSTRACT FROM AUTHOR]