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Primary hyperparathyroidism represents the third most prevalent endocrine disease in the general population, consisting of an excessive secretion of parathyroid hormone from one or, more frequently, more of the parathyroid glands, leading to a dysregulation of calcium homeostasis. Schematically, its development occurs primarily by pathophysiological events with genetic mutation, at the germline and/or somatic level, that favor the neoplastic transformation of parathyroid cells and promote their aberrant proliferation, and mutations determining the shift in the PTH "set-point", thus interfering with the normal pathways of PTH secretion and leading to a "resetting" of Ca 2+ -dependent PTH secretion or to a secretion of PTH insensitive to changes in extracellular Ca 2+ levels. Familial syndromic and non-syndromic forms of primary hyperparathyroidism are responsible for approximately 2-5% of primary hyperparathyroidism cases and most of them are inherited forms. The history of the genetic/molecular studies of parathyroid tumorigenesis associated with multiple endocrine neoplasia type 1 syndrome (MEN1) represents an interesting model to understand genetic-epigenetic-molecular aspects underlying the pathophysiology of primary hyperparathyroidism, both in relation to syndromic and non-syndromic forms. This minireview aims to take a quick and simplified look at the MEN1-associated parathyroid tumorigenesis, focusing on the molecular underlying mechanisms. Clinical, epidemiological, and observational studies, as well as specific guidelines, molecular genetics studies, and reviews, have been considered. Only studies submitted to PubMed in the English language were included, without time constraints.

Follicular lymphoma (FL) is the most prevalent indolent B-cell lymphoma entity, often characterized by the t(14;18) BCL2-IGH translocation. The malignancy represents a clinically and biologically highly heterogeneous disease. Most patients have favorable prognoses; however, despite therapeutic advancements, the disease remains incurable, with recurrent relapses or early disease progression. Moreover, transformation to an aggressive histology, most often diffuse large-B-cell lymphoma, remains a critical event in the disease course, which is associated with poor outcomes. Understanding the individual patient's risk of transformation remains challenging, which has motivated much research on novel biomarkers within the past four decades. This review systematically assessed the research on molecular biomarkers in FL transformation and outcome. Following the PRISMA guidelines for systemic reviews, the PubMed database was searched for English articles published from January 1984 through September 2024, yielding 6769 results. The identified publications were carefully screened and reviewed, of which 283 original papers met the inclusion criteria. The included studies focused on investigating molecular biomarkers as predictors of transformation or as prognostic markers of time-related endpoints (survival, progression, etc.). The effects of each biomarker were categorized based on their impact on prognosis or risk of transformation as none, favorable, or inferior. The biomarkers included genetic abnormalities, gene expression, microRNAs, markers of B cells/FL tumor cells, markers of the tumor microenvironment, and soluble biomarkers. This comprehensive review provides an overview of the research conducted in the past four decades, underscoring the persistent challenge in risk anticipation of FL patients.

Liver cancer, recognized as a significant global health issue, is increasingly correlated with Hepatitis B virus (HBV) infection, as evidenced by numerous scientific studies. This study aims to examine the correlation between HBV infection and the development of liver cancer, focusing on using RNA sequencing (RNA-seq) to detect HBV sequences and applying deep learning techniques to estimate the likelihood of oncogenic transformation in individuals with HBV. Our study utilized RNA-seq data and employed Pathseq software and sophisticated deep learning models, including a convolutional neural network (CNN), to analyze the prevalence of HBV sequences in the samples of patients with liver cancer. Our research successfully identified the prevalence of HBV sequences and demonstrated that the CNN model achieved an exceptional Area Under the Curve (AUC) of 0.998 in predicting cancerous transformations. We observed no viral synergism that enhanced the pathogenicity of HBV. A detailed analysis of sequences misclassified by the CNN model revealed that longer sequences were more conducive to accurate recognition. The findings from this study provide critical insights into the management and prognosis of patients infected with HBV, highlighting the potential of advanced analytical techniques in understanding the complex interactions between viral infections and cancer development.

The clinical impact of therapy-related acute leukemias is increasing with the extension of cancer-related survival; however, the origins remain largely unknown. Acute erythroleukemia (AEL), a rare unfavorable type of myeloid neoplasia, may also develop secondary to cytotoxic therapy. The disorder is featured by specific genetic alterations, most importantly multi-allelic mutations of the TP53 gene. While AEL might appear as a part of the therapy-related MDS/AML, spectrum information regarding the genetic complexity and progression is largely missing. We present two AEL cases arising after cytotoxic therapy and melphalan-based myeloablation/autologous peripheral stem cell transplantation due to multiple myeloma (MM). As stated, multiple pathogenic TP53 variants were present unrelated to preexisting MM, in parallel with uninvolved/wild-type hemopoiesis. Potential mechanisms of leukemic transformation are discussed, which include (1) preexisting preneoplastic hemopoietic stem cells (HSC) serving as the common origin for both MM and AEL, (2) the generation and intramedullary survival of p53-deficient post-chemotherapy HSCs, (3) reinoculation of mobilized autologous TP53 mutated HSCs, and (4) melphalan treatment-related late-onset myelodysplasia/leukemia with newly acquired TP53 mutations.

Abnormal cell proliferation and growth leading to cancer primarily result from cumulative genome mutations. Single gene mutations alone do not fully explain cancer onset and progression; instead, clustered mutations-simultaneous occurrences of multiple mutations-are considered to be pivotal in cancer development and advancement. These mutations can affect different genes and pathways, resulting in cells undergoing malignant transformation with multiple functional abnormalities. Clustered mutations influence cancer growth rates, metastatic potential, and drug treatment sensitivity. This summary highlights the various types and characteristics of clustered mutations to understand their associations with carcinogenesis and discusses their potential clinical significance in cancer. As a unique mutation type, clustered mutations may involve genomic instability, DNA repair mechanism defects, and environmental exposures, potentially correlating with responsiveness to immunotherapy. Understanding the characteristics and underlying processes of clustered mutations enhances our comprehension of carcinogenesis and cancer progression, providing new diagnostic and therapeutic approaches for cancer.

Ovarian mature teratomas (OMTs) originate from post-meiotic germ cells. Malignant transformation occurs in approximately 1-2% of OMTs; however, sebaceous carcinoma arising from OMTs is rare. This is the first report of a detailed genomic analysis of sebaceous carcinoma arising from an OMT. A 36-year-old woman underwent evaluation for abdominal tumors and subsequent hysterectomy and salpingo-oophorectomy. Pathologically, a diagnosis of stage IA sebaceous carcinoma arising from an OMT was established. Eight months post-surgery, the patient was alive without recurrence. Immunohistochemically, the tumor was negative for mismatch repair proteins. A nonsense mutation in TP53 (p.R306*) and a deletion in PIK3R1 were identified. Single nucleotide polymorphisms across all chromosomes displayed a high degree of homozygosity, suggestive of uniparental disomy. Herein, the OMT resulting from the endoreduplication of oocytes underwent a malignant transformation to sebaceous carcinoma via TP53 as an early event and PIK3R1 as a late event.

The reprogramming of somatic cells to pluripotent stem cells has immense potential for use in regenerating or redeveloping tissues for transplantation, and the future application of this method is one of the most important research topics in regenerative medicine. These cells are generated from normal cells, adult stem cells, or neoplastic cancer cells. They express embryonic stem cell markers, such as OCT4, SOX2, and NANOG, and can differentiate into all tissue types in adults, both in vitro and in vivo. However, tumorigenicity, immunogenicity, and heterogeneity of cell populations may hamper the use of this method in medical therapeutics. The risk of cancer formation is dependent on mutations of these stemness genes during the transformation of pluripotent stem cells to cancer cells and on the alteration of the microenvironments of stem cell niches at genetic and epigenetic levels. Recent reports have shown that the generation of induced pluripotent stem cells (iPSCs) derived from human fibroblasts could be induced using chemicals, which is a safe, easy, and clinical-grade manufacturing strategy for modifying the cell fate of human cells required for regeneration therapies. This strategy is one of the future routes for the clinical application of reprogramming therapy. Therefore, this review highlights the recent progress in research focused on decreasing the tumorigenic risk of iPSCs or iPSC-derived organoids and increasing the safety of iPSC cell preparation and their application for therapeutic benefits.

Activated TGFβ signaling in the tumor microenvironment, which occurs independently of epithelial cancer cells, has emerged as a key driver of tumor progression in late-stage colorectal cancer (CRC). This study aimed to elucidate the contribution of TGFβ-activated stroma to serrated carcinogenesis, representing approximately 25% of CRCs and often characterized by oncogenic BRAF mutations. We used a transcriptional signature developed based on TGFβ-responsive, stroma-specific genes to infer TGFβ-dependent stromal activation and conducted in silico analyses in 3 single-cell RNA-seq datasets from a total of 39 CRC samples and 12 bulk transcriptomic datasets consisting of 2014 CRC and 416 precursor samples, of which 33 were serrated lesions. Single-cell analyses validated that the signature was expressed specifically by stromal cells, effectively excluding transcriptional signals derived from epithelial cells. We found that the signature was upregulated during malignant transformation and cancer progression, and it was particularly enriched in CRCs with mutant BRAF compared to wild-type counterparts. Furthermore, across four independent precursor datasets, serrated lesions exhibited significantly higher levels of TGFβ-responsive stromal activation compared to conventional adenomas. This large-scale analysis suggests that TGFβ-dependent stromal activation occurs early in serrated carcinogenesis. Our study provides novel insights into the molecular mechanisms underlying CRC development via the serrated pathway.

FUT8, the sole glycosyltransferase responsible for N-glycan core fucosylation, plays a crucial role in tumorigenesis and development. Aberrant FUT8 expression disrupts the function of critical cellular components and triggers the abnormality of tumor signaling pathways, leading to malignant transformations such as proliferation, invasion, metastasis, and immunosuppression. The association between FUT8 and unfavorable outcomes in various tumors underscores its potential as a valuable diagnostic marker. Given the remarkable variation in biological functions and regulatory mechanisms of FUT8 across different tumor types, gaining a comprehensive understanding of its complexity is imperative. Here, we review how FUT8 plays roles in tumorigenesis and development, and how this outcome could be utilized to develop potential clinical therapies for tumors.

Hexavalent chromium, Cr(VI), is a known carcinogen and environmental health concern. It has been established that reactive oxygen species, genomic instability, and DNA damage repair deficiency are important contributors to the Cr(VI)-induced carcinogenesis mechanism. However, some hallmarks of cancer remain under-researched regarding the mechanism behind Cr(VI)-induced carcinogenesis. Increased lipogenesis is important to carcinogenesis and tumorigenesis in multiple types of cancers, yet the role increased lipogenesis has in Cr(VI) carcinogenesis is unclear. We report here that Cr(VI)-induced transformation of three human lung cell lines (BEAS-2B, BEP2D, and WTHBF-6) resulted in increased lipogenesis (palmitic acid levels), and Cr(VI)-transformed cells had an increased expression of key lipogenesis proteins (ATP citrate lyase [ACLY], acetyl-CoA carboxylase [ACC1], and fatty acid synthase [FASN]). We also determined that the Cr(VI)-transformed cells did not exhibit an increase in fatty acid oxidation or lipid droplets compared to their passage-matched control cells. Additionally, we observed increases in ACLY, ACC1, and FASN in lung tumor tissue compared with normal-adjacent lung tissue (in chromate workers that died of chromate-induced tumors). Next, using a known FASN inhibitor (C75), we treated Cr(VI)-transformed BEAS-2B with this inhibitor and measured cell growth, FASN protein expression, and growth in soft agar. We observed that FASN inhibition results in a decreased protein expression, decreased cell growth, and the inhibition of colony growth in soft agar. Next, using shRNA to knock down the FASN protein in Cr(VI)-transformed BEAS-2B cells, we saw a decrease in FASN protein expression and a loss of the xenograft tumor development of Cr(VI)-transformed BEAS-2B cells. These results demonstrate that FASN is important for Cr(VI)-transformed cell growth and cancer properties. In conclusion, these data show that Cr(VI)-transformation in vitro caused an increase in lipogenesis, and that this increase is vital for Cr(VI)-transformed cells.

MYCN amplification occurs in approximately 20-30% of neuroblastoma patients and correlates with poor prognosis. The TH-MYCN transgenic mouse model mimics the development of human high-risk neuroblastoma and provides strong evidence for the oncogenic function of MYCN. In this study, we identified mitotic dysregulation as a hallmark of tumor initiation in the pre-cancerous ganglia from TH-MYCN mice that persists through tumor progression. Single-cell quantitative-PCR of coeliac ganglia from 10-day-old TH-MYCN mice revealed overexpression of mitotic genes in a subpopulation of premalignant neuroblasts at a level similar to single cells derived from established tumors. Prophylactic treatment using antimitotic agents barasertib and vincristine significantly delayed the onset of tumor formation, reduced pre-malignant neuroblast hyperplasia, and prolonged survival in TH-MYCN mice. Analysis of human neuroblastoma tumor cohorts showed a strong correlation between dysregulated mitosis and features of MYCN amplification, such as MYC(N) transcriptional activity, poor overall survival, and other clinical predictors of aggressive disease. To explore the therapeutic potential of targeting mitotic dysregulation, we showed that genetic and chemical inhibition of mitosis led to selective cell death in neuroblastoma cell lines with MYCN over-expression. Moreover, combination therapy with antimitotic compounds and BCL2 inhibitors exploited mitotic stress induced by antimitotics and was synergistically toxic to neuroblastoma cell lines. These results collectively suggest that mitotic dysregulation is a key component of tumorigenesis in early neuroblasts, which can be inhibited by the combination of antimitotic compounds and pro-apoptotic compounds in MYCN-driven neuroblastoma.

The human T-cell leukemia virus type 1 (HTLV-1) is the only known human oncogenic retrovirus. HTLV-1 can cause a type of cancer called adult T-cell leukemia/lymphoma (ATL). The virus is transmitted through the body fluids of infected individuals, primarily breast milk, blood, and semen. At least 5-10 million people in the world are infected with HTLV-1. In addition to ATL, HTLV-1 infection can also cause HTLV-I-associated myelopathy (HAM/TSP). ATL is characterized by a low viral expression and poor prognosis. The oncogenic mechanism triggered by HTLV-1 is extremely complex and the molecular pathways are not fully understood. However, viral regulatory proteins Tax and HTLV-1 bZIP factor (HBZ) have been shown to play key roles in the transformation of HTLV-1-infected T cells. Moreover, several studies have shown that the final fate of HTLV-1-infected transformed Tcell clones is the result of a complex interplay of HTLV-1 oncogenic protein expression with cellular transcription factors that subvert the cell cycle and disrupt regulated cell death, thereby exerting their transforming effects. This review provides updated information on the mechanisms underlying the transforming action of HTLV-1 and highlights potential therapeutic targets to combat ATL.

Among breast cancer (BC) subtypes, the most aggressive is triple negative BC (TNBC), which is prone to metastasis. We previously found that microRNA (miR)-194-5p is downregulated at the early stages of TNBC brain metastasis development. Additionally, the transcription factor myocyte enhancer factor 2 (MEF2)C, a bioinformatically predicted miR-194-5p target, was increasingly expressed throughout TNBC brain metastasis formation and disease severity. However, the contributions of these two players to malignant cells' features remain undetermined. This study aimed at disclosing the role of miR-194-5p and MEF2C in TNBC tumorigenesis. The transfection of 4T1 cells with a silencer for MEF2C or with a pre-miRNA for miR-194-5p was employed to study TNBC cells' phenotypic alterations regarding epithelial and mesenchymal markers, as well as migratory capability alterations. MEF2C-silenced cells presented a decline in both vimentin and cytokeratin expression, whereas the overexpression of miR-194-5p promoted an increase in cytokeratin and a reduction in vimentin, reflecting the acquisition of an epithelial phenotype. Both treatments reduced TNBC cells' migration. These results suggest that MEF2C may determine TNBC cells' invasive properties by partially determining the occurrence of epithelial-mesenchymal transition, while the overexpression of miR-194-5p promotes a decline in TNBC cells' aggressive behavior and reinforces this miRNA's role as a tumor suppressor in TNBC.

The highly dynamic nature of chromatin's structure, due to the epigenetic alterations of histones and DNA, controls cellular plasticity and allows the rewiring of the epigenetic landscape required for either cell differentiation or cell (re)programming. To dissect the epigenetic switch enabling the programming of a cancer cell, we carried out wide genome analysis of Histone 3 (H3) modifications during osteogenic differentiation of SH-SY5Y neuroblastoma cells. The most significant modifications concerned H3K27me2/3, H3K9me2, H3K79me1/2, and H3K4me1 that specify the process of healthy adult stem cell differentiation. Next, we translated these findings in vivo, assessing H3K27, H3K9, and H3K79 methylation states in biopsies derived from patients affected by basalioma, head and neck carcinoma, and bladder tumors. Interestingly, we found a drastic decrease in H3K9me2 and H3K79me3 in cancer specimens with respect to their healthy counterparts and also a positive correlation between these two epigenetic flags in all three tumors. Therefore, we suggest that elevated global levels of H3K9me2 and H3K79me3, present in normal differentiated cells but lost in malignancy, may reflect an important epigenetic barrier to tumorigenesis. This suggestion is further corroborated, at least in part, by the deranged expression of the most relevant H3 modifier enzymes, as revealed by bioinformatic analysis. Overall, our study indicates that the simultaneous occurrence of H3K9me2 and H3K79me3 is fundamental to ensure the integrity of differentiated tissues and, thus, their combined evaluation may represent a novel diagnostic marker and potential therapeutic target.

Thyroid cancer is the most common endocrine malignant tumor with an increasing incidence rate. Although differentiated types of thyroid cancer generally present good clinical outcomes, some dedifferentiate into aggressive and lethal forms. However, the molecular mechanisms governing aggressiveness and dedifferentiation are still poorly understood. Aberrant expression of miRNAs is often correlated to tumor development, and miR-204-5p has previously been identified in papillary thyroid carcinoma as downregulated and associated with aggressiveness. This study aimed to explore its role in thyroid tumorigenesis. To address this, gain-of-function experiments were performed by transiently transfecting miR-204-5p in thyroid cancer cell lines. Then, the clinical relevance of our data was evaluated in vivo. We prove that this miRNA inhibits cell invasion by regulating several targets associated with an epithelial-mesenchymal transition, such as SNAI2, TGFBR2, SOX4 and HMGA2. HMGA2 expression is regulated by the MAPK pathway but not by the PI3K, IGF1R or TGFβ pathways, and the inhibition of cell invasion by miR-204-5p involves direct binding and repression of HMGA2. Finally, we confirmed in vivo the relationship between miR-204-5p and HMGA2 in human PTC and a corresponding mouse model. Our data suggest that HMGA2 inhibition offers promising perspectives for thyroid cancer treatment.

Currently, ovarian cancer (OC) is a target of intense biomarkers research because of its frequent late diagnosis and poor prognosis. Serum determination of Human epididymis protein 4 (HE4) is a very important early detection test. Most interestingly, HE4 plays a unique role in OC as it has been implicated not only in OC diagnosis but also in the prognosis and recurrence of this lethal neoplasm, actually acting as a clinical biomarker. There are several evidence about the predictive power of HE4 clinically, conversely less has been described concerning its role in OC oncogenesis. Based on these considerations, the main goal of this review is to clarify the role of HE4 in OC proliferation, angiogenesis, metastatization, immune response and also in the development of targeted therapy. Through a deeper understanding of its functions as a key molecule in the oncogenetic processes underlying OC, HE4 could be possibly considered as an essential resource not only for diagnosis but also for prognosis and therapy choice.

Despite colorectal cancer remaining a leading worldwide cause of cancer-related death, there remains a paucity of effective treatments for advanced disease. The molecular mechanisms underlying the development of colorectal cancer include altered cell signaling and cell cycle regulation that may result from epigenetic modifications of gene expression and function. Acting as important transcriptional regulators of normal biological processes, zinc finger proteins also play key roles in regulating the cellular mechanisms underlying colorectal neoplasia. These actions impact cell differentiation and proliferation, epithelial-mesenchymal transition, apoptosis, homeostasis, senescence, and maintenance of stemness. With the goal of highlighting promising points of therapeutic intervention, we review the oncogenic and tumor suppressor roles of zinc finger proteins with respect to colorectal cancer tumorigenesis and progression., Competing Interests: The authors declare no conflict of interest.

Inflammatory bowel disease (IBD), characterized by infiltration of polymorphonuclear neutrophils (PMNs), increases the risk of colon cancer. PMN activation corresponds to the accumulation of intracellular Lipid Droplets (LDs). As increased LDs are negatively regulated by transcription factor Forkhead Box O3 (FOXO3), we aim to determine the significance of this regulatory network in PMN-mediated IBD and tumorigenesis. Affected tissue of IBD and colon cancer patients, colonic and infiltrated immune cells, have increased LDs' coat protein, PLIN2. Mouse peritoneal PMNs with stimulated LDs and FOXO3 deficiency have elevated transmigratory activity. Transcriptomic analysis of these FOXO3-deficient PMNs showed differentially expressed genes (DEGs; FDR < 0.05) involved in metabolism, inflammation, and tumorigenesis. Upstream regulators of these DEGs, similar to colonic inflammation and dysplasia in mice, were linked to IBD and human colon cancer. Additionally, a transcriptional signature representing FOXO3-deficient PMNs (PMN-FOXO3 389 ) separated transcriptomes of affected tissue in IBD ( p = 0.00018) and colon cancer ( p = 0.0037) from control. Increased PMN-FOXO3 389 presence predicted colon cancer invasion (lymphovascular p = 0.015; vascular p = 0.046; perineural p = 0.03) and poor survival. Validated DEGs from PMN-FOXO3 389 ( P2RX1, MGLL, MCAM, CDKN1A, RALBP1, CCPG1, PLA2G7 ) are involved in metabolism, inflammation, and tumorigenesis ( p < 0.05). These findings highlight the significance of LDs and FOXO3-mediated PMN functions that promote colonic pathobiology.

Breast cancer is the most prevalent cancer in the world. Currently, the main treatments for breast cancer are radiotherapy, chemotherapy, targeted therapy and surgery. The treatment measures for breast cancer depend on the molecular subtype. Thus, the exploration of the underlying molecular mechanisms and therapeutic targets for breast cancer remains a hotspot in research. In breast cancer, a high level of expression of DNMTs is highly correlated with poor prognosis, that is, the abnormal methylation of tumor suppressor genes usually promotes tumorigenesis and progression. MiRNAs, as non-coding RNAs, have been identified to play key roles in breast cancer. The aberrant methylation of miRNAs could lead to drug resistance during the aforementioned treatment. Therefore, the regulation of miRNA methylation might serve as a therapeutic target in breast cancer. In this paper, we reviewed studies on the regulatory mechanisms of miRNA and DNA methylation in breast cancer from the last decade, focusing on the promoter region of tumor suppressor miRNAs methylated by DNMTs and the highly expressed oncogenic miRNAs inhibited by DNMTs or activating TETs.

The major challenges in Osteosarcoma (OS) therapy are its heterogeneity and drug resistance. The development of new therapeutic approaches to overcome the major growth mechanisms of OS is urgently needed. The search for specific molecular targets and promising innovative approaches in OS therapy, including drug delivery methods, is an urgent problem. Modern regenerative medicine focuses on harnessing the potential of mesenchymal stem cells (MSCs) because they have low immunogenicity. MSCs are important cells that have received considerable attention in cancer research. Currently, new cell-based methods for using MSCs in medicine are being actively investigated and tested, especially as carriers for chemotherapeutics, nanoparticles, and photosensitizers. However, despite the inexhaustible regenerative potential and known anticancer properties of MSCs, they may trigger the development and progression of bone tumors. A better understanding of the complex cellular and molecular mechanisms of OS pathogenesis is essential to identify novel molecular effectors involved in oncogenesis. The current review focuses on signaling pathways and miRNAs involved in the development of OS and describes the role of MSCs in oncogenesis and their potential for antitumor cell-based therapy.

nc886 is a medium-sized non-coding RNA that is transcribed by RNA polymerase III (Pol III) and plays diverse roles in tumorigenesis, innate immunity, and other cellular processes. Although Pol III-transcribed ncRNAs were previously thought to be expressed constitutively, this concept is evolving, and nc886 is the most notable example. The transcription of nc886 in a cell, as well as in human individuals, is controlled by multiple mechanisms, including its promoter CpG DNA methylation and transcription factor activity. Additionally, the RNA instability of nc886 contributes to its highly variable steady-state expression levels in a given situation. This comprehensive review discusses nc886's variable expression in physiological and pathological conditions and critically examines the regulatory factors that determine its expression levels.

The history of the development of the cell transformation assays (CTAs) is described, providing an overview of in vitro cell transformation from its origin to the new transcriptomic-based CTAs. Application of this knowledge is utilized to address how the different types of CTAs, variously addressing initiation and promotion, can be included on a mechanistic basis within the integrated approach to testing and assessment (IATA) for non-genotoxic carcinogens. Building upon assay assessments targeting the key events in the IATA, we identify how the different CTA models can appropriately fit, following preceding steps in the IATA. The preceding steps are the prescreening transcriptomic approaches, and assessment within the earlier key events of inflammation, immune disruption, mitotic signaling and cell injury. The CTA models address the later key events of (sustained) proliferation and change in morphology leading to tumor formation. The complementary key biomarkers with respect to the precursor key events and respective CTAs are mapped, providing a structured mechanistic approach to represent the complexity of the (non-genotoxic) carcinogenesis process, and specifically their capacity to identify non-genotoxic carcinogenic chemicals in a human relevant IATA.

We investigated the expression and biological function of retinoic acid inducible gene I (RIG-I) in esophageal squamous cell carcinoma (ESCC). Materials and methods: An immunohistochemical analysis was performed on 86 pairs of tumor tissue and adjacent normal tissue samples of patients with ESCC. We generated RIG-I-overexpressing ESCC cell lines KYSE70 and KYSE450, and RIG-I- knockdown cell lines KYSE150 and KYSE510. Cell viability, migration and invasion, radioresistance, DNA damage, and cell cycle were evaluated using CCK-8, wound-healing and transwell assay, colony formation, immunofluorescence, and flow cytometry and Western blotting, respectively. RNA sequencing was performed to determine the differential gene expression between controls and RIG-I knockdown. Tumor growth and radioresistance were assessed in nude mice using xenograft models. RIG-I expression was higher in ESCC tissues compared with that in matched non-tumor tissues. RIG-I overexpressing cells had a higher proliferation rate than RIG-I knockdown cells. Moreover, the knockdown of RIG-I slowed migration and invasion rates, whereas the overexpression of RIG-I accelerated migration and invasion rates. RIG-I overexpression induced radioresistance and G2/M phase arrest and reduced DNA damage after exposure to ionizing radiations compared with controls; however, it silenced the RIG-I enhanced radiosensitivity and DNA damage, and reduced the G2/M phase arrest. RNA sequencing revealed that the downstream genes DUSP6 and RIG-I had the same biological function; silencing DUSP6 can reduce the radioresistance caused by the overexpression of RIG-I. RIG-I knockdown depleted tumor growth in vivo, and radiation exposure effectively delayed the growth of xenograft tumors compared with the control group. RIG-I enhances the progression and radioresistance of ESCC; therefore, it may be a new potential target for ESCC-targeted therapy.

SWI/SNF related, matrix associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4, also known as BRG1), an ATPase subunit of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex, plays an important regulatory role in many cytogenetic and cytological processes during cancer development. However, the biological function and mechanism of SMARCA4 in oral squamous cell carcinoma (OSCC) remain unclear. The present study aimed to investigate the role of SMARCA4 in OSCC and its potential mechanism. Using a tissue microarray, SMARCA4 expression was found to be highly upregulated in OSCC tissues. In addition, SMARCA4 upregulate expression led to increased migration and invasion of OSCC cells in vitro, as well as tumor growth and invasion in vivo. These events were associated with the promotion of epithelial-mesenchymal transition (EMT). Bioinformatic analysis and luciferase reporter assay confirmed that SMARCA4 is a target gene of microRNA miR-199a-5p. Further mechanistic studies showed that the miR-199a-5p regulated SMARCA4 can promote the invasion and metastasis of tumor cells through EMT. These findings indicate that the miR-199a-5p- SMARCA4 axis plays a role in tumorigenesis by promoting OSCC cell invasion and metastasis through EMT regulation. Our findings provide insights into the role of SMARCA4 in OSCC and the mechanism involved, which may have important implications for therapeutic purposes.

In testicular germ cell tumor type II (TGCT), a seminoma subtype expresses an induced pluripotent stem cell (iPSC) panel with four upregulated genes, OCT4/ POU5F1, SOX17, KLF4, and MYC, and embryonal carcinoma (EC) has four upregulated genes, OCT4/ POU5F1, SOX2, LIN28, and NANOG. The EC panel can reprogram cells into iPSC, and both iPSC and EC can differentiate into teratoma. This review summarizes the literature on epigenetic regulation of the genes. Epigenetic mechanisms, such as methylations of cytosines on the DNA string and methylations and acetylations of histone 3 lysines, regulate expression of these driver genes between the TGCT subtypes. In TGCT, the driver genes contribute to well-known clinical characteristics and the driver genes are also important for aggressive subtypes of many other malignancies. In conclusion, epigenetic regulation of the driver genes are important for TGCT and for oncology in general.

Ki67 is a well-known proliferation marker with a large size of around 350 kDa, but its biological function remains largely unknown. The roles of Ki67 in tumor prognosis are still controversial. Ki67 has two isoforms generated by alternative splicing of exon 7. The roles and regulatory mechanisms of Ki67 isoforms in tumor progression are not clear. In the present study, we surprisingly find that the increased inclusion of Ki67 exon 7, not total Ki67 expression level, was significantly associated with poor prognosis in multiple cancer types, including head and neck squamous cell carcinoma (HNSCC). Importantly, the Ki67 exon 7-included isoform is required for HNSCC cell proliferation, cell cycle progression, cell migration, and tumorigenesis. Unexpectedly, Ki67 exon 7-included isoform is positively associated with intracellular reactive oxygen species (ROS) level. Mechanically, splicing factor SRSF3 could promote exon 7 inclusion via its two exonic splicing enhancers. RNA-seq revealed that aldo-keto reductase AKR1C2 is a novel tumor-suppressive gene targeted by Ki67 exon 7-included isoform in HNSCC cells. Our study illuminates that the inclusion of Ki67 exon 7 has important prognostic value in cancers and is essential for tumorigenesis. Our study also suggested a new SRSF3/Ki67/AKR1C2 regulatory axis during HNSCC tumor progression.

Primary tumors of the airways in the pediatric population are very rare entities. For this reason, little is known about the pathogenesis of these neoplasms. Understanding the biology has different practical implications: for example, it could help in the differential diagnosis, have a prognostic significance, or may lead to the development of a targeted therapy. The aim of this article is to present the current knowledge about pediatric airways tumors, focusing on the molecular mechanisms that cause the onset and progression of these neoplasms. After a brief introduction of epidemiology and clinical presentation, the tumorigenesis of the most frequent pediatric airways tumors will be described: Juvenile-onset recurrent respiratory papillomatosis (JORRP), Subglottic Hemangiona (SH), Rhabdomyosarcoma (RMS), and Mucoepidermoid carcinoma (MEC).

Micro ribonucleic acids (microRNAs or miRNAs) form a distinct subtype of non-coding RNA and are widely recognized as one of the most significant gene expression regulators in mammalian cells. Mechanistically, the regulation occurs through microRNA binding with its response elements in the 3'-untranslated region of target messenger RNAs (mRNAs), resulting in the post-transcriptional silencing of genes, expressing target mRNAs. Compared to small interfering RNAs, microRNAs have more complex regulatory patterns, making them suitable for fine-tuning gene expressions in different tissues. Dysregulation of microRNAs is well known as one of the causative factors in malignant cell growth. Today, there are numerous data points regarding microRNAs in different cancer transcriptomes, the specificity of microRNA expression changes in various tissues, and the predictive value of specific microRNAs as cancer biomarkers. Breast cancer (BCa) is the most common cancer in women worldwide and seriously impairs patients' physical health. Its incidence has been predicted to rise further. Mounting evidence indicates that microRNAs play key roles in tumorigenesis and development. Prostate cancer (PCa) is one of the most commonly diagnosed cancers in men. Different microRNAs play an important role in PCa. Early diagnosis of BCa and PCa using microRNAs is very useful for improving individual outcomes in the framework of predictive, preventive, and personalized (3P) medicine, thereby reducing the economic burden. This article reviews the roles of different types of microRNA in BCa and PCa progression.

The mammalian DNA methylation landscape is established and maintained by the combined activities of the two key epigenetic modifiers, DNA methyltransferases (DNMT) and Ten-eleven-translocation (TET) enzymes. Once DNMTs produce 5-methylcytosine (5mC), TET proteins fine-tune the DNA methylation status by consecutively oxidizing 5mC to 5-hydroxymethylcytosine (5hmC) and further oxidized derivatives. The 5mC and oxidized methylcytosines are essential for the maintenance of cellular identity and function during differentiation. Cytosine modifications with DNMT and TET enzymes exert pleiotropic effects on various aspects of hematopoiesis, including self-renewal of hematopoietic stem/progenitor cells (HSPCs), lineage determination, differentiation, and function. Under pathological conditions, these enzymes are frequently dysregulated, leading to loss of function. In particular, the loss of DNMT3A and TET2 function is conspicuous in diverse hematological disorders, including myeloid and lymphoid malignancies, and causally related to clonal hematopoiesis and malignant transformation. Here, we update recent advances in understanding how the maintenance of DNA methylation homeostasis by DNMT and TET proteins influences normal hematopoiesis and malignant transformation, highlighting the potential impact of DNMT3A and TET2 dysregulation on clonal dominance and evolution of pre-leukemic stem cells to full-blown malignancies. Clarification of the normal and pathological functions of DNA-modifying epigenetic regulators will be crucial to future innovations in epigenetic therapies for treating hematological disorders.

The carcinogenesis of glial tumors appears complex because of the many genetic and epigenetic phenomena involved. Among these, cellular prion protein (PrPC) is considered a key factor in cell-death resistance and important aspect implicated in tumorigenesis. Autophagy also plays an important role in cell death in various pathological conditions. These two cellular phenomena are related and share the same activation by specific alterations in the cellular microenvironment. Furthermore, there is an interdependence between autophagy and prion activity in glioma tumorigenesis. Glioma is one of the most aggressive known cancers, and the fact that such poorly studied processes as autophagy and PrPC activity are so strongly involved in its carcinogenesis suggests that by better understanding their interaction, more can be understood about its origin and treatment. Few studies in the literature relate these two cellular phenomena, much less try to explain their combined activity and role in glioma carcinogenesis. In this study, we explored the recent findings on the molecular mechanism and regulation pathways of autophagy, examining the role of PrPC in autophagy processes and how they may play a central role in glioma tumorigenesis. Among the many molecular interactions that PrP physiologically performs, it appears that processes shared with autophagy activity are those most implicated in glial tumor carcinogeneses such as activity on MAP kinases, PI3K, and mTOR. This work can be supportive and valuable as a basis for further future studies on this topic.

Expanding knowledge of the molecular mechanisms at the basis of tumor development, especially the cross-talk between oncogenic pathways, will possibly lead to better tailoring of anticancer therapies. Nuclear factor erythroid 2-related factor 2 (NRF2) plays a central role in cancer progression, not only because of its antioxidant activity but also because it establishes cross-talk with several oncogenic pathways, including Heat Shock Factor1 (HSF1), mammalian target of rapamycin (mTOR), and mutant (mut) p53. Moreover, the involvement of NRF2 in gammaherpesvirus-driven carcinogenesis is particularly interesting. These viruses indeed hijack the NRF2 pathway to sustain the survival of tumor cells in which they establish a latent infection and to avoid a too-high increase of reactive oxygen species (ROS) when these cancer cells undergo treatments that induce viral replication. Interestingly, NRF2 activation may prevent gammaherpesvirus-driven oncogenic transformation, highlighting how manipulating the NRF2 pathway in the different phases of gammaherpesvirus-mediated carcinogenesis may lead to different outcomes. This review will highlight the mechanistic interplay between NRF2 and some oncogenic pathways and its involvement in gammaherpesviruses biology to recapitulate published evidence useful for potential application in cancer therapy.

Cancer develops in a multi-step process where environmental carcinogenic exposure is a primary etiological component, and where cell-cell communication governs the biological activities of tissues. Identifying the molecular genes that regulate this process is essential to targeting metastatic breast cancer. Ionizing radiation can modify and damage DNA, RNA, and cell membrane components such as lipids and proteins by direct ionization. Comparing differential gene expression can help to determine the effect of radiation and estrogens on cell adhesion. An in vitro experimental breast cancer model was developed by exposure of the immortalized human breast epithelial cell line MCF-10F to low doses of high linear energy transfer α particle radiation and subsequent growth in the presence of 17β-estradiol. The MCF-10F cell line was analyzed in different stages of transformation that showed gradual phenotypic changes including altered morphology, increase in cell proliferation relative to the control, anchorage-independent growth, and invasive capability before becoming tumorigenic in nude mice. This model was used to determine genes associated with cell adhesion and communication such as E-cadherin, the desmocollin 3, the gap junction protein alpha 1, the Integrin alpha 6, the Integrin beta 6, the Keratin 14, Keratin 16, Keratin 17, Keratin 6B, and the laminin beta 3. Results indicated that most genes had greater expression in the tumorigenic cell line Tumor2 derived from the athymic animal than the Alpha3, a non-tumorigenic cell line exposed only to radiation, indicating that altered expression levels of adhesion molecules depended on estrogen. There is a significant need for experimental model systems that facilitate the study of cell plasticity to assess the importance of estrogens in modulating the biology of cancer cells.

Obesity is a known risk factor for the development of gastroesophageal reflux disease (GERD), Barrett's Esophagus (BE) and the progression to esophageal adenocarcinoma. The mechanisms by which obesity contributes to GERD, BE and its progression are currently not well understood. Recently, changes in lipid metabolism especially in the context of a high fat diet have been linked to GERD and BE leading us to explore whether fatty acid oxidation plays a role in the disease progression from GERD to esophageal adenocarcinoma. To that end, we analyzed the expression of the rate-limiting enzyme, carnitine palmytoyltransferase 1A (CPT1A), in human tissues and cell lines representing different stages in the sequence from normal squamous esophagus to cancer. We determined uptake of palmitic acid, the most abundant fatty acid in human serum, with fluorescent dye-labeled lipids as well as functional consequences of stimulation with palmitic acid relevant to Barrett's tumorigenesis, e.g., proliferation, characteristics of stemness and IL8 mediated inflammatory signaling. We further employed different mouse models including a genetic model of Barrett's esophagus based on IL1β overexpression in the presence and absence of a high fat diet and deoxycholic acid to physiologically mimic gastrointestinal reflux in the mice. Together, our data demonstrate that CPT1A is upregulated in Barrett's tumorigenesis and that experimental palmitic acid is delivered to mitochondria and associated with increased cell proliferation and stem cell marker expression.

We recently determined the RNA sequencing-based microRNA (miRNA) expression signature of colorectal cancer (CRC). Analysis of the signature showed that the expression of both strands of pre- miR-139 ( miR-139-5p , the guide strand, and miR-139-3p , the passenger strand) was significantly reduced in CRC tissues. Transient transfection assays revealed that expression of miR-139-3p blocked cancer cell malignant transformation (e.g., cell proliferation, migration, and invasion). Notably, expression of miR-139-3p markedly blocked RAC-alpha serine/threonine-protein kinase (AKT) phosphorylation in CRC cells. A combination of in silico database and gene expression analyses of miR-139-3p -transfected cells revealed 29 putative targets regulated by miR-139-3p in CRC cells. RNA immunoprecipitation analysis using an Argonaute2 (AGO2) antibody revealed that KRT80 was efficiently incorporated into the RNA-induced silencing complex. Aberrant expression of Keratin 80 ( KRT80 ) was detected in CRC clinical specimens by immunostaining. A knockdown assay using small interfering RNA (siRNA) targeting KRT80 showed that reducing KRT80 expression suppressed the malignant transformation (cancer cell migration and invasion) of CRC cells. Importantly, inhibiting KRT80 expression reduced AKT phosphorylation in CRC cells. Moreover, hexokinase-2 (HK2) expression was reduced in cells transfected with the KRT80 siRNAs or miR-139-3p . The involvement of miRNA passenger strands (e.g., miR-139-3p ) in CRC cells is a new concept in miRNA studies. Our tumor-suppressive miRNA-based approach helps elucidate the molecular pathogenesis of CRC.

The WNT1 inducible signaling pathway protein 1 (WISP1), a member of the connective tissue growth factor family, plays a crucial role in several important cellular functions in a highly tissue-specific manner. Results of a RT-qPCR indicated that WISP1 expressed only in cells of the human prostate fibroblasts, HPrF and WPMY-1, but not the prostate carcinoma cells in vitro. Two major isoforms (WISP1v1 and WISP1v2) were identified in the HPrF cells determined by RT-PCR and immunoblot assays. The knock-down of a WISP1 blocked cell proliferation and contraction, while treating respectively with the conditioned medium from the ectopic WISP1v1- and WISPv2-overexpressed 293T cells enhanced the migration of HPrF cells. The TNFα induced WISP1 secretion and cell contraction while the knock-down of WISP1 attenuated these effects, although TNFα did not affect the proliferation of the HPrF cells. The ectopic overexpression of WISP1v1 but not WISP1v2 downregulated the N-myc downstream regulated 1 (NDRG1) while upregulating N-cadherin, slug, snail, and vimentin gene expressions which induced not only the cell proliferation and invasion in vitro but also tumor growth of prostate carcinoma cells in vivo. The results confirmed that WISP1 is a stroma-specific secreting protein, enhancing the cell migration and contraction of prostate fibroblasts, as well as the proliferation, invasion, and tumor growth of prostate carcinoma cells.

Mitochondria are dynamic organelles managing crucial processes of cellular metabolism and bioenergetics. Enabling rapid cellular adaptation to altered endogenous and exogenous environments, mitochondria play an important role in many pathophysiological states, including cancer. Being under the control of mitochondrial and nuclear DNA (mtDNA and nDNA), mitochondria adjust their activity and biogenesis to cell demands. In cancer, numerous mutations in mtDNA have been detected, which do not inactivate mitochondrial functions but rather alter energy metabolism to support cancer cell growth. Increasing evidence suggests that mtDNA mutations, mtDNA epigenetics and miRNA regulations dynamically modify signalling pathways in an altered microenvironment, resulting in cancer initiation and progression and aberrant therapy response. In this review, we discuss mitochondria as organelles importantly involved in tumorigenesis and anti-cancer therapy response. Tumour treatment unresponsiveness still represents a serious drawback in current drug therapies. Therefore, studying aspects related to genetic and epigenetic control of mitochondria can open a new field for understanding cancer therapy response. The urgency of finding new therapeutic regimens with better treatment outcomes underlines the targeting of mitochondria as a suitable candidate with new therapeutic potential. Understanding the role of mitochondria and their regulation in cancer development, progression and treatment is essential for the development of new safe and effective mitochondria-based therapeutic regimens.

The Transformics Assay is an in vitro test which combines the BALB/c 3T3 Cell Transformation Assay (CTA) with microarray transcriptomics. It has been shown to improve upon the mechanistic understanding of the CTA, helping to identify mechanisms of action leading to chemical-induced transformation thanks to RNA extractions in specific time points along the process of in vitro transformation. In this study, the lowest transforming concentration of the carcinogenic benzo(a)pyrene (B(a)P) has been tested in order to find molecular signatures of initial events relevant for oncotransformation. Application of Enrichment Analysis (Metacore) to the analyses of the results facilitated key biological interpretations. After 72 h of exposure, as a consequence of the molecular initiating event of aryl hydrocarbon receptor (AhR) activation, there is a cascade of cellular events and microenvironment modification, and the immune and inflammatory responses are the main processes involved in cell response. Furthermore, pathways and processes related to cell cycle regulation, cytoskeletal adhesion and remodeling processes, cell differentiation and transformation were observed.

HOX proteins are transcription factors that regulate stem cell (SC) function, but their role in the SC origin of cancer is under-studied. Aberrant expression of HOX genes occurs in many cancer types. Our goal is to ascertain how retinoic acid (RA) signaling and the regulation of HOXA9 expression might play a role in the SC origin of human colorectal cancer (CRC). Previously, we reported that aldehyde dehydrogenase (ALDH) and other RA pathway components are co-expressed in colonic cancer SCs (CSCs) and that overpopulation of ALDH-positive CSCs occurs during colon tumorigenesis. Our hypothesis is RA signaling regulates HOXA9 expression, and dysregulated RA signaling results in HOXA9 overexpression, which contributes to CSC overpopulation in CRC. Immunostaining showed that HOXA9 was selectively expressed in ALDH-positive SCs, and HOXA9 expression was increased in CRCs compared to normal epithelium. Modulating RA signaling in CRC cells (HT29 and SW480) with ATRA and DEAB decreased cell proliferation and reduced HOXA9 expression. Bioinformatics analyses identified a network of proteins that functionally interact with HOXA9, and the genes that encode these proteins, as well as HOXA9 , contain RA receptor binding sites. These findings indicate that the expression of HOXA9 and its functional network is regulated by RA signaling in normal colonic SCs, and, when dysregulated, HOXA9 may contribute to CSC overpopulation that drives CRC development and growth. Our study provides a regulatory mechanism that might be useful in developing treatments against CSC overpopulation in CRC.

MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. An aberrant regulation of gene expression by miRNAs is associated with numerous diseases, including cancer. MiRNAs expression can be influenced by various stimuli, among which hypoxia; however, the effects of different types of continuous hypoxia (moderate or marked) on miRNAs are still poorly studied. Lately, some hypoxia-inducible miRNAs (HRMs, hypoxia-regulated miRNAs) have been identified. These HRMs are often activated in different types of cancers, suggesting their role in tumorigenesis. The aim of this study was to evaluate changes in miRNAs expression both in moderate continuous hypoxia and marked continuous hypoxia to better understand the possible relationship between hypoxia, miRNAs, and colorectal cancer. We used RT-PCR to detect the miRNAs expression in colorectal cancer cell lines in conditions of moderate and marked continuous hypoxia. The expression of miRNAs was analyzed using a two-way ANOVA test to compare the differential expression of miRNAs among groups. The levels of almost all analyzed miRNAs (miR-21, miR-23b, miR-26a, miR-27b, and miR-145) were greater in moderate hypoxia versus marked hypoxia, except for miR-23b and miR-21. This study identified a series of miRNAs involved in the response to different types of continuous hypoxia (moderate and marked), highlighting that they play a role in the development of cancer. To date, there are no other studies that demonstrate how these two types of continuous hypoxia could be able to activate different molecular pathways that lead to a different expression of specific miRNAs involved in tumorigenesis.

The progression of anchorage-dependent epithelial cells to anchorage-independent growth represents a critical hallmark of malignant transformation. Using an in vitro model of human papillomavirus (HPV)-induced transformation, we previously showed that acquisition of anchorage-independent growth is associated with marked (epi)genetic changes, including altered expression of microRNAs. However, the laborious nature of the conventional growth method in soft agar to measure this phenotype hampers a high-throughput analysis. We developed alternative functional screening methods using 96- and 384-well ultra-low attachment plates to systematically investigate microRNAs regulating anchorage-independent growth. SiHa cervical cancer cells were transfected with a microRNA mimic library (n = 2019) and evaluated for cell viability. We identified 84 microRNAs that consistently suppressed growth in three independent experiments. Further validation in three cell lines and comparison of growth in adherent and ultra-low attachment plates yielded 40 microRNAs that specifically reduced anchorage-independent growth. In conclusion, ultra-low attachment plates are a promising alternative for soft-agar assays to study anchorage-independent growth and are suitable for high-throughput functional screening. Anchorage independence suppressing microRNAs identified through our screen were successfully validated in three cell lines. These microRNAs may provide specific biomarkers for detecting and treating HPV-induced precancerous lesions progressing to invasive cancer, the most critical stage during cervical cancer development.

MiRNAs (microRNAs) are the most abundant family of small noncoding RNAs in mammalian cells. Increasing evidence shows that miRNAs are crucial regulators of individual development and cell homeostasis by controlling various biological processes. Therefore, miRNA dysfunction can lead to human diseases, especially in cancers with high morbidity and mortality worldwide. MiRNAs play different roles in these processes. In recent years, studies have found that miR-424-5p is closely related to the occurrence, development, prognosis and treatment of tumors. This review discusses how miR-424-5p plays a role in different kinds of cancers from different stages of tumors, including its roles in (i) promoting or inhibiting tumorigenesis, (ii) regulating tumor development in the tumor microenvironment and (iii) participating in cancer chemotherapy. This review provides a deep discussion of the latest findings on miR-424-5p and its importance in cancer, as well as a mechanistic analysis of the role of miR-424-5p in various tissues through target gene verification and pathway analysis.

The Bhas 42 cell transformation assay (Bhas 42 CTA) is the first Organization for Economic Cooperation and Development (OECD)-certificated method used as a specific tool for the detection of the cell-transformation potential of tumor-promoting compounds, including non-genotoxic carcinogens (NGTxCs), as separate from genotoxic carcinogens. This assay offers the great advantage of enabling the phenotypic detection of oncotransformation. A key benefit of using the Bhas 42 CTA in the study of the cell-transformation mechanisms of tumor-promoting compounds, including non-genotoxic carcinogens, is that the cell-transformation potential of the chemical can be detected directly without treatment with a tumor-initiating compound since Bhas 42 cell line was established by transfecting the v-Ha- ras gene into a mouse fibroblast cloned cell line. Here, we analyzed the gene expression over time, using DNA microarrays, in Bhas 42 cells treated with the tumor-promoting compound 12- O -tetradecanoylphorbol-13-acetate (TPA), and NGTxC, with a total of three repeat experiments. This is the first paper to report on gene expression over time during the process of cell transformation with only a tumor-promoting compound. Pathways that were activated or inactivated during the process of cell transformation in the Bhas 42 cells treated with TPA were related not only directly to RAS but also to various pathways in the hallmarks of cancer.

Self-maintaining hematopoietic stem cells are a cell population that is primarily 'at risk' to malignant transformation, and the cell-of-origin for some leukemias. Tissue-specific stem cells replenish the different types of functional cells within a particular tissue to meet the demands of an organism. For hematopoietic stem cells, this flexibility is important to satisfy the changing requirements for a certain type of immune cell, when needed. From studies of the natural history of childhood acute lymphoblastic leukemia, an initial oncogenic and prenatal insult gives rise to a preleukemic clone. At least a second genomic insult is needed that gives rise to a leukemia stem cell: this cell generates a hierarchy of leukemia cells. For some leukemias, there is evidence to support the concept that one of the genomic insults leads to dysregulation of the tissue homeostatic role of hematopoietic stem cells so that the hierarchy of differentiating leukemia cells belongs to just one cell lineage. Restricting the expression of particular oncogenes in transgenic mice to hematopoietic stem and progenitor cells led to different human-like lineage-restricted leukemias. Lineage restriction is seen for human leukemias by virtue of their sub-grouping with regard to a phenotypic relationship to just one cell lineage.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) control gene expression by acting at multiple levels and are often deregulated in epithelial tumors; however, their roles in the fine regulation of cellular reprogramming, specifically in epithelial-mesenchymal transition (EMT), remain largely unknown. Here, we focused on the hnRNP-Q (also known as SYNCRIP), showing by molecular analysis that in hepatocytes it acts as a "mesenchymal" gene, being induced by TGFβ and modulating the EMT. SYNCRIP silencing limits the induction of the mesenchymal program and maintains the epithelial phenotype. Notably, in HCC invasive cells, SYNCRIP knockdown induces a mesenchymal-epithelial transition (MET), negatively regulating their mesenchymal phenotype and significantly impairing their migratory capacity. In exploring possible molecular mechanisms underlying these observations, we identified a set of miRNAs (i.e., miR-181-a1-3p, miR-181-b1-3p, miR-122-5p, miR-200a-5p, and miR-let7g-5p), previously shown to exert pro- or anti-EMT activities, significantly impacted by SYNCRIP interference during EMT/MET dynamics and gathered insights, suggesting the possible involvement of this RNA binding protein in their transcriptional regulation.

Ataxia-telangiectasia mutated (ATM) functions as a key initiator and coordinator of DNA damage and cellular stress responses. ATM signaling pathways contain many downstream targets that regulate multiple important cellular processes, including DNA damage repair, apoptosis, cell cycle arrest, oxidative sensing, and proliferation. Over the past few decades, associations between germline ATM pathogenic variants and cancer risk have been reported, particularly for breast and pancreatic cancers. In addition, given that ATM plays a critical role in repairing double-strand breaks, inhibiting other DNA repair pathways could be a synthetic lethal approach. Based on this rationale, several DNA damage response inhibitors are currently being tested in ATM-deficient cancers. In this review, we discuss the current knowledge related to the structure of the ATM gene, function of ATM kinase, clinical significance of ATM germline pathogenic variants in patients with hereditary cancers, and ongoing efforts to target ATM for the benefit of cancer patients.

Many studies have reported an increase in the level of circulating cell-free DNA (cfDNA) in the blood of patients with cancer. cfDNA mainly comes from tumor cells and, therefore, carries features of its genomic profile. Moreover, tumor-derived cfDNA can act like oncoviruses, entering the cells of vulnerable organs, transforming them and forming metastatic nodes. Another source of cfDNA is immune cells, including neutrophils that generate neutrophil extracellular traps (NETs). Despite the potential eliminative effect of NETs on tumors, in some cases, their excessive generation provokes tumor growth as well as invasion. Considering both possible pathological contributions of cfDNA, as an agent of oncotransformation and the main component of NETs, the study of deoxyribonucleases (DNases) as anticancer and antimetastatic agents is important and promising. This review considers the pathological role of cfDNA in cancer development and the role of DNases as agents to prevent and/or prohibit tumor progression and the development of metastases.

SELENOF is a member of the class of selenoproteins in which the amino acid selenocysteine is co-translationally inserted into the elongating peptide in response to an in-frame UGA codon located in the 3'-untranslated (3'-UTR) region of the SELENOF mRNA. Polymorphisms in the 3'-UTR are associated with an increased risk of dying from prostate cancer and these variations are functional and 10 times more frequent in the genomes of African American men. SELENOF is dramatically reduced in prostate cancer compared to benign adjacent regions. Using a prostate cancer tissue microarray, it was previously established that the reduction of SELENOF in the cancers from African American men was significantly greater than in cancers from Caucasian men. When SELENOF levels in human prostate immortalized epithelial cells were reduced with an shRNA construct, those cells acquired the ability to grow in soft agar, increased the ability to migrate in a scratch assay and acquired features of energy metabolism associated with prostate cancer. These results support a role of SELENOF loss in prostate cancer progression and further indicate that SELENOF loss and genotype may contribute to the disparity in prostate cancer mortality experienced by African American men.

Upregulation of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1, also known as nuclear-enriched abundant transcript 2 (NEAT2) or LINC00047) was found in various solid tumors, including epithelial ovarian cancer (EOC). MALAT1 is a long noncoding (lnc)RNA that regulates many functional signaling pathways, including tumorigenesis. Herein, we observed the consistent upregulation of MALAT1 in MYST4-overexpressing cell lines, while MALAT1 was frequently found to be upregulated in various types of clinical carcinoma tissues, especially EOC. To further investigate the lncRNA MALAT1 in EOC progression, the transduced overexpression of MALAT1 in EOC cell lines and cancer-associated fibroblasts (CAFs) was employed. We found that MALAT1 overexpression in EOC cell lines significantly increased drug resistance, cell migration, and invasion. Furthermore, the concomitant overexpression of MALAT1 in EOC cells and CAFs dramatically increased EOC cell invasion. Accordingly, a mechanistic investigation of MALAT1 overexpression in EOC cells showed that expressions of the cytokines interleukin (IL)-1β and p-P38/p-NFκB/Cox2/prostaglandin E2 (PGE2) signaling were significantly increased, which stimulated inflammatory responses, whereas cell apoptosis was inhibited due to increased Bcl-2 levels and reduced Caspase3 levels. After MALAT1 was overexpressed in EOC cells, and the cyclin D1, p-PI3K, and p-Akt expressions increased, suggesting the promotion of tumor cell proliferation, while increased zinc finger E-box-binding homeobox-2 (ZEB2), yes-associated protein (YAP), and vimentin expression with E-cadherin downregulation indicated the enhancement of the epithelial-to-mesenchymal transition (EMT) in terms of metastasis, thereby triggering EOC progression. Together, our findings demonstrate how MALAT1 overexpression facilitates an oncogenic function through inhibiting tumor cell apoptosis, combined with increasing tumor cell inflammation, proliferation, and invasion in the EOC tumor microenvironment. MALAT1 is thus a potential diagnostic marker and therapeutic for this malignancy.

In principle, an oncogene is a cellular gene (proto-oncogene) that is dysfunctional, due to mutation and fusion with another gene or overexpression. Generally, oncogenes are viewed as deregulating cell proliferation or suppressing apoptosis in driving cancer. The cancer stem cell theory states that most, if not all, cancers are a hierarchy of cells that arises from a transformed tissue-specific stem cell. These normal counterparts generate various cell types of a tissue, which adds a new dimension to how oncogenes might lead to the anarchic behavior of cancer cells. It is that stem cells, such as hematopoietic stem cells, replenish mature cell types to meet the demands of an organism. Some oncogenes appear to deregulate this homeostatic process by restricting leukemia stem cells to a single cell lineage. This review examines whether cancer is a legacy of stem cells that lose their inherent versatility, the extent that proto-oncogenes play a role in cell lineage determination, and the role that epigenetic events play in regulating cell fate and tumorigenesis.