Onco-Ontogeny of Squamous Cell Cancer of the First Pharyngeal Arch Derivatives.

Head and neck squamous cell carcinoma (H&NSCC) is an anatomic, biological, and genetic complex disease. It involves more than 1000 genes implied in its oncogenesis; for this review, we limit our search and description to the genes implied in the onco-ontogeny of the derivates from the first pharyngeal arch during embryo development. They can be grouped as transcription factors and signaling molecules (that act as growth factors that bind to receptors). Finally, we propose the term embryo-oncogenesis to refer to the activation, reactivation, and use of the genes involved in the embryo's development during the oncogenesis or malignant tumor invasion and metastasis events as part of an onco-ontogenic inverse process.

Exploring in vitro modeling in hepatocarcinogenesis research: morphological and molecular features and similarities to the corresponding human disease.

The hepatocellular carcinoma (HCC) features a remarkable epidemiological burden, ranking as the third most lethal cancer worldwide. As the HCC-related molecular and cellular complexity unfolds as the disease progresses, the use of a myriad of in vitro models available is mandatory in translational preclinical research setups. In this review paper, we will compile cutting-edge information on the in vitro bioassays for HCC research, (A) emphasizing their morphological and molecular parallels with human HCC; (B) delineating the advantages and limitations of their application; and (C) offering perspectives on their prospective applications. While bidimensional (2D) (co) culture setups provide a rapid low-cost strategy for metabolism and drug screening investigations, tridimensional (3D) (co) culture bioassays - including patient-derived protocols as organoids and precision cut slices - surpass some of the 2D strategies limitations, mimicking the complex microarchitecture and cellular and non-cellular microenvironment observed in human HCC. 3D models have become invaluable tools to unveil HCC pathophysiology and targeted therapy. In both setups, the recapitulation of HCC in different etiologies/backgrounds (i.e., viral, fibrosis, and fatty liver) may be considered as a fundamental guide for obtaining translational findings. Therefore, a "multimodel" approach - encompassing the advantages of different in vitro bioassays - is encouraged to circumvent "model-biased" outcomes in preclinical HCC research.

Clinical Correlation of Transcription Factor SOX3 in Cancer: Unveiling Its Role in Tumorigenesis.

Members of the SOX (SRY-related HMG box) family of transcription factors are crucial for embryonic development and cell fate determination. This review investigates the role of SOX3 in cancer, as aberrations in SOX3 expression have been implicated in several cancers, including osteosarcoma, breast, esophageal, endometrial, ovarian, gastric, hepatocellular carcinomas, glioblastoma, and leukemia. These dysregulations modulate key cancer outcomes such as apoptosis, epithelial-mesenchymal transition (EMT), invasion, migration, cell cycle, and proliferation, contributing to cancer development. SOX3 exhibits varied expression patterns correlated with clinicopathological parameters in diverse tumor types. This review aims to elucidate the nuanced role of SOX3 in tumorigenesis, correlating its expression with clinical and pathological characteristics in cancer patients and cellular modelsBy providing a comprehensive exploration of SOX3 involvement in cancer, this review underscores the multifaceted role of SOX3 across distinct tumor types. The complexity uncovered in SOX3 function emphasizes the need for further research to unravel its full potential in cancer therapeutics.

PITPNA-AS1 Inhibits Cell Proliferation and Migration in Ovarian Cancer by Regulating the MIR-223-3p/RHOB Axis.

Background: Ovarian cancer is a fatal gynecologic malignancy. Long non-coding RNA (lncRNA) has been verified to serve as key regulator in ovarian cancer tumorigenesis. Objective: The aim of the study was to study the functions and mechanism of lncRNA PITPNA-AS1 in ovarian cancer cellular process. Methods: Clinical ovarian cancer samples were collected and stored at an academic medical center. Cellular fractionation assays and fluorescence in situ hybridization were conducted to locate PITPNA-AS1 in OC cells. TUNEL staining, colony-forming assays, and Transwell assays were performed for evaluating cell apoptosis as well as proliferative and migratory abilities. Western blot was conducted for quantifying protein levels of epithelialmesenchymal transition markers. The binding relation between genes was verified by RNA pulldown, RNA immunoprecipitation, and luciferase reporter assays. Gene expression levels in ovarian cancer tissues and cells were subjected to RT-qPCR. Results: PITPNA-AS1 level was downregulated in ovarian cancer samples and cells. PITPNA-AS1 overexpression contributed to the accelerated ovarian cancer cell apoptosis and inhibited cell migration, proliferation, and epithelial-mesenchymal transition process. In addition, PITPNA-AS1 interacted with miR-223-3p to regulate RHOB. RHOB knockdown partially counteracted the repressive impact of PITPNA-AS1 on ovarian cancer cell activities. Conclusion: PITPNA-AS1 inhibited ovarian cancer cellular behaviors by targeting miR-223-3p and regulating RHOB.

Copy number signatures and CCNE1 amplification reveal the involvement of replication stress in high-grade endometrial tumors oncogenesis.

PURPOSE: Managing high-grade endometrial cancer in Martinique poses significant challenges. The diversity of copy number alterations in high-grade endometrial tumors, often associated with a TP53 mutation, is a key factor complicating treatment. Due to the high incidence of high-grade tumors with poor prognosis, our study aimed to characterize the molecular signature of these tumors within a cohort of 25 high-grade endometrial cases. METHODS: We conducted a comprehensive pangenomic analysis to categorize the copy number alterations involved in these tumors. Whole-Exome Sequencing (WES) and Homologous Recombination (HR) analysis were performed. The alterations obtained from the WES were classified into various signatures using the Copy Number Signatures tool available in COSMIC. RESULTS: We identified several signatures that correlated with tumor stage and disctinct prognoses. These signatures all seem to be linked to replication stress, with CCNE1 amplification identified as the primary driver of oncogenesis in over 70% of tumors analyzed. CONCLUSION: The identification of CCNE1 amplification, which is currently being explored as a therapeutic target in clinical trials, suggests new treatment strategies for high-grade endometrial cancer. This finding holds particular significance for Martinique, where access to care is challenging.

Dynamic Role of miRNAs in Salivary Gland Carcinomas: From Biomarkers to Therapeutic Targets.

BACKGROUND: Salivary gland carcinomas (SGCs) are a rare group of malignant neoplasms of the head and neck region. MicroRNAs (miRNAs) are a class of small non-coding RNAs that have been associated with the control biological process and oncogenic mechanism by the regulation of gene expression at the post-transcriptional level. Recent evidence has suggested that miRNA expression may play a role in the tumorigenesis and carcinogenesis process in SGCs. METHODS: This review provides a comprehensive literature review of the role of miRNAs expression in SGCs focusing on the diagnostic, prognostic, and therapeutic applications. RESULTS: In this review, numerous dysregulated miRNAs have demonstrated an oncogenic and suppressor role in SGCs. CONCLUSION: In the future, these miRNAs may eventually constitute useful diagnostic and prognostic biomarkers that may lead to a better understanding of SGCs oncogenesis. Additionally, the development of therapeutic agents based on miRNAs may be a promising target in SGC treatment.

Inhibition of PORCN Blocks Wnt Signaling to Attenuate Progression of Oral Carcinogenesis.

PURPOSE: Oral squamous cell carcinoma (OSCC) is commonly preceded by potentially malignant lesions, referred to as oral dysplasia. We recently reported that oral dysplasia is associated with aberrant activation of the Wnt/ß-catenin pathway, due to overexpression of Wnt ligands in a Porcupine (PORCN)-dependent manner. Pharmacologic inhibition of PORCN precludes Wnt secretion and has been proposed as a potential therapeutic approach to treat established cancers. Nevertheless, there are no studies that explore the effects of PORCN inhibition at the different stages of oral carcinogenesis. EXPERIMENTAL DESIGN: We performed a model of tobacco-induced oral cancer in vitro, where dysplastic oral keratinocytes (DOK) were transformed into oral carcinoma cells (DOK-TC), and assessed the effects of inhibiting PORCN with the C59 inhibitor. Similarly, an in vivo model of oral carcinogenesis and ex vivo samples derived from patients diagnosed with oral dysplasia and OSCC were treated with C59. RESULTS: Both in vitro and ex vivo oral carcinogenesis approaches revealed decreased levels of nuclear ß-catenin and Wnt3a, as observed by immunofluorescence and IHC analyses. Consistently, reduced protein and mRNA levels of survivin were observed after treatment with C59. Functionally, treatment with C59 in vitro resulted in diminished cell migration, viability, and invasion. Finally, by using an in vivo model of oral carcinogenesis, we found that treatment with C59 prevented the development of OSCC by reducing the size and number of oral tumor lesions. CONCLUSIONS: The inhibition of Wnt ligand secretion with C59 represents a feasible treatment to prevent the progression of early oral lesions toward OSCC.

Deregulation of ABCG1 early in life contributes to prostate carcinogenesis in maternally malnourished offspring rats.

AIMS: The developmental Origins of Health and Disease (DOHaD) concept has provided the framework to assess how early life experiences can shape health and disease throughout the life course. Using a model of maternal exposure to a low protein diet (LPD; 6% protein) during the gestational and lactational periods, we demonstrated changes in the ventral prostate (VP) transcriptomic landscape in young rats exposed to maternal malnutrition. Male offspring Sprague Dawley rats were submitted to maternal malnutrition during gestation and lactation, and they were weighed, and distance anogenital was measured, followed were euthanized by an overdose of anesthesia at 21 postnatal days. Next, the blood and the ventral prostate (VP) were collected and processed by morphological analysis, biochemical and molecular analyses. RNA-seq analysis identified 411 differentially expressed genes (DEGs) in the VP of maternally malnourished offspring compared to the control group. The molecular pathways enriched by these DEGs are related to cellular development, differentiation, and tissue morphogenesis, all of them involved in both normal prostate development and carcinogenesis. Abcg1 was commonly deregulated in young and old maternally malnourished offspring rats, as well in rodent models of prostate cancer (PCa) and in PCa patients. Our results described ABCG1 as a potential DOHaD gene associated with perturbation of prostate developmental biology with long-lasting effects on carcinogenesis in old offspring rats. A better understanding of these mechanisms may help with the discussion of preventive strategies against early life origins of non-communicable chronic diseases.

Role of miR-424 in the carcinogenesis.

Recent studies have revealed the impact of microRNAs (miRNAs) in the carcinogenic process. miR-424 is a miRNA whose role in this process is being to be identified. Experiments in the ovarian cancer, cervical cancer, hepatocellular carcinoma, neuroblastoma, breast cancer, osteosarcoma, intrahepatic cholangiocarcinoma, prostate cancer, endometrial cancer, non-small cell lung cancer, hemangioma and gastric cancer have reported down-regulation of miR-424. On the other hand, this miRNA has been found to be up-regulated in melanoma, laryngeal and esophageal squamous cell carcinomas, glioma, multiple myeloma and thyroid cancer. Expression of this miRNA is regulated by methylation status of its promoter. Besides, LINC00641, CCAT2, PVT1, LIN00657, LINC00511 and NNT-AS1 are among lncRNAs that act as molecular sponges for miR-424, thus regulating its expression. Moreover, several members of SNHG family of lncRNAs have been found to regulate expression of miR-424. This miRNA is also involved in the regulation of E2F transcription factors. The current review aims at summarization of the role of miR-424 in the process of cancer evolution and its impact on clinical outcome of patients in order to find appropriate markers for malignancies.

Molecular biomarkers in prostate cancer tumorigenesis and clinical relevance.

Prostate cancer (PCa) is the second most frequent type of cancer in men and assessing circulating tumor cells (CTCs) by liquid biopsy is a promising tool to help in cancer early detection, staging, risk of recurrence evaluation, treatment prediction and monitoring. Blood-based liquid biopsy approaches enable the enrichment, detection and characterization of CTCs by biomarker analysis. Hence, comprehending the molecular markers, their role on each stage of cancer development and progression is essential to provide information that can help in future implementation of these biomarkers in clinical assistance. In this review, we studied the molecular markers most associated with PCa CTCs to better understand their function on tumorigenesis and metastatic cascade, the methodologies utilized to analyze these biomarkers and their clinical significance, in order to summarize the available information to guide researchers in their investigations, new hypothesis formulation and target choice for the development of new diagnostic and treatment tools.

Comet assay as a suitable biomarker for in vivo oral carcinogenesis: a systematic review.

BACKGROUND AND OBJECTIVES: In order to detect genetic damage, different methods have been developed, such as micronuclei and comet assay. The comet assay presents some advantages when compared to the other aforementioned methods, including wide versatility, as any eukaryotic cell can be evaluated at an individual cellular level. In this context, the aim of this systematic review was designed to help further elucidate the following question: is the comet assay a suitable biomarker of in vivo oral carcinogenesis? MATERIAL AND METHODS: The present systematic review was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Full manuscripts from 18 studies were carefully selected in this setting. RESULTS: A total of 15 studies demonstrated positive findings for genotoxicity in peripheral blood or oral cells in patients with pre-malignant lesions or oral cancer. In the quality assessment of studies, 1 was classified as Strong, 5 were considered as Moderate, and 12 were classified as Weak. CONCLUSION: In summary, the comet assay can be a useful biomarker for oral carcinogenesis. However, further studies with more strict parameters are suggested (with less uncontrolled confounders) in order to increase findings reliability for diagnosis of oral potentially malignant lesions.

Tumor-Promoting Effects of Microrna-421/4-Aminobutyrate Aminotransferase Axis in Hepatocellular Carcinoma.

Background: MicroRNA-421 (miR-421) has been implicated in hepatocellular carcinoma (HCC), but its potential mechanism in HCC remains unclear. Objectives: The study aimed to study the potential mechanism of miR-421 in HCC which is necessary. Methods: The downstream target genes of miR-421 were screened in HCC tissues and cells using miDIP, Targetscan, and starBase databases. Differential analysis, survival analysis, and Pearson correlation analysis were performed between miR-421 and its downstream target genes. Quantitative reverse transcription polymerase chain reaction and western blot were used to assay RNA and protein levels of 4-aminobutyrate aminotransferase (ABAT) and epithelial-mesenchymal transition (EMT)-related proteins. Cell-based assays, including CCK-8, wound healing, transwell, flow cytometry, and metabolic measurements, were implemented to assess proliferation, migration, invasion, cell cycle, and apoptosis of HCC cells with different treatments. Dual-luciferase assay was utilized to detect the targeting relationship between miR-421 and ABAT. Results: miR-421 level was elevated in HCC tissues and cells, and low miR-421 expression hindered phenotype progression of HCC cells. ABAT was identified as a direct target of miR-421 in HCC cells, and miR-421 could inhibit ABAT expression. Rescue assay revealed that miR-421 promoted HCC cell tumorigenesis progress and affected cell metabolic remodeling through down-regulating ABAT. Conclusion: The miR-421/ABAT regulatory axis promoted HCC cell tumorigenesis progress, highlighting its potential as a therapeutic target for HCC.

Transcriptomic analysis reveals a tissue-specific loss of identity during ageing and cancer.

INTRODUCTION: Understanding changes in cell identity in cancer and ageing is of great importance. In this work, we analyzed how gene expression changes in human tissues are associated with tissue specificity during cancer and ageing using transcriptome data from TCGA and GTEx. RESULTS: We found significant downregulation of tissue-specific genes during ageing in 40% of the tissues analyzed, which suggests loss of tissue identity with age. For most cancer types, we have noted a consistent pattern of downregulation in genes that are specific to the tissue from which the tumor originated. Moreover, we observed in cancer an activation of genes not usually expressed in the tissue of origin as well as an upregulation of genes specific to other tissues. These patterns in cancer were associated with patient survival. The age of the patient, however, did not influence these patterns. CONCLUSION: We identified loss of cellular identity in 40% of the tissues analysed during human ageing, and a clear pattern in cancer, where during tumorigenesis cells express genes specific to other organs while suppressing the expression of genes from their original tissue. The loss of cellular identity observed in cancer is associated with prognosis and is not influenced by age, suggesting that it is a crucial stage in carcinogenesis.

Panx1 knockout promotes preneoplastic aberrant crypt foci development in a chemically induced model of mouse colon carcinogenesis.

Colorectal cancer, which is the third leading cause of cancer-related deaths worldwide, is a multistep disease, featuring preneoplastic aberrant crypt foci (ACF) as the early morphological manifestation. The roles of hemichannel-forming transmembrane Pannexin 1 (Panx1) protein have not been investigated in the context of colon carcinogenesis yet, although it has contrasting roles in other cancer types. Thus, this study was conducted to examine the effects of Panx1 knockout (Panx1-/- ) on the early events of chemically induced colon carcinogenesis in mouse. Wild type (WT) and Panx1-/- female C57BL6J mice were submitted to a chemically induced model of colon carcinogenesis by receiving six intraperitoneal administrations of 1,2-dimethylhydrazine (DMH) carcinogen. Animals were euthanized 8 h (week 7) or 30 weeks (week 37) after the last DMH administration in order to evaluate sub-acute colon toxicity outcomes or the burden of ACF, respectively. At week 7, Panx1 genetic ablation increased DMH-induced genotoxicity in peripheral blood cells, malondialdehyde levels in the colon, and apoptosis (cleaved caspase-3) in colonic crypts. Of note, at week 37, Panx1-/- animals showed an increase in aberrant crypts (AC), ACF mean number, and ACF multiplicity (AC per ACF) by 56%, 57% and 20%, respectively. In essence, our findings indicate that Panx1 genetic ablation promotes preneoplastic ACF development during chemically induced mouse colon carcinogenesis, and a protective role of Panx1 is postulated.

Epstein­Barr virus as a promoter of tumorigenesis in the tumor microenvironment of breast cancer (Review).

Epstein­Barr virus (EBV) is an oncovirus associated with various neoplasms, including breast cancer (BC). EBV­associated oncogenesis requires the action of several viral molecules, such as EBV nuclear antigen 3C, latent membrane protein 1, microRNAs and long non­coding RNAs, which are able of manipulating the cellular machinery, inducing an evasion of the immune system, blocking apoptosis processes, promoting cell survival and metastasis. The risk of developing cancer is associated with epigenetic alterations and alterations in various signaling pathways. The activation of all these molecules can modify the expression of EBV proteins with oncogenic activity, influencing the oncogenic process. It is clear that BC, being multifactorial, presents a greater complexity; in numerous cases, the infection associated with EBV may be crucial for this neoplasia, if particular conditions for both the virus and host are present. In the present review, all these variables are analyzed in an aim to improve the understanding of the participation of EBV in BC.

Identification of MicroRNA Expression Profiles Related to the Aggressiveness of Salivary Gland Adenoid Cystic Carcinomas.

Adenoid cystic carcinoma (ACC) has been reported as the second most common carcinoma of the salivary glands. Few studies have associated miRNA expression with ACC aggressiveness. In this study, we evaluated the miRNA profile of formalin-fixed, paraffin-embedded (FFPE) samples of salivary gland ACC patients using the NanoString platform. We studied the miRNA expression levels associated with the solid growth pattern, the more aggressive histologic feature of ACCs, compared with the tubular and cribriform growth patterns. Moreover, the perineural invasion status, a common clinicopathological feature of the disease that is frequently associated with the clinical progression of ACC, was investigated. The miRNAs showing significant differences between the study groups were selected for target prediction and functional enrichment, which included associations with the disease according to dedicated databases. We observed decreased expression of miR-181d, miR-23b, miR-455, miR-154-5p, and miR-409 in the solid growth pattern compared with tubular and cribriform growth patterns. In contrast, miR-29c, miR-140, miR-195, miR-24, miR-143, and miR-21 were overexpressed in patients with perineural invasion. Several target genes of the miRNAs identified have been associated with molecular processes involved in cell proliferation, apoptosis, and tumor progression. Together, these findings allowed the characterization of miRNAs potentially associated with aggressiveness in salivary gland adenoid cystic carcinoma. Our results highlight important new miRNA expression profiles involved in ACC carcinogenesis that could be associated with the aggressive behavior of this tumor type.

Involvement of CXCL12/CXCR4 axis in colorectal cancer: a mini-review.

Migration of metastatic tumor cells is similar to the traffic of leukocytes and has been reported that can be guided by chemokines and their receptors, through the circulation to distant organs. The chemokine CXCL12 and its receptor CXCR4 play an essential role in hematopoietic stem cell homing and the activation of this axis supports malignant events. Binding of CXCL12 to CXCR4 activates signal transduction pathways, with broad effects on chemotaxis, cell proliferation, migration and gene expression. Thus, this axis serves as a bridge for tumor-stromal cell communication, creating a permissive microenvironment for tumor development, survival, angiogenesis and metastasis. Evidence suggests that this axis may be involved in the colorectal cancer (CRC) carcinogenesis. Therefore, we review emerging data and correlations between CXCL12/CXCR4 axis in CRC, the implications for cancer progression and possible therapeutic strategies that exploit this system.

Iroquois Family Genes in Gastric Carcinogenesis: A Comprehensive Review.

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, TGFß, 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.

Potential role of exitron-containing homeobox genes in cancer.

Homeobox genes are protagonists in developmental and cancer biology, making comprehending their regulation pivotal in multiple molecular pathways. Exitrons, also known as intronic exons, are new players in the transcriptional organization, providing additional splicing variants whose functions are still vastly unknown. Exitron splicing sites were identified in eight homeobox genes, which has not been yet debated in the scientific literature. Due to the intimate connection between homeobox genes and tumorigenesis, it is worth investing more time in understanding how these less explored exitron-containing transcriptional isoforms could play a role in modulating the homeobox gene's biological functions. The perspectives devised in this article are meant to instigate fresh debates on how the transcriptional variants retaining exitrons identified in the human homeobox genes HOXA1, HOXA9, HOXD8, NKX3.1, and DLX6 can be examined in the context of tumorigenesis. This article is categorized under: Cancer > Genetics/Genomics/Epigenetics.

JHDM1D-AS1-driven inhibition of miR-940 releases ARTN expression to induce breast carcinogenesis.

INTRODUCTION: As ceRNA network of long non-coding RNA (lncRNA)-microRNA (miR)-messenger RNAs (mRNA) can be predicted on the basis of bioinformatics tools, we are now one step closer to deeper understanding carcinogenic mechanisms. In this study, we clarified the mechanistic understanding of JHDM1D-AS1-miR-940-ARTN ceRNA network in the development of breast cancer (BC). MATERIALS AND METHODS: The lncRNA-miRNA-mRNA interaction of interest was predicted by in silico analysis and identified by conducting RNA immunoprecipitation, RNA pull-down and luciferase assays. The expression patterns of JHDM1D-AS1, miR-940 and ARTN in BC cells were altered by lentivirus infection and plasmid transfection for functional assays on the biological properties of BC cells. Finally, the tumorigenic and metastatic abilities of BC cells were assessed in vivo. RESULTS: JHDM1D-AS1 was highly expressed, while miR-940 was poorly expressed in BC tissues and cells. JHDM1D-AS1 could competitively bind to miR-940, whereby promoting the malignant behaviors of BC cells. Furthermore, ARTN was identified as a target gene of miR-940. Through targeting ARTN, miR-940 exerted a tumor-suppressive role. In vivo experiments further confirmed that JHDM1D-AS1 enhanced the tumorigenesis and metastasis through up-regulation of ARTN. CONCLUSIONS: Taken together, our study demonstrated the involvement of ceRNA network JHDM1D-AS1-miR-940-ARTN in the progression of BC, which highlighted promising therapeutic targets for BC treatment.