Cell Cycle Checkpoint Research Articles

Molecular basis for the disease-modifying effects of belimumab in systemic lupus erythematosus and molecular predictors of early response: blood transcriptome analysis implicates the innate immunity and DNA damage response pathways

ObjectivesBelimumab is a putative disease-modifying agent in systemic lupus erythematosus (SLE), yet the molecular underpinnings of its effects and the ability to predict early clinical response remain unexplored. To address...

A pan-cancer study of ADAM9’s immunological function and prognostic value particularly in liver cancer

A pan-cancer analysis summarizing the overall changes in mRNA and protein stability of ADM9, as well as its oncogenic function on immune cell line modulation and checkpoints within the tumor microenvironment (TME), is lacking, despite the fact that ADM9 up-regulation is correlated with the progression of many cancers. Therefore, in this study, we comprehensively analyzed the role of ADAM9 expression and its prognostic value in different cancers to fill this gap. Multiple bioinformatics databases such as Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Clinical Proteomic Tumor Analysis Consortium (CPTAC) were used to evaluate the ADAM9 genetic alternation, phosphorylation, and methylation, and indicated highly positive correlated genes that might play a critical interaction with ADAM9 and their molecular function with GO analysis. We also evaluate the effect of higher ADAM9 with prominent immune modulatory genes and immune infiltration especially in liver cancer pathogenesis stimulates lower NK cell effector functions based on its role in MICA shedding and increasing the Tregs infiltration. Immunohistochemistry (IHC) staining from 90 pathologically verified samples proved the positive correlation between ADAM9 and tumor stages and proved the higher expression of ADAM9 correlated genes (SNX9, APP, TNF, CDH1, ITGAV, MAD2L2) in HCC pathogenesis. In conclusion, this pan-cancer study provides a comprehensive understanding of the prognostic value of ADAM9 in various tumors emphasizing its importance to be considered as an innovative treatment approach, especially in tumor immunity shortly.

Characterising Cancer Cell Responses to Cyclic Hypoxia Using Mathematical Modelling

In vivo observations show that oxygen levels in tumours can fluctuate on fast and slow timescales. As a result, cancer cells can be periodically exposed to pathologically low oxygen levels; a phenomenon known as cyclic hypoxia. Yet, little is known about the response and adaptation of cancer cells to cyclic, rather than, constant hypoxia. Further, existing in vitro models of cyclic hypoxia fail to capture the complex and heterogeneous oxygen dynamics of tumours growing in vivo. Mathematical models can help to overcome current experimental limitations and, in so doing, offer new insights into the biology of tumour cyclic hypoxia by predicting cell responses to a wide range of cyclic dynamics. We develop an individual-based model to investigate how cell cycle progression and cell fate determination of cancer cells are altered following exposure to cyclic hypoxia. Our model can simulate standard in vitro experiments, such as clonogenic assays and cell cycle experiments, allowing for efficient screening of cell responses under a wide range of cyclic hypoxia conditions. Simulation results show that the same cell line can exhibit markedly different responses to cyclic hypoxia depending on the dynamics of the oxygen fluctuations. We also use our model to investigate the impact of changes to cell cycle checkpoint activation and damage repair on cell responses to cyclic hypoxia. Our simulations suggest that cyclic hypoxia can promote heterogeneity in cellular damage repair activity within vascular tumours.

Targeting the EGFR and Spindle Assembly Checkpoint Pathways in Oral Cancer: A Plausible Alliance to Enhance Cell Death

Background/Objectives: Head and neck cancer (HNC) is among the most common cancer types globally, with its incidence expected to increase significantly in the coming years. Oral squamous cell carcinoma (OSCC), the predominant subtype, exhibits significant heterogeneity and resistance to treatment. Current therapies, including surgery, radiation, and chemotherapy, often result in poor outcomes for advanced stages. Cetuximab, an EGFR inhibitor, is widely used but faces limitations. This study explores the combined inhibition of EGFR and mitotic proteins to enhance treatment efficacy. Methods: We analyzed the effects of co-treating OSCC cells with small molecules targeting MPS-1 (BAY1217389), Aurora-B (Barasertib), or KSP (Ispinesib), alongside Cetuximab. The rationale is based on targeting EGFR-mediated survival pathways and the mitotic checkpoint, addressing multiple cell cycle phases and reducing resistance. Results: Our findings indicate that inhibiting MPS-1, Aurora-B, or KSP enhances Cetuximab’s therapeutic potential, promoting increased cancer cell death. Additionally, we examined EGFR, MPS-1, Aurora-B, and KSP expression in OSCC patient samples, revealing their clinicopathologic significance. Conclusions: This combinatorial approach suggests a promising strategy to improve treatment outcomes in OSCC.

Single-agent Adavosertib Shows Anticancer Effects Against Colorectal Cancer Cells.

Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related deaths worldwide. Adavosertib (AZD1775), a small molecule inhibitor of WEE1 kinase, abrogates G2/M cell cycle arrest and induces double-stranded DNA breaks. According to previous findings, adavosertib, in combination with other DNA-damaging agents, causes premature mitosis and cell death in p53-mutated cancer cells mainly via abrogation of the G2/M cell cycle checkpoint. This study aims to evaluate the inhibition of WEE1 kinase by adavosertib as monotherapy in the TP53-wildtype human CRC cell line HCT116. In this study, HCT116 cells were treated with different concentrations of adavosertib for 24 to 72 hours. Cell viability was assessed by Water-Soluble Tetrazolium 1 (WST-1) assay and crystal violet assays. Cell migration was evaluated by the wound healing assay. Cell cycle distribution and apoptosis were analyzed by flow cytometry. The IC50 value of adavosertib for the HCT116 cell line was 0.1310 μM. Adavosertib monotherapy (both 0.125 and 0.250 μM) significantly reduced cell viability, inhibited cell migration and abrogated intra-S phase cell cycle arrest. In addition, 0.250 μM of adavosertib significantly induced apoptosis in HCT116 cells. Adavosertib effectively inhibits the TP53-wildtype HCT116 cells via the abrogation of intra-S phase cell cycle arrest. Our findings suggest that adavosertib monotherapy may be a potential targeted therapy for CRC.

Synergistic effects of MK-1775 and gemcitabine on cytotoxicity in non-small cell lung cancer

BackgroundNon-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality. Chemotherapy is crucial in NSCLC treatment, and targeting Wee1 kinase, a key regulator of the G2/M cell cycle checkpoint, may enhance the efficacy of cytotoxic agents. This study investigates the potential of the Wee1 inhibitor MK-1775 in combination with gemcitabine and pemetrexed to enhance cytotoxicity in NSCLC cell lines. MethodsHuman NSCLC cell lines H1975, HCC827, A549, and H460 were treated with MK-1775 and chemotherapeutic agents, both alone and in combination. Growth inhibitory effects were assessed using the CCK8 assay. Apoptotic markers were evaluated via Western blotting, and cell cycle distribution was analyzed using FACS. In vivo efficacy was assessed using xenograft mouse models with H1975 and H460 cells, monitoring tumor growth and treatment toxicity. ResultsMK-1775 combined with gemcitabine or pemetrexed significantly decreased cell survival rates and IC50 values in A549 and HCC827 cell lines. Increased levels of phosphorylated cdc2, γ-H2AX, and PARP indicated enhanced apoptosis. Cell cycle analysis revealed G2/M phase arrest in p53-mutant HCC827 and H1975 cells treated with MK-1775 and gemcitabine. In xenograft models, the combination significantly inhibited tumor growth without significant toxicity. ConclusionsMK-1775 enhances the cytotoxic effects of gemcitabine and pemetrexed in NSCLC cell lines and effectively inhibits tumor growth in vivo. These findings suggest that Wee1 inhibition by MK-1775, combined with chemotherapy, represents a promising therapeutic strategy for NSCLC treatment.

The Effect of Circulating Exosomes Obtained from Young and Old Individuals on the Aging related hTERT and P16 Expression in Hematopoietic Stem Cells

Introduction: Functional reduction of telomeres can induce DNA damage response through cell cycle checkpoints and contribute to the senescence of stem cells. The effect of exosomes on the aging and rejuvenation of hematopoietic stem cells (HSCs) is not well known. Therefore, the present study is designed to examine the impact of plasma exosomes derived from young and old individuals on hTERT and P16 expression involved in the cellular aging process. Methods: Exosomes isolated from four young (Y-Exo) and four old (O-Exo) men were evaluated for CD63 protein expression, morphology, size and zeta potential. HSCs were treated with exosomes, and then, the cell viability and the mRNA expression (hTERT and P16) were evaluated using MTT and qRT-PCR methods, respectively. To measure the hTERT protein level, a western blot technique was performed. Results: The gene expression of hTERT was significantly decreased in HSCs treated with 5 μg/ml (O5-Exo) and 10 μg/ml (O10-Exo) doses of exosomes obtained from elderly individuals compared to the cells treated with young exosomes and the untreated HSCs (p < 0.05). In addition, there was a profound elevation of hTERT protein in the HSCs treated with both doses of young exosomes in comparison with the cells treated with both doses of old exosomes (p < 0.05). Moreover, P16 expression was markedly upregulated in the O5-Exo and O10-Exo groups compared to the untreated group (p < 0.05). Conclusion: Our findings reinforce the concept that depending on the age of individuals, circulating exosomes may acquire properties that affect the pathways involved in the aging process in HSCs.

The Application of CRISPR/Cas9 in Cancer Immunotherapy

Currently, Cancer is the number one killer of human health. The death rate from cancer is increasing year over year as the population ages and grows, particularly since 2019, when there were almost 10 million cases globally recorded by the World Health Organization every year. In light of this trend, it is imperative to continue developing medications and to update and iterate on anti-cancer therapeutic technologies. CAR-T cell therapy, microphage-based therapy, oncolytic virotherapy, and checkpoint blockade therapy are the most popular cancer treatments, but a few patients still cannot tolerate these therapies. A post-optimized strategy is to use gene editing to alter the characteristics of cancer treatment. New therapeutic options for the treatment of complex disorders have become available with the development of CRISPR/Cas9 gene editing technology in recent years. This method is widely used in market research for gene knockdown, endogenous gene expression, and chromosome locus markers because of its accuracy and efficiency in processing harmful gene fragments. Also, it is extremely valuable from a medical standpoint when researching immunomodulator resistance. Despite its great potential, there remain concerns over the technology’s usefulness and efficacy and negative prognostic reactions. This review primarily focuses on the current use of CRISPR/Cas9 in cancer immunotherapies.

EGFR-mediated HSP70 phosphorylation facilitates PCNA association with chromatin and DNA replication.

Efficient DNA replication requires highly coordinated programs for the timely recruitment of protein complexes to DNA replication forks. Defects in this process result in replication stress, which in turn activates cell cycle checkpoints, suppresses cell proliferation and induces apoptosis. In response to persistent cell growth signals that speed up DNA replication processes, cells accelerate the recruitment of DNA replication proteins to avoid DNA replication stress. The mechanisms by which cell growth signals induce processes to facilitate the recruitment of DNA replication proteins onto the replication sites remain unclear. Here, we report that the epidermal growth factor receptor (EGFR) phosphorylates heat shock protein 70 (HSP70) for DNA replication. Such a modification promotes nuclear localization and chromatin association of HSP70, which interacts with the DNA replication coordinator, proliferating cell nuclear antigen (PCNA). HSP70 subsequently facilitates the loading of PCNA onto chromatin. Knockdown or chemical inhibition of HSP70 suppresses PCNA association with chromatin and impairs DNA synthesis and Okazaki fragment maturation, leading to replicative DNA double-strand breaks and apoptosis. Furthermore, chemical inhibition of HSP70 potentiates EGFR-tyrosine kinase inhibitor-induced tumor reduction in vivo. This work expands our understanding of oncogenesis-induced DNA replication processes and provides a foundation for improved treatments for EGFR-mutated lung cancer by simultaneously targeting HSP70.

Role of TRIP13 in human cancer development.

As an AAA + ATPase, thyroid hormone receptor interacting protein 13 (TRIP13) primarily functions in DNA double-strand break repair, chromosome recombination, and cell cycle checkpoint regulation; aberrant expression of TRIP13 can result in chromosomal instability (CIN). According to recent research, TRIP13 is aberrantly expressed in a variety of cancers, and a patient's poor prognosis and tumor stage are strongly correlated with high expression of TRIP13. Tumor cell and subcutaneous xenograft growth can be markedly inhibited by TRIP13 knockdown or TRIP13 inhibitor administration. In the initiation and advancement of human malignancies, TRIP13 seems to function as an oncogene. Based on available data, TRIP13 may function as a biological target and biomarker for cancer. The creation of inhibitors that specifically target TRIP13 may present novel approaches to treating cancer.

Targeting cancer-associated fibroblasts/tumor cells cross-talk inhibits intrahepatic cholangiocarcinoma progression via cell-cycle arrest

BackgroundCancer-associated fibroblasts (CAFs), mainly responsible for the desmoplastic reaction hallmark of intrahepatic Cholangiocarcinoma (iCCA), likely have a role in tumor aggressiveness and resistance to therapy, although the molecular mechanisms involved are unknown. Aim of the study is to investigate how targeting hCAF/iCCA cross-talk with a Notch1 inhibitor, namely Crenigacestat, may affect cancer progression.MethodsWe used different in vitro models in 2D and established new 3D hetero-spheroids with iCCA cells and human (h)CAFs. The results were confirmed in a xenograft model, and explanted tumoral tissues underwent transcriptomic and bioinformatic analysis.ResultshCAFs/iCCA cross-talk sustains increased migration of both KKU-M213 and KKU-M156 cells, while Crenigacestat significantly inhibits only the cross-talk stimulated migration. Hetero-spheroids grew larger than homo-spheroids, formed by only iCCA cells. Crenigacestat significantly reduced the invasion and growth of hetero- but not of homo-spheroids. In xenograft models, hCAFs/KKU-M213 tumors grew significantly larger than KKU-M213 tumors, but were significantly reduced in volume by Crenigacestat treatment, which also significantly decreased the fibrotic reaction. Ingenuity pathway analysis revealed that genes of hCAFs/KKU-M213 but not of KKU-M213 tumors increased tumor lesions, and that Crenigacestat treatment inhibited the modulated canonical pathways. Cell cycle checkpoints were the most notably modulated pathway and Crenigacestat reduced CCNE2 gene expression, consequently inducing cell cycle arrest. In hetero-spheroids, the number of cells increased in the G2/M cell cycle phase, while Crenigacestat significantly decreased cell numbers in the G2/M phase in hetero but not in homo-spheroids.ConclusionsThe hCAFs/iCCA cross-talk is a new target for reducing cancer progression with drugs such as Crenigacestat.Graphical abstract

Computational insights into irinotecan's interaction with UBE2I in ovarian and endometrial cancers

Endometrial and Ovarian cancers are two highly prevalent and fatal reproductive diseases with poor prognoses among women. Elevated estrogen levels in Ovarian Cancer (OC) stimulate the endometrium, causing Endometrial Cancer (EC). Although numerous studies have reported the crucial genes and pathways in this cancer, the pathogenesis of this disease remains unclear. In this study, used bioinformatics tools to analyse GSE63678, GSE115810, GSE36389, GSE26712, GSE36668, GSE27651, GSE6008, GSE69429, GSE69428, GSE18521, GSE185209, GSE54388 gene expression microarray datasets for both the cancers. We analyzed the differential gene expression, functional association, and structural studies. The analysis identified crucial differentially expressed genes (DEGs) in both cancers associated with DNA damage, DNA integrity, and cell-cycle checkpoint signaling pathways. CLDN7, UBE2I, WT1, JAM2, FOXL2, F11R, JAM3, ZFPM2, MEF2C, and PIAS1 are the top 10 hub genes commonly identified in both cancer types. Only CLDN7 and F11R are upregulated, whereas the remaining hub genes are downregulated in both cancers, suggesting a common framework for contributing to tumorigenesis. Molecular docking and dynamics were performed on the UBE2I protein with Irinotecan Hydrochloride, which could serve as the new approach for treating and managing both cancers. The study reveals the common molecular pathways, pointing out the role of cell cycle and DNA damage and integrity checkpoint signaling in the pathogenesis of both cancer types. This study explored the UBE2I gene as a potential biomarker in OC and EC. Further, this study concludes that the irinotecan hydrochloride drug has higher therapeutic effects on UBE2I protein through docking and dynamics studies.

Cell Cycle Complexity: Exploring the Structure of Persistent Subsystems in 414 Models.

Background: The regulation of cellular proliferation and genomic integrity is controlled by complex surveillance mechanisms known as cell cycle checkpoints. Disruptions in these checkpoints can lead to developmental defects and tumorigenesis. Methods: To better understand these mechanisms, computational modeling has been employed, resulting in a dataset of 414 mathematical models in the BioModels database. These models vary significantly in detail and simulated processes, necessitating a robust analytical approach. Results: In this study, we apply the chemical organization theory (COT) to these models to gain insights into their dynamic behaviors. COT, which handles both ordinary and partial differential equations (ODEs and PDEs), is utilized to analyze the compartmentalized structures of these models. COT's framework allows for the examination of persistent subsystems within these models, even when detailed kinetic parameters are unavailable. By computing and analyzing the lattice of organizations, we can compare and rank models based on their structural features and dynamic behavior. Conclusions: Our application of the COT reveals that models with compartmentalized organizations exhibit distinctive structural features that facilitate the understanding of phenomena such as periodicity in the cell cycle. This approach provides valuable insights into the dynamics of cell cycle control mechanisms, refining existing models and potentially guiding future research in this area.

Transcriptome Analysis Reveals the Early Development in Subcutaneous Adipose Tissue of Laiwu Piglets.

Adipose tissue plays an important role in pig production efficiency. Studies have shown that postnatal development has a vital impact on adipose tissue; however, the mechanisms behind pig adipose tissue early-life programming remain unknown. In this study, we analyzed the transcriptomes of the subcutaneous adipose tissue (SAT) of 1-day and 21-day old Laiwu piglets. The results showed that the SAT of Laiwu piglets significantly increased from 1-day to 21-day, and transcriptome analysis showed that there were 2352 and 2596 differentially expressed genes (DEGs) between 1-day and 21-day SAT in male and female piglets, respectively. Expression of genes in glycolysis, gluconeogenesis, and glycogen metabolism such as pyruvate kinase M1/2 (PKM), phosphoenolpyruvate carboxy kinase 1 (PCK1) and amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase (AGL) were significantly different between 1-day and 21-day SAT. Genes in lipid uptake, synthesis and lipolysis such as lipase E (LIPE), acetyl-CoA carboxylase alpha (ACACA), Stearoyl-CoA desaturase (SCD), and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) were also differentially expressed. Functional analysis showed enrichment of DEGs in transcriptional regulation, protein metabolism and cellular signal transduction. The protein-protein interaction (PPI) networks of these DEGs were analyzed and potential hub genes in these pathways were identified, such as transcriptional factors forkhead box O4 (FOXO4), CCAAT enhancer binding protein beta (CEBPB) and CCAAT enhancer binding protein delta (CEBPD), signal kinases BUB1 mitotic checkpoint serine/threonine kinase (BUB1) and cyclin-dependent kinase 1 (CDK1), and proteostasis-related factors ubiquitin conjugating enzyme E2 C (UBE2C) and cathepsin D (CTSD). Moreover, we further analyzed the transcriptomes of SAT between genders and the results showed that there were 54 and 72 DEGs in 1-day and 21-day old SAT, respectively. Genes such as KDM5D and KDM6C showed gender-specific expression in 1-day and 21-day SAT. These results showed the significant changes in SAT between 1-day and 21-day in male and female Laiwu pigs, which would provide information to comprehensively understand the programming of adipose tissue early development and to regulate adipose tissue function.

Cell cycle checkpoint revolution: targeted therapies in the fight against malignant tumors.

Malignant tumors are among the most important causes of death worldwide. The pathogenesis of a malignant tumor is complex and has not been fully elucidated. Studies have shown that such pathogenesis is related to abnormal cell cycle progression. The expression levels of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors as well as functions of the cell cycle checkpoints determine whether the cell cycle progression is smooth. Cell-cycle-targeting drugs have the advantages of high specificity, low toxicity, low side effects, and low drug resistance. Identifying drugs that target the cell cycle and applying them in clinical treatments are expected to promote chemotherapeutic developments against malignant tumors. This article aims to review drugs targeted against the cell cycle and their action mechanisms.

TET2 promotes tumor antigen presentation and T cell IFN-γ which is enhanced by vitamin C.

Immune evasion by tumors is promoted by low T cell infiltration, ineffective T cell activity directed against the tumor and reduced tumor antigen presentation. The TET2 DNA dioxygenase gene is frequently mutated in hematopoietic malignancies and loss of TET enzymatic activity is found in a variety of solid tumors. We showed previously that vitamin C (VC), a co-factor of TET2, enhances tumor-associated T cell recruitment and checkpoint inhibitor therapy responses in a TET2-dependent manner. Using single-cell RNA sequencing (scRNA-seq) analysis performed on B16-OVA melanoma tumors, we have shown here that an additional function for TET2 in tumors is to promote expression of certain antigen presentation machinery genes, which is potently enhanced by VC. Consistently, VC promoted antigen presentation in cell-based and tumor assays in a TET2-dependent manner. Quantifying intercellular signaling from the scRNA-seq dataset showed that T cell-derived IFNγ-induced signaling within the tumor and tumor microenvironment requires tumor-associated TET2 expression which is enhanced by VC treatment. Analysis of patient tumor samples indicated that TET activity directly correlates with antigen-presentation gene expression and with patient outcomes. Our results demonstrate the importance of tumor-associated TET2 activity as a critical mediator of tumor immunity which is augmented by high-dose VC therapy.

Salivary biomarkers: a promising approach for predicting immunotherapy response in head and neck cancers.

Head and neck cancers, including cancers of the mouth, throat, voice box, salivary glands, and nose, are a significant global health issue. Radiotherapy and surgery are commonly used treatments. However, due to treatment resistance and disease recurrence, new approaches such as immunotherapy are being explored. Immune checkpoint inhibitors (ICIs) have shown promise, but patient responses vary, necessitating predictive markers to guide appropriate treatment selection. This study investigates the potential of non-invasive biomarkers found in saliva, oral rinses, and tumor-derived exosomes to predict ICI response in head and neck cancer patients. The tumor microenvironment significantly impacts immunotherapy efficacy. Oral biomarkers can provide valuable information on composition, such as immune cell presence and checkpoint expression. Elevated tumor mutation load is also associated with heightened immunogenicity and ICI responsiveness. Furthermore, the oral microbiota may influence treatment outcomes. Current research aims to identify predictive salivary biomarkers. Initial studies indicate that tumor-derived exosomes and miRNAs present in saliva could identify immunosuppressive pathways and predict ICI response. While tissue-based markers like PD-L1 have limitations, combining multiple oral fluid biomarkers could create a robust panel to guide treatment decisions and advance personalized immunotherapy for head and neck cancer patients.

MAD1 upregulation sensitizes to inflammation-mediated tumor formation.

Mitotic Arrest Deficient 1 (gene name MAD1L1), an essential component of the mitotic spindle assembly checkpoint, is frequently overexpressed in colon cancer, which correlates with poor disease-free survival. MAD1 upregulation induces two phenotypes associated with tumor promotion in tissue culture cells-low rates of chromosomal instability (CIN) and destabilization of the tumor suppressor p53. Using CRISPR/Cas9 gene editing, we generated a novel mouse model by inserting a doxycycline (dox)-inducible promoter and HA tag into the endogenous mouse Mad1l1 gene, enabling inducible expression of HA-MAD1 following exposure to dox in the presence of the reverse tet transactivator (rtTA). A modest 2-fold overexpression of MAD1 in murine colon resulted in decreased p53 expression and increased mitotic defects consistent with CIN. After exposure to the colon-specific inflammatory agent dextran sulfate sodium (DSS), 31% of mice developed colon lesions, including a mucinous adenocarcinoma, while none formed in control animals. Lesion incidence was particularly high in male mice, 57% of which developed at least one hyperplastic polyp, adenoma or adenocarcinoma in the colon. Notably, mice expressing HA-MAD1 also developed lesions in tissues in which DSS is not expected to induce inflammation. These findings demonstrate that MAD1 upregulation is sufficient to promote colon tumorigenesis in the context of inflammation in immune-competent mice.

Alterations in miRNA Expression and Their Role in the Pathogenesis of Cervical Cancer.

Cervical cancer has a high incidence and mortality rate, affecting more than half a million women in 2018. Its development is strongly related to high-risk HPV infection. After infection, several cellular molecules are affected, including microRNAs (miRNAs), which are the focus of our study. We aimed to investigate changes in microRNA expression associated with cervical cancer and analyze the biological significance of these changes induced by HPV proteins. We analyzed transcriptome data retrieved from the NCBI website to investigate miRNA and gene expression in cervical cancer. We evaluated the alteration in expression of miRNAs and genes (between normal tissues and cervical cancer) using the GEO2R tool and selected those with significantly altered expression (p-value < 0.05). The target genes of miRNAs were predicted using the miRNA Pathway Dictionary Database. Subsequently, we created a network of biological pathways affected by miRNA deregulation using Cytoscape software and associated the altered miRNAs with the Hallmarks of Cancer using COSMIC v84. We identified 10 miRNAs and 82 target genes with significantly altered expression levels in cervical cancer that matched the predicted results. In addition, the deregulation of these genes causes changes in 52 biological pathways. These miRNAs affected pathways such as interferon signaling (miR-106b-5p and miR-1183), signaling by interleukins (miR-557, miR-106b-5p, miR-15a-5p, and miR-21-5p), oxidative stress-induced senescence (miR-557 and miR-15a-5p), cell cycle checkpoints (miR-557), transcriptional regulation by P53 (miR-557 and miR-15a-5p), and the exchange of oxygen and carbon dioxide in erythrocytes (miR-15a-5p). Alterations in miRNA expression play an important role in the pathogenesis of cervical cancer, affecting several biological pathways and Hallmarks of Cancer, such as immune system regulation, cell cycle regulation, and energy metabolism. Thus, their analysis can contribute to the development of diagnostic and prognostic biomarkers and more effective treatments for cervical cancer.

Comparative Transcriptomic Analyses Reveal Differences in the Responses of Diploid and Triploid Eastern Oysters to Environmental Stress.

Triploid oysters are commonly used as the basis for production in the aquaculture of eastern oysters along the USA East and Gulf of Mexico coasts. While they are valued for their rapid growth, incidents of triploid mortality during summer months have been well documented in eastern oysters, especially at low salinity sites. We compared global transcriptomic responses of diploid and triploid oysters bred from the same three maternal source populations at two different hatcheries and outplanted to a high (annual mean salinity = 19.4 ± 6.7) and low (annual mean salinity = 9.3 ± 5.0) salinity site. Oysters were sampled for gene expression at the onset of a mortality event in the summer of 2021 to identify triploid-specific gene expression patterns associated with low salinity sites, which ultimately experienced greater triploid mortality. We also examined chromosome-specific gene expression to test for instances of aneuploidy in experimental triploid oyster lines, another possible contributor to elevated mortality in triploids. We observed a strong effect of hatchery conditions (cohort) on triploid-specific mortality (field data) and a strong interactive effect of hatchery, ploidy, and outplant site on gene expression. At the low salinity site where triploid oysters experienced high mortality, we observed downregulation of transcripts related to calcium signaling, ciliary activity, and cell cycle checkpoints in triploids relative to diploids. These transcripts suggest dampening of the salinity stress response and problems during cell division as key cellular processes associated with elevated mortality risk in triploid oysters. No instances of aneuploidy were detected in our triploid oyster lines. Our results suggest that triploid oysters may be fundamentally less tolerant of rapid decreases in salinity, indicating that oyster farmers may need to limit the use of triploid oysters to sites with more stable salinity conditions.