Identification of AURKA as a Biomarker Associated with Cuproptosis and Ferroptosis in HNSCC.

Cuproptosis and ferroptosis represent copper- and iron-dependent forms of cell death, respectively, and both are known to play pivotal roles in head and neck squamous cell carcinoma (HNSCC). However, few studies have explored the prognostic signatures related to cuproptosis and ferroptosis in HNSCC. Our objective was to construct a prognostic model based on genes associated with cuproptosis and ferroptosis. We randomly assigned 502 HSNCC samples from The Cancer Genome Atlas (TCGA) into training and testing sets. Pearson correlation analysis was utilized to identify cuproptosis-associated ferroptosis genes in the training set. Cox proportional hazards (COX) regression and least absolute shrinkage operator (LASSO) were employed to construct the prognostic model. The performance of the prognostic model was internally validated using single-factor COX regression, multifactor COX regression, Kaplan-Meier analysis, principal component analysis (PCA), and receiver operating curve (ROC) analysis. Additionally, we obtained 97 samples from the Gene Expression Omnibus (GEO) database for external validation. The constructed model, based on 12 cuproptosis-associated ferroptosis genes, proved to be an independent predictor of HNSCC prognosis. Among these genes, the increased expression of aurora kinase A (AURKA) has been implicated in various cancers. To further investigate, we employed small interfering RNAs (siRNAs) to knock down AURKA expression and conducted functional experiments. The results demonstrated that AURKA knockdown significantly inhibited the proliferation and migration of HNSCC cells (Cal27 and CNE2). Therefore, AURKA may serve as a potential biomarker in HNSCC.

Synergy of EGFR and AURKA Inhibitors in KRAS-mutated Non-small Cell Lung Cancers.

The most common oncogenic driver mutations for non-small cell lung cancer (NSCLC) activate EGFR or KRAS. Clinical trials exploring treatments for EGFR- or KRAS-mutated (EGFRmut or KRASmut) cancers have focused on small-molecule inhibitors targeting the driver mutations. Typically, these inhibitors perform more effectively based on combination with either chemotherapies, or other targeted therapies. For EGFRmut NSCLC, a combination of inhibitors of EGFR and Aurora-A kinase (AURKA), an oncogene commonly overexpressed in solid tumors, has shown promising activity in clinical trials. Interestingly, a number of recent studies have indicated that EGFR activity supports overall viability of tumors lacking EGFR mutations, and AURKA expression is abundant in KRASmut cell lines. In this study, we have evaluated dual inhibition of EGFR and AURKA in KRASmut NSCLC models. These data demonstrate synergy between the EGFR inhibitor erlotinib and the AURKA inhibitor alisertib in reducing cell viability and clonogenic capacity in vitro, associated with reduced activity of EGFR pathway effectors, accumulation of enhanced aneuploid cell populations, and elevated cell death. Importantly, the erlotinib-alisertib combination also synergistically reduces xenograft growth in vivo. Analysis of signaling pathways demonstrated that the combination of erlotinib and alisertib was more effective than single-agent treatments at reducing activity of EGFR and pathway effectors following either brief or extended administration of the drugs. In sum, this study indicates value of inhibiting EGFR in KRASmut NSCLC, and suggests the specific value of dual inhibition of AURKA and EGFR in these tumors. SIGNIFICANCE: The introduction of specific KRAS G12C inhibitors to the clinical practice in lung cancer has opened up opportunities that did not exist before. However, G12C alterations are only a subtype of all KRAS mutations observed. Given the high expression of AURKA in KRASmut NSCLC, our study could point to a potential therapeutic option for this subgroup of patients.

Meningioma achieves malignancy and erastin-induced ferroptosis resistance through FOXM1-AURKA-NRF2 axis.

The oncogene Aurora kinase A (AURKA) has been implicated in various tumor, yet its role in meningioma remains unexplored. Recent studies have suggested a potential link between AURKA and ferroptosis, although the underlying mechanisms are unclear. This study presented evidence of AURKA upregulation in high grade meningioma and its ability to enhance malignant characteristics. We identified AURKA as a suppressor of erastin-induced ferroptosis in meningioma. Mechanistically, AURKA directly interacted with and phosphorylated kelch-like ECH-associated protein 1 (KEAP1), thereby activating nuclear factor erythroid 2 related factor 2 (NFE2L2/NRF2) and target genes transcription. Additionally, forkhead box protein M1 (FOXM1) facilitated the transcription of AURKA. Suppression of AURKA, in conjunction with erastin, yields significant enhancements in the prognosis of a murine model of meningioma. Our study elucidates an unidentified mechanism by which AURKA governs ferroptosis, and strongly suggests that the combination of AURKA inhibition and ferroptosis-inducing agents could potentially provide therapeutic benefits for meningioma treatment.

eEF1A2 promotes PTEN-GSK3ß-SCF complex-dependent degradation of Aurora kinase A and is inactivated in breast cancer.

The translation elongation factor eEF1A promotes protein synthesis. Its methylation by METTL13 increases its activity, supporting tumor growth. However, in some cancers, a high abundance of eEF1A isoforms is associated with a good prognosis. Here, we found that eEF1A2 exhibited oncogenic or tumor-suppressor functions depending on its interaction with METTL13 or the phosphatase PTEN, respectively. METTL13 and PTEN competed for interaction with eEF1A2 in the same structural domain. PTEN-bound eEF1A2 promoted the ubiquitination and degradation of the mitosis-promoting Aurora kinase A in the S and G2 phases of the cell cycle. eEF1A2 bridged the interactions between the SKP1-CUL1-FBXW7 (SCF) ubiquitin ligase complex, the kinase GSK3ß, and Aurora-A, thereby facilitating the phosphorylation of Aurora-A in a degron site that was recognized by FBXW7. Genetic ablation of Eef1a2 or Pten in mice resulted in a greater abundance of Aurora-A and increased cell cycling in mammary tumors, which was corroborated in breast cancer tissues from patients. Reactivating this pathway using fimepinostat, which relieves inhibitory signaling directed at PTEN and increases FBXW7 expression, combined with inhibiting Aurora-A with alisertib, suppressed breast cancer cell proliferation in culture and tumor growth in vivo. The findings demonstrate a therapeutically exploitable, tumor-suppressive role for eEF1A2 in breast cancer.

AurkA/TPX2 co-overexpression in nontransformed cells promotes genome instability through induction of chromosome mis-segregation and attenuation of the p53 signalling pathway.

The Aurora-A kinase (AurkA) and its major regulator TPX2 (Targeting Protein for Xklp2) are key mitotic players frequently co-overexpressed in human cancers, and the link between deregulation of the AurkA/TPX2 complex and tumourigenesis is actively investigated. Chromosomal instability, one of the hallmarks of cancer related to the development of intra-tumour heterogeneity, metastasis and chemo-resistance, has been frequently associated with TPX2-overexpressing tumours. In this study we aimed to investigate the actual contribution to chromosomal instability of deregulating the AurkA/TPX2 complex, by overexpressing it in nontransformed hTERT RPE-1 cells. Our results show that overexpression of both AurkA and TPX2 results in increased AurkA activation and severe mitotic defects, compared to AurkA overexpression alone. We also show that AurkA/TPX2 co-overexpression yields increased aneuploidy in daughter cells and the generation of micronucleated cells. Interestingly, the p53/p21 axis response is impaired in AurkA/TPX2 overexpressing cells subjected to different stimuli; consistently, cells acquire increased ability to proliferate after independent induction of mitotic errors, i.e. following nocodazole treatment. Based on our observation that increased levels of the AurkA/TPX2 complex affect chromosome segregation fidelity and interfere with the activation of a pivotal surveillance mechanism in response to altered cell division, we propose that co-overexpression of AurkA and TPX2 per se represents a condition promoting the generation of a genetically unstable context in nontransformed human cells.

Inhibition of the AURKA/YAP1 axis is a promising therapeutic option for overcoming cetuximab resistance in colorectal cancer stem cells.

BACKGROUND: Primary resistance to anti-EGFR therapies affects 40% of metastatic colorectal cancer patients harbouring wild-type RAS/RAF. YAP1 activation is associated with this resistance, prompting an investigation into AURKA's role in mediating YAP1 phosphorylation at Ser397, as observed in breast cancer. METHODS: We used transcriptomic analysis along with in vitro and in vivo models of RAS/RAF wild-type CRC to study YAP1 Ser397 phosphorylation as a potential biomarker for cetuximab resistance. We assessed cetuximab efficacy using CCK8 proliferation assays and cell cycle analysis. Additionally, we examined the effects of AURKA inhibition with alisertib and created a dominant-negative YAP1 Ser397 mutant to assess its impact on cancer stem cell features. RESULTS: The RAS/RAF wild-type CRC models exhibiting primary resistance to cetuximab prominently displayed elevated YAP1 phosphorylation at Ser397 primarily mediated by AURKA. AURKA-induced YAP1 phosphorylation was identified as a key trigger for cancer stem cell reprogramming. Consequently, we found that AURKA inhibition had the capacity to effectively restore cetuximab sensitivity and concurrently suppress the cancer stem cell phenotype. CONCLUSIONS: AURKA inhibition holds promise as a therapeutic approach to overcome cetuximab resistance in RAS/RAF wild-type colorectal cancer, offering a potential means to counter the development of cancer stem cell phenotypes associated with cetuximab resistance.

ZNF468 inhibits irradiation-induced G2/M cell cycle arrest and apoptosis by facilitating AURKA transcription in Esophageal Squamous Cell Carcinoma.

BACKGROUND: ZNF468 is a relatively unexplored gene that has been implicated in potential oncogenic properties in various cancer types. However, the exact role of ZNF468 in radiotherapy resistance of esophageal squamous cell carcinomas (ESCCs) is not well understood. METHODS: Bioinformatic analysis was performed using the TCGA database to assess ZNF468 expression and prognostic significance in pan-cancer and ESCC. Functional experiments were conducted using ZNF468 overexpressing and knockdown cell lines to assess its impact on cell survival, DNA damage response, cell cycle, and apoptosis upon radiation. A luciferase reporter assay was utilized to validate ZNF468 binding to the AURKA promoter. RESULTS: ZNF468 was significantly upregulated in diverse cancer types, including ESCC, and its high expression correlated with adverse prognosis in specific tumors. In the ESCC cohort, ZNF468 exhibited substantial upregulation in post-radiotherapy tissues, indicating its potential role in conferring radiotherapy resistance. Functional experiments revealed that ZNF468 enhances cell viability and facilitates DNA damage repair in radiotherapy-treated ESCC cells, while dampening the G2/M cell cycle arrest and apoptosis induced by radiation. Moreover, ZNF468 facilitated AURKA transcription, resulting in upregulated Aurora A expression, and subsequently inhibited P53 expression, unveiling key molecular mechanisms underlying radiotherapy resistance in ESCC. CONCLUSION: ZNF468 plays an oncogenic role in ESCC and contributes to radiotherapy resistance. It enhances cell survival while dampening radiation-induced G2/M cell cycle arrest and apoptosis. By modulating AURKA and P53 expression, ZNF468 represents a promising therapeutic target for enhancing radiotherapy efficacy in ESCC.

AURKA Enhances the Glycolysis and Development of Ovarian Endometriosis Through ERß.

Ovarian endometriosis (EMs) is a benign, estrogen-dependent gynecological disorder. Estrogen receptor beta (ERß), a nuclear receptor for estradiol, plays an important role in the development of ovarian EMs. Here, we investigated the biological significance of aurora kinase A (AURKA) in ovarian EMs and the mechanism by which it regulates ERß. We used immunohistochemical assays to verify that AURKA and ERß were highly expressed in ectopic endometrial tissues. Cell proliferation and colony formation assays were used to demonstrate that AURKA promoted the proliferation of EMs cells. Wound-healing assay, Transwell migration assay, and Matrigel invasion assay further showed that AURKA enhanced the ability of EMs cells to migrate and invade. In addition, AURKA was shown to stimulate glycolysis in EMs cells by measuring the concentration of glucose and lactate in the cell supernatants. Moreover, the AURKA inhibitor alisertib was found to inhibit the progression of ovarian EMs and glycolysis in a mouse model of EMs by measuring ectopic tissues as well as by testing the peritoneal fluid of mice. Furthermore, coimmunoprecipitation assay showed that AURKA interacted with ERß. The rescue experiments confirmed that AURKA regulated the development and glycolysis of ovarian EMs in an ERß-dependent manner. AURKA contributed to the development of ovarian EMs by upregulating of ERß. AURKA may represent a new target for the treatment of ovarian EMs.

Male meiotic spindle poles are stabilized by TACC3 and cKAP5/chTOG differently from female meiotic or somatic mitotic spindles in mice.

Transforming acidic acid coiled-coil protein 3 (TACC3) and cytoskeleton associated protein 5 (cKAP5; or colonic hepatic tumor overexpressed gene, chTOG) are vital for spindle assembly and stabilization initiated through TACC3 Aurora-A kinase interaction. Here, TACC3 and cKAP5/chTOG localization with monospecific antibodies is investigated in eGFP-centrin-2- expressing mouse meiotic spermatocytes. Both proteins bind spermatocyte spindle poles but neither kinetochore nor interpolar microtubules, unlike in mitotic mouse fibroblasts or female meiotic oocyte spindles. Spermatocytes do not display a liquid-like spindle domain (LISD), although fusing them into maturing oocytes generates LISD-like TACC3 condensates around sperm chromatin but sparse microtubule assembly. Microtubule inhibitors do not reduce TACC3 and cKAP5/chTOG spindle pole binding. MLN 8237 Aurora-A kinase inhibitor removes TACC3, not cKAP5/chTOG, disrupting spindle organization, chromosome alignment, and impacting spindle pole γ-tubulin intensity. The LISD disruptor 1,6-hexanediol abolished TACC3 in spermatocytes, impacting spindle bipolarity and chromosome organization. Cold microtubule disassembly and rescue experiments in the presence of 1,6-hexanediol reinforce the concept that spermatocyte TACC3 spindle pole presence is not required for spindle pole microtubule assembly. Collectively, meiotic spermatocytes without a LISD localize TACC3 and cKAP5/chTOG exclusively at spindle poles to support meiotic spindle pole stabilization during male meiosis, different from either female meiosis or mitosis.

Deletion of Aurora kinase A prevents the development of polycystic kidney disease in mice.

Aurora Kinase A (AURKA) promotes cell proliferation and is overexpressed in different types of polycystic kidney disease (PKD). To understand AURKA's role in regulating renal cyst development we conditionally deleted the gene in mouse models of Autosomal Dominant PKD (ADPKD) and Joubert Syndrome, caused by Polycystin 1 (Pkd1) and Inositol polyphosphate-5-phosphatase E (Inpp5e) mutations respectively. We show that while Aurka is dispensable for collecting duct development and homeostasis, its deletion prevents cyst formation in both disease models. Cross-comparison of transcriptional changes implicated AKT signaling in cyst prevention and we show that (i) AURKA and AKT physically interact, (ii) AURKA regulates AKT activity in a kinase-independent manner and (iii) inhibition of AKT can reduce disease severity. AKT activation also regulates Aurka expression, creating a feed-forward loop driving renal cystogenesis. We find that the AURKA kinase inhibitor Alisertib stabilises the AURKA protein, agonizing its cystogenic functions. These studies identify AURKA as a master regulator of renal cyst development in different types of PKD, functioning in-part via AKT.

Single-cell multi-omics profiling of human preimplantation embryos identifies cytoskeletal defects during embryonic arrest.

Human in vitro fertilized embryos exhibit low developmental capabilities, and the mechanisms that underlie embryonic arrest remain unclear. Here using a single-cell multi-omics sequencing approach, we simultaneously analysed alterations in the transcriptome, chromatin accessibility and the DNA methylome in human embryonic arrest due to unexplained reasons. Arrested embryos displayed transcriptome disorders, including a distorted microtubule cytoskeleton, increased genomic instability and impaired glycolysis, which were coordinated with multiple epigenetic reprogramming defects. We identified Aurora A kinase (AURKA) repression as a cause of embryonic arrest. Mechanistically, arrested embryos induced through AURKA inhibition resembled the reprogramming abnormalities of natural embryonic arrest in terms of the transcriptome, the DNA methylome, chromatin accessibility and H3K4me3 modifications. Mitosis-independent sequential activation of the zygotic genome in arrested embryos showed that YY1 contributed to human major zygotic genome activation. Collectively, our study decodes the reprogramming abnormalities and mechanisms of human embryonic arrest and the key regulators of zygotic genome activation.

An emerging biomarker for the diagnosis and treatment of esophageal squamous cell carcinoma - Aurora A.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a prominent form of esophageal cancer. Aurora A (AURKA), an enzyme that phosphorylates serine and threonine, has a vital function in controlling the process of separating chromosomes during cell division. The contribution of this entity has been documented in the advancement of malignant proliferations, including tumors occurring in the breast, stomach, and ovaries. METHODS: The potential molecular mechanism of AURKA is comprehensively examined through the analysis of bulk RNA-seq and single-cell RNA-seq data obtained from publicly available databases. This analysis encompasses various aspects such as expression levels, prognosis, and functional pathways, among others. RESULTS: The upregulation of AURKA in ESCC has been found to be correlated with the overall survival of patients. The functional annotation and pathway enrichment analysis conducted in this study lead to the conclusion that AURKA participates in the regulation of a number of malignant processes connected to cell proliferation, such as cell cycle control, apoptosis, and the p53 signaling pathway. Additionally, AURKA has been found to be associated with drug sensitivity and has an impact on the infiltration of tumor-infiltrating immune cells in ESCC. CONCLUSIONS: AURKA exhibits potential as a prognostic and therapeutic biomarker linked to the regulation of cell cycle and cell proliferation.

Store-operated calcium entry inhibits primary ciliogenesis via the activation of Aurora A.

The primary cilium is an antenna-like organelle protruding from the cell surface that can detect physical and chemical stimuli in the extracellular space to activate specific signaling pathways and downstream gene expressions. Calcium ion (Ca2+ ) signaling regulates a wide spectrum of cellular processes, including fertilization, proliferation, differentiation, muscle contraction, migration, and death. This study investigated the effects of the regulation of cytosolic Ca2+ levels on ciliogenesis using chemical, genetic, and optogenetic approaches. We found that ionomycin-induced Ca2+ influx inhibited ciliogenesis and Ca2+ chelator BATPA-AM-induced Ca2+ depletion promoted ciliogenesis. In addition, store-operated Ca2+ entry and the endoplasmic reticulum Ca2+ sensor stromal interaction molecule 1 (STIM1) negatively regulated ciliogenesis. Moreover, an optogenetic platform was used to create different Ca2+ oscillation patterns by manipulating lighting parameters, including density, frequency, exposure time, and duration. Light-activated Ca2+ -translocating channelrhodopsin (CatCh) is activated by 470-nm blue light to induce Ca2+ influx. Our results show that high-frequency Ca2+ oscillations decrease ciliogenesis. Furthermore, the inhibition of cilia formation induced by Ca2+ may occur via the activation of Aurora kinase A. Cilia not only induce Ca2+ signaling but also regulate cilia formation by Ca2+ signaling.

The PIN1-YTHDF1 axis promotes breast tumorigenesis via the m6A-dependent stabilization of AURKA mRNA.

The post-transcriptional processing of N6-methyladenosine (m6A)-modified mRNA by YTH domain-containing family protein 1 (YTHDF1) plays a crucial role in the regulation of gene expression. Although YTHDF1 expression is frequently upregulated in breast cancer, the regulatory mechanisms for this remain unclear. In this study, we examined the role of peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) in regulating YTHDF1 stability in breast cancer cells. The WW domain of PIN1 interacted with YTHDF1 in a phosphorylation-dependent manner. Additionally, PIN1 overexpression increased YTHDF1 stability by preventing ubiquitin-dependent proteasomal degradation. Furthermore, using the MS2-tagged RNA pull-down assay, we identified Aurora kinase A (AURKA) mRNA as a bona fide substrate of YTHDF1. PIN1-mediated YTHDF1 stabilization increased the stability of AURKA mRNA in an m6A-dependent manner. Furthermore, YTHDF1 knockout reduced AURKA protein expression levels, resulting in anticancer effects in breast cancer cells, including decreased cell proliferation, cell cycle arrest at the G0/G1 phase, apoptotic cell death, and decreased spheroid formation. The anticancer effects induced by YTHDF1 knockout were reversed by AURKA overexpression. Similarly, the knockout of PIN1 produced comparable anticancer effects to those observed in YTHDF1-knockout cells, and these effects were reversed upon overexpression of YTHDF1. In conclusion, the findings of our study suggest that increased YTHDF1 stability induced by PIN1 promotes breast tumorigenesis via the stabilization of AURKA mRNA. Targeting the PIN1/YTHDF1 axis may represent a novel therapeutic strategy for breast cancer.

AURKAIP1 actuates tumor progression through stabilizing DDX5 in triple negative breast cancer.

Aurora-A kinase interacting protein 1 (AURKAIP1) has been proved to take an intermediary role in cancer by functioning as a negative regulator of Aurora-A kinase. However, it remains unclear whether and how AURKAIP1 itself would directly engage in regulating malignancies. The expression levels of AURKAIP1 were detected in triple negative breast cancer (TNBC) by immunohistochemistry and western blots. The CCK8, colony formation assays and nude mouse model were conducted to determine cell proliferation whereas transwell and wound healing assays were performed to observe cell migration. The interaction of AURKAIP1 and DEAD-box helicase 5 (DDX5) were verified through co-immunoprecipitation and successively western blots. From the results, we found that AURKAIP1 was explicitly upregulated in TNBC, which was positively associated with tumor size, lymph node metastases, pathological stage and unfavorable prognosis. AURKAIP1 silencing markedly inhibited TNBC cell proliferation and migration in vitro and in vivo. AURKAIP1 directly interacted with and stabilized DDX5 protein by preventing ubiquitination and degradation, and DDX5 overexpression successfully reversed proliferation inhibition induced by knockdown of AURKAIP1. Consequently, AURKAIP1 silencing suppressed the activity of Wnt/ß-catenin signaling in a DDX5-dependent manner. Our study may primarily disclose the molecular mechanism by which AURKAIP1/DDX5/ß-catenin axis modulated TNBC progression, indicating that AURKAIP1 might serve as a therapeutic target as well as a TNBC-specific biomarker for prognosis.

Aurora A kinase inhibition induces accumulation of SCLC tumor cells in mitosis with restored interferon signaling to increase response to PD-L1.

Despite small cell lung cancers (SCLCs) having a high mutational burden, programmed death-ligand 1 (PD-L1) immunotherapy only modestly increases survival. A subset of SCLCs that lose their ASCL1 neuroendocrine phenotype and restore innate immune signaling (termed the "inflammatory" subtype) have durable responses to PD-L1. Some SCLCs are highly sensitive to Aurora kinase inhibitors, but early-phase trials show short-lived responses, suggesting effective therapeutic combinations are needed to increase their durability. Using immunocompetent SCLC genetically engineered mouse models (GEMMs) and syngeneic xenografts, we show durable efficacy with the combination of a highly specific Aurora A kinase inhibitor (LSN3321213) and PD-L1. LSN3321213 causes accumulation of tumor cells in mitosis with lower ASCL1 expression and higher expression of interferon target genes and antigen-presentation genes mimicking the inflammatory subtype in a cell-cycle-dependent manner. These data demonstrate that inflammatory gene expression is restored in mitosis in SCLC, which can be exploited by Aurora A kinase inhibition.

Aurora A Kinase Plays a Key Role in Mitosis Skip during Senescence Induced by Ionizing Radiation.

Objective: To investigate the fate and underlying mechanisms of G2 phase arrest in cancer cells elicited by ionizing radiation (IR). Methods: Human melanoma A375 and 92-1 cells were treated with X-rays radiation or Aurora A inhibitor MLN8237 (MLN) and/or p21 depletion by small interfering RNA (siRNA). Cell cycle distribution was determined using flow cytometry and a fluorescent ubiquitin-based cell cycle indicator (FUCCI) system combined with histone H3 phosphorylation at Ser10 (pS10 H3) detection. Senescence was assessed using senescence-associated-ß-galactosidase (SA-ß-Gal), Ki67, and γH2AX staining. Protein expression levels were determined using western blotting. Results: Tumor cells suffered severe DNA damage and underwent G2 arrest after IR treatment. The damaged cells did not successfully enter M phase nor were they stably blocked at G2 phase but underwent mitotic skipping and entered G1 phase as tetraploid cells, ultimately leading to senescence in G1. During this process, the p53/p21 pathway is hyperactivated. Accompanying p21 accumulation, Aurora A kinase levels declined sharply. MLN treatment confirmed that Aurora A kinase activity is essential for mitosis skipping and senescence induction. Conclusion: Persistent p21 activation during IR-induced G2 phase blockade drives Aurora A kinase degradation, leading to senescence via mitotic skipping.

Unraveling the Aurora kinase A and Epstein-Barr nuclear antigen 1 axis in Epstein Barr virus associated gastric cancer.

Aurora kinase A (AURKA) is one of the crucial cell cycle regulators associated with gastric cancer. Here, we explored Epstein Barr Virus-induced gastric cancer progression through EBV protein EBNA1 with AURKA. We found that EBV infection enhanced cell proliferation and migration of AGS cells and upregulation of AURKA levels. AURKA knockdown markedly reduced the proliferation and migration of the AGS cells even with EBV infection. Moreover, MD-simulation data deciphered the probable connection between EBNA1 and AURKA. The in-vitro analysis through the transcript and protein expression showed that AURKA knockdown reduces the expression of EBNA1. Moreover, EBNA1 alone can enhance AURKA protein expression in AGS cells. Co-immunoprecipitation and NMR analysis between AURKA and EBNA1 depicts the interaction between two proteins. In addition, AURKA knockdown promotes apoptosis in EBV-infected AGS cells through cleavage of Caspase-3, -9, and PARP1. This study demonstrates that EBV oncogenic modulators EBNA1 possibly modulate AURKA in EBV-mediated gastric cancer progression.

A novel risk model of three gefitinib-related genes FBP1, SBK1 and AURKA is related to the immune microenvironment and is predicting prognosis of lung adenocarcinoma patients.

PURPOSE: Gefitinib, an anticancer drug, has been reported to potentially improve the prognosis of patients with lung adenocarcinoma (LUAD). This study aims to investigate the roles and mechanisms of Gefitinib. METHODS: The effects of Gefitinib on the growth and migration of LUAD cells were assessed using various methods, including CCK-8, flow cytometry, wound healing, and Transwell assays. To analyze the function and mechanisms of the differentially expressed Gefitinib target genes (GTGs), data from the TCGA database were utilized. Kaplan-Meier survival and ROC analysis identified prognostic-related GTGs and constructed a prognostic nomogram in LUAD. Consensus clustering, COX analysis and survival analysis evaluated the relationship between GTGs and the prognosis of LUAD patients. The mechanisms of the risk model involved LUAD progression, and the relationship between the risk model and immune microenvironment were investigated. RESULTS: Gefitinib could inhibit proliferation, migration and invasion and promote cell apoptosis. 84 DEGTGs were involved in RAS, MAPK, ERBB pathways. The DEGTGs (FBP1, SBK1, and AURKA) were the independent risk factors for dismal prognosis of LUAD patients and were used to establish risk model and nomogram. Gefitinib could promote the expression of FBP1 and inhibit the expression of SBK1 and AURKA. High-risk LUAD patients had the dismal prognosis, and the high-risk score group was significantly associated with the immune microenvironment. CONCLUSION: FBP1, SBK1, and AURKA are prognostic risk factors, and the risk model and nomogram of FBP1, SBK1 and AURKA are associated with dismal prognosis and immune cell infiltration, and have huge prospects for application in evaluating the prognosis in LUAD.

Proliferation-Related Features of the Human Mesenchymal Stem Cells Derived from Palatine Tonsils, Adipose Tissues, and Bone Marrow.

BACKGROUND: Mesenchymal stem cells (MSCs) are widely used in regenerative medicine and cell-based transplantations. However, an in-depth comparison of the different MSC origins is lacking. This study aimed to compare the expression of adipose-derived (AMSCs), bone marrow-derived (BMSCs), and tonsil-derived (TMSCs) and evaluate whether TMSCs are good alternatives for AMSCs or BMSCs. METHODS: We analyzed the expression levels of 47,000 transcripts in AMSCs (n = 4), BMSCs (n = 4), and TMSCs (n = 4) using GeneChip. Microarray data were analyzed using the LIMMA package to compare the TMSCs, AMSCs, and BMSCs. Hub genes were analyzed using STRING and Cytoscape. To ascertain the functional roles of AURKA and AURKB, small interfering RNA (siRNA) molecules specifically targeting AURKA and AURKB mRNA were synthesized and employed to induce knockdown of AURKA and AURKB in TMSC and AMSC. We analyzed the expression level of OCT4, SOX-2, and NANOG genes in TMSC and AMSCs by cell culture and real-time PCR. RESULTS: We identified commonly increased 256 and decreased 160 genes in TMSCs from the differentially expressed genes (DEGs) between the TMSCs, AMSCs, and BMSCs. In the DEG-based protein-protein interaction and gene set enrichment analysis, hub genes (AURKA, AURKB, CDC20, and BUB1) highly expressed in TMSCs were enriched for development- and progression-related oocyte meiosis, the cell cycle, and ubiquitin-mediated proteolysis. In vitro analysis demonstrated that cells with downregulated expression of AURKA and AURKB exhibited a significant reduction in proliferation compared to control cells. However, silencing of the genes did not affect the differentiation capacity in TMSCs and AMSCs. CONCLUSION: Our study compared MSCs of different origins to better understand the similarities and differences among these cell types.