hsa-miR-CHA2, a novel microRNA, exhibits anticancer effects by suppressing cyclin E1 in human non-small cell lung cancer cells.

Despite considerable therapeutic advancements, the global survival rate for lung cancer patients remains poor, posing challenges in developing an effective treatment strategy. In many cases, microRNAs (miRNAs) exhibit abnormal expression levels in cancers, including lung cancer. Dysregulated miRNAs often play a crucial role in the development and progression of cancer. Therefore, understanding the mechanisms underlying aberrant miRNA expression during carcinogenesis may provide crucial clues to develop novel therapeutics. In this study, we identified and cloned a novel miRNA, hsa-miR-CHA2, which is abnormally downregulated in non-small cell lung cancer (NSCLC)-derived cell lines and tissues of patients with NSCLC. Furthermore, we found that hsa-miR-CHA2 regulates the post-transcriptional levels of Cyclin E1 (CCNE1) by binding to the 3'-UTR of CCNE1 mRNA. CCNE1, a cell cycle regulator involved in the G1/S transition, is often amplified in various cancers. Notably, hsa-miR-CHA2 overexpression led to the alteration of the Rb-E2F pathway, a significant signaling pathway in the cell cycle, by targeting CCNE1 in A549 and SK-LU-1 cells. Subsequently, we confirmed that hsa-miR-CHA2 induced G1-phase arrest and exhibited an anti-proliferative effect by targeting CCNE1. Moreover, in subcutaneous xenograft mouse models, intra-tumoral injection of polyplexed hsa-miR-CHA2 mimic suppressed tumor growth and development. In conclusion, hsa-miR-CHA2 exhibited an anticancer effect by targeting CCNE1 both in vitro and in vivo. These findings suggest the potential role of hsa-miR-CHA2 as an important regulator of cell proliferation in molecular-targeted therapy for NSCLC.

AURKB promotes colorectal cancer progression by triggering the phosphorylation of histone H3 at serine 10 to activate CCNE1 expression.

Aurora kinase B (AURKB) initiates the phosphorylation of serine 10 on histone H3 (pH3S10), a crucial process for chromosome condensation and cytokinesis in mammalian mitosis. Nonetheless, the precise mechanisms through which AURKB regulates the cell cycle and contributes to tumorigenesis as an oncogenic factor in colorectal cancer (CRC) remain unclear. Here, we report that AURKB was highly expressed and positively correlated with Ki-67 expression in CRC. The abundant expression of AURKB promotes the growth of CRC cells and xenograft tumors in animal model. AURKB knockdown substantially suppressed CRC proliferation and triggered cell cycle arrest in G2/M phase. Interestingly, cyclin E1 (CCNE1) was discovered as a direct downstream target of AURKB and functioned synergistically with AURKB to promote CRC cell proliferation. Mechanically, AURKB activated CCNE1 expression by triggering pH3S10 in the promoter region of CCNE1. Furthermore, it was showed that the inhibitor specific for AURKB (AZD1152) can suppress CCNE1 expression in CRC cells and inhibit tumor cell growth. To conclude, this research demonstrates that AURKB accelerated the tumorigenesis of CRC through its potential to epigenetically activate CCNE1 expression, suggesting AURKB as a promising therapeutic target in CRC.

CircROR1 upregulates CCNE1 expression to promote melanoma invasion and metastasis by recruiting KAT2A.

Circular RNAs (circRNAs) play important roles in cancer occurrence and progression. To explore and elucidate the clinical significance of specific circular RNA in melanoma and its potential molecular mechanism. CircROR1 expression in melanoma cells and tissues was confirmed by qRT-PCR and ISH. qRT-PCR and Western blotting were performed to measure the levels of CCNE1, KAT2A, MMP9 and TIMP2. MTT, Transwell and wound healing assays were performed to evaluate cell proliferation, invasion and metastasis. A xenograft mouse model was established to further verify the CircROR1/CCNE1 axis in vivo. RNA pull-down and RIP assays were performed to detect the direct interaction KAT2A and CircROR1. A ChIP assay was used to investigate the enrichment of H3K9ac acetylation in the CCNE1 promoter. CircROR1 was significantly upregulated in metastatic melanoma cells and tissues, promoting proliferation, invasion and metastasis in vitro and tumour growth in vivo. CircROR1 overexpression increased CCNE1 and MMP9 protein expression and decreased TIMP2 protein expression. Functional rescue assays demonstrated that CircROR1 played a role in promoting malignant progression through CCNE1. CircROR1 specifically bound to the KAT2A protein without affecting its expression. CircROR1 overexpression increased the level of H3K9ac modification in the CCNE1 promoter region by recruiting KAT2A, thus upregulating CCNE1 expression. CircROR1 upregulates CCNE1 expression through KAT2A-mediated histone acetylation. Our research confirms the critical role of CircROR1 in melanoma invasion and metastasis, and CircROR1 could serve as a potential therapeutic target for melanoma treatment.

Discovery of novel macrocyclic derivatives as potent and selective cyclin-dependent kinase 2 inhibitors.

Cyclin-dependent kinase 2 (CDK2) is a member of CDK family of kinases (CDKs) that regulate the cell cycle. Its inopportune or over-activation leads to uncontrolled cell cycle progression and drives numerous types of cancers, especially ovarian, uterine, gastric cancer, as well as those associated with amplified CCNE1 gene. However, developing selective lead compound as CDK2 inhibitors remains challenging owing to similarities in the ATP pockets among different CDKs. Herein, we described the optimization of compound 1, a novel macrocyclic inhibitor targeting CDK2/5/7/9, aiming to discover more selective and metabolically stable lead compound as CDK2 inhibitor. Molecular dynamic (MD) simulations were performed for compound 1 and 9 to gain insights into the improved selectivity against CDK5. Further optimization efforts led to compound 22, exhibiting excellent CDK2 inhibitory activity, good selectivity over other CDKs and potent cellular effects. Based on these characterizations, we propose that compound 22 holds great promise as a potential lead candidate for drug development.

RAD52-dependent mitotic DNA synthesis is required for genome stability in Cyclin E1-overexpressing cells.

Overexpression of Cyclin E1 perturbs DNA replication, resulting in DNA lesions and genomic instability. Consequently, Cyclin E1-overexpressing cancer cells increasingly rely on DNA repair, including RAD52-mediated break-induced replication during interphase. We show that not all DNA lesions induced by Cyclin E1 overexpression are resolved during interphase. While DNA lesions upon Cyclin E1 overexpression are induced in S phase, a significant fraction of these lesions is transmitted into mitosis. Cyclin E1 overexpression triggers mitotic DNA synthesis (MiDAS) in a RAD52-dependent fashion. Chemical or genetic inactivation of MiDAS enhances mitotic aberrations and persistent DNA damage. Mitosis-specific degradation of RAD52 prevents Cyclin E1-induced MiDAS and reduces the viability of Cyclin E1-overexpressing cells, underscoring the relevance of RAD52 during mitosis to maintain genomic integrity. Finally, analysis of breast cancer samples reveals a positive correlation between Cyclin E1 amplification and RAD52 expression. These findings demonstrate the importance of suppressing mitotic defects in Cyclin E1-overexpressing cells through RAD52.

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.

miR-26a-5p inhibits the proliferation of psoriasis-like keratinocytes in vitro and in vivo by dual interference with the CDC6/CCNE1 axis.

Psoriasis is a chronic inflammatory proliferative dermatological ailment that currently lacks a definitive cure. Employing data mining techniques, this study identified a collection of substantially downregulated miRNAs (top 10). Notably, 32 targets were implicated in both the activation of the IL-17 signaling pathway and cell cycle dysregulation. In silico analysis revealed that one of these miRNAs, miR-26a-5p, is a highly conserved cross-species miRNA. Strikingly, the miR-26a-5p sequences in humans and mice are identical, and mmu-miR-26a-5p was found to target the same 7 cell cycle targets as its human counterpart, hsa-miR-26a-5p. Among these targets, CDC6 and CCNE1 were the most effective targets of miR-26a-5p, which was further validated in vitro using a dual luciferase reporter system and qPCR assay. The therapeutic assessment of miR-26a-5p revealed its remarkable efficacy in inhibiting the proliferation and G1/S transition of keratinocytes (HaCaT and HEKs) in vitro. In vivo experiments corroborated these findings, demonstrating that miR-26a-5p effectively suppressed imiquimod (IMQ)-induced psoriasis-like skin lesions in mice over an 8-day treatment period. Histological analysis via H&E staining revealed that miR-26a-5p treatment resulted in reduced keratinocyte thickness and immune cell infiltration into the spleens of IMQ-treated mice. Mechanistic investigations revealed that miR-26a-5p induced a cascade of downregulated genes associated with the IL-23/IL-17A axis, which is known to be critical in psoriasis pathogenesis, while concomitantly suppressing CDC6 and CCNE1 expression. These findings were corroborated by qPCR and Western blot analyses. Collectively, our study provides compelling evidence supporting the therapeutic potential of miR-26a-5p as a safe and reliable endogenous small nucleic acid for the treatment of psoriasis.

Targeting CCNE1 amplified ovarian and endometrial cancers by combined inhibition of PKMYT1 and ATR.

Ovarian cancers (OVCAs) and endometrial cancers (EMCAs) with CCNE1-amplification are often resistant to standard of care treatment and represent an unmet clinical need. Previously, synthetic-lethal screening identified loss of the CDK1 regulator, PKMYT1, as synthetically lethal with CCNE1-amplification. We hypothesized that CCNE1-amplification associated replication stress will be more effectively targeted by combining the PKMYT1 inhibitor, lunresertib (RP-6306), with the ATR inhibitor, camonsertib (RP-3500/RG6526). Low dose combination RP-6306 with RP-3500 synergistically increased cytotoxicity more in CCNE1 amplified compared to non-amplified cells. Combination treatment produced durable antitumor activity and increased survival in CCNE1 amplified patient-derived and cell line-derived xenografts. Mechanistically, low doses of RP-6306 with RP-3500 increase CDK1 activation more so than monotherapy, triggering rapid and robust induction of premature mitosis, DNA damage and apoptosis in a CCNE1-dependent manner. These findings suggest that targeting CDK1 activity by combining RP-6306 with RP-3500 is a novel therapeutic approach to treat CCNE1-amplifed OVCAs and EMCAs.

Exploring the Molecular Targets and Therapeutic Potential of Coptisine in Colon Cancer: A Network Pharmacology Approach.

INTRODUCTION: Colon cancer is a frequent malignancy, and surgery is still the primary therapy for people with colon cancer. Other treatments, including radiation, chemotherapy, and biologic therapy, may be utilized as a supplement. Chemotherapy, a prominent treatment for colon cancer, has failed to provide positive outcomes. This necessitates the development of more effective and less harmful treatment drugs. Coptisine was discovered to inhibit the development of colon cancer cell line HCT-116 in vivo, decrease the growth of HCT-116 cells, and cause apoptosis in vitro in colon cancer. Coptisine (COP) has shown antitumor activity in colon cancer, but its molecular mechanism and its molecular targets have not been fully understood. METHODS: In this study, the biological behavior was verified in vitro. The targets of Huanglian alkaloids on colon cancer were predicted, and the protein-protein interaction (PPI) network was constructed. The core targets of safranine for colon cancer were extracted and analyzed by GO and KEGG enrichment to identify the possible molecular mechanisms of safranine treatment. Western blot was used to detect the changes of related pathway proteins in colon cancer cells. The differential expression of hub genes in colon cancer was analyzed using the GEPIA2 website. The binding ability of safranine to the target was verified by molecular docking. Finally, the targets were preliminarily verified by q-PCR analysis. RESULTS: Coptisine can inhibit the survival, migration, and proliferation of colon cancer cells DLD1 and HCT-116. Based on network pharmacology, ninety-one targets for colon cancer were screened. ESR1, ALB, AR, CDK2, PARP1, HSP90AB1, IGF1R, CCNE1, and CDC42 were found in the top 10. Enrichment analysis showed that these targets were mainly related to pathways in cancer, FC γ R-mediated phagocytosis, prostate cancer, progesterone-mediated oocyte maturation, the oestrogen signal pathway, proteoglycan in cancer and the PI3K-Akt signal pathway. WB results showed that after the treatment of colon cancer DLD1 cells with coptisine, the expression of P-AKT and AKT decreased, that of its downstream protein Bcl-2 decreased, and that of BAX increased. Differential expression analysis of hub genes showed that CCNE1, CDK2, HSP90AB1, and CHEK2 were upregulated in colon cancer samples, and molecular docking showed that these targets had a good ability to bind to coptisine. After the treatment of colon cancer DLD1 cells with coptisine, q-PCR results showed that CCNE1 and HSP90AB1 were significantly downregulated, while CDK2 and CHEK2 had no significant changes. CONCLUSION: Coptisine may be a candidate drug for the treatment of colon cancer, and its therapeutic effect may be related to the cancer pathway and PI3K-Akt signalling pathway. CCNE1 and HSP90AB1 may be potential targets of coptisine in the treatment of colon cancer.

PKMYT1: A Potential Target for CCNE1 Amplificated Colorectal Tumors.

Colorectal cancer is a malignant tumor with higher morbidity and mortality. The purpose of this study is to investigate whether inhibition of Protein Kinase, Membrane Associated Tyrosine/Threonine 1 (PKMYT1) affects tumor cell proliferation, survival and migration in colon tumors with high Cyclin E1 (CCNE1) expression. PcDNA3.1-CCNE1 vector and si-PKMYT1 were transfected in SW480 cells by Lipofectamine 2000. Q-PCR and western blot assay were processed to detect the expression. Transwell assay and Edu assay were undertaken to verify the migration and proliferation. CCNE1 promotes the proliferation and migration of SW480. Silencing of PKMYT1 inhibited the proliferation of tumor cells. Silencing the expression of PKMYT1 under the premise of overexpression of CCNE1, the level of Cyclin Dependent Kinase 1 (CDK1)-PT14 was reduced, indicating that the cell cycle was blocked. The expression of γH2AX increased significantly, indicating that the DDR pathway of tumor cells was activated and DNA damage accumulated. The results of immunofluorescence microscopy showed significantly increased expression of DNA damage-associated marker (γH2AX: H2AX Variant Histone). In CCNE1 amplificated colorectal tumor cells, knockdown of PKMYT1 reduced cells in S phase, inhibited cell proliferation and promoted cell apoptosis, confirming that PKMYT1 was a potential therapeutic target for colorectal tumor. This study may verify a potential therapeutic target and provide a new idea for the treatment of colorectal cancer in the future.

Circular RNA circSEMA5A facilitates colorectal cancer development by regulating microRNA-195-5p to target CCNE1 axis.

Colorectal cancer (CRC) is one of the most prevalent malignancies with a high mortality rate worldwide. Circular RNAs (circRNAs) have lately emerged as key molecules involved in cancer development and metastasis. CircSEMA5 is reported to be oncogenic in some cancers, yet its role in the pathogenesis of CRC remains unknown. Herein, we attempted to investigate the functional role and molecular mechanism of circSEMA5A underlying CRC progression. RT-qPCR and RNase R digestion assays were used to evaluate circSEMA5A expression characteristics in CRC cells. Loss-of-function assays were performed to clarify circSEMA5A role in CRC biological processes. Bioinformatics and mechanism experiments were conducted to assess the association of circSEMA5A or CCNE1 with miR-195-5p in CRC cells. Rescue assays were conducted to explore the regulatory function of circSEMA5A-miR-195-5p-CCNE1 in CRC cellular processes. Through bioinformatics and functional screening, we found that circSEMA5A was highly expressed in CRC cells and was mainly localized in the nucleus. CircSEMA5A promoted CRC proliferative, migratory, and invasive capabilities in cultured cells and facilitated the tumorigenic process in xenografts; however, circSEMA5A silencing repressed tumor metastasis in CRC cells. Mechanistically, circSEMA5A was competitively bound with miR-195-5p to upregulate CCNE1 expression. Moreover, the impact of circSEMA5A knockdown on CRC cell proliferative, migratory, and invasive capabilities was countervailed by miR-195-5p inhibitor or CCNE1 overexpression. To summarize, circSEMA5A is a novel circRNA that serves as an oncogene in CRC progression. CircSEMA5A facilitates CRC cell malignancy and tumor growth through sponging miR-195-5p to upregulate CCNE1, thus providing a new direction for CRC diagnosis and targeted therapy.

CCNE1 is a predictive and immunotherapeutic indicator in various cancers including UCEC: a pan-cancer analysis.

BACKGROUND: CCNE1 plays an important oncogenic role in several tumors, especially high-stage serous ovarian cancer and endometrial cancer. Nevertheless, the fundamental function of CCNE1 has not been explored in multiple cancers. Therefore, bioinformatics analyses of pan-cancer datasets were carried out to explore how CCNE1 regulates tumorigenesis. METHODS: A variety of online tools and cancer databases, including GEPIA2, SangerBox, LinkedOmics and cBioPortal, were applied to investigate the expression of CCNE1 across cancers. The pan-cancer datasets were used to search for links between CCNE1 expression and prognosis, DNA methylation, m6A level, genetic alterations, CCNE1-related genes, and tumor immunity. We verified that CCNE1 has biological functions in UCEC cell lines using CCK-8, EdU, and Transwell assays. RESULTS: In patients with different tumor types, a high mRNA expression level of CCNE1 was related to a poor prognosis. Genes related to CCNE1 were connected to the cell cycle, metabolism, and DNA damage repair, according to GO and KEGG enrichment analyses. Genetic alterations of CCNE1, including duplications and deep mutations, have been observed in various cancers. Immune analysis revealed that CCNE1 had a strong correlation with TMB, MSI, neoantigen, and ICP in a variety of tumor types, and this correlation may have an impact on the sensitivity of various cancers to immunotherapy. CCK-8, EdU and Transwell assays suggested that CCNE1 knockdown can suppress UCEC cell proliferation, migration and invasion. CONCLUSION: Our study demonstrated that CCNE1 is upregulated in multiple cancers in the TCGA database and may be a promising predictive biomarker for the immunotherapy response in some types of cancers. Moreover, CCNE1 knockdown can suppress the proliferation, migration and invasion of UCEC cells.

PTEN Deficiency in Tubo-Ovarian High-Grade Serous Carcinoma is Associated with Poor Progression-Free Survival and is Mutually Exclusive with CCNE1 Amplification.

As a critical tumor suppressor, PTEN has gained much attention in cancer research. Emerging evidence suggests an association between PTEN status and clinical outcome in certain tumors, and may be predictive of response to several therapies. However, the significance of PTEN deficiency in tubo-ovarian high-grade serous carcinomas (HGSCs) is still poorly understood. We evaluated PTEN expression in HGSCs and determined its clinical relevance. A cohort of 76 HGSC specimens was profiled using tissue microarray. Immunohistochemistry (IHC) of PTEN, ER, PR, AR, CD8, FOXP3, and PD-L1 was performed. Targeted gene panel testing by massively parallel sequencing was performed in 51 cases. PTEN deficiency (complete or subclonal loss) detected by IHC was identified in 13 of the 62 HGSCs (21%) and was significantly correlated with reduced expression of ER and worse first progression-free survival (P < .05) but not with PD-L1 expression, the density of intratumoral T lymphocytes, or overall survival. In our cohort, tumor progression within 1 year of PARP inhibitor therapy was found more frequently in PTEN-deficient cases than in PTEN-intact cases (100% vs 52%). Molecular profiling showed that intragenic mutation or deletion was not the predominant mechanism for PTEN inactivation in HGSCs. In addition, CCNE1 amplification was found to be mutually exclusive with PTEN deficiency at both protein and DNA levels. An analysis of the genomic data from 1702 HGSC samples deposited with The Cancer Genome Atlas database obtained from cBioPortal confirmed the low rate of detection of PTEN gene alterations and the mutually exclusive nature of PTEN loss and CCNE1 amplification in HGSCs. These findings indicate that PTEN deficiency defines a distinct clinically significant subgroup of HGSCs with a tendency for ER negativity, wild-type CCNE1 status, inferior clinical outcomes, and potential drug resistance. These tumors may benefit from PI3K pathway inhibitors in combination with other ovarian cancer regimens, which deserves further investigation.

CCNE1 is a potential target of Metformin for tumor suppression of ovarian high-grade serous carcinoma.

High-grade serous ovarian cancer (HGSOC) is the most common and malignant type of ovarian cancer, accounting for 70%-80% of mortality. However, the treatment of HGSOC has improved little in the past few decades. Metformin is the first-line medication for the treatment of type 2 diabetes and has now gained more attention in cancer treatment. In this study, we sought to identify potential hub genes that metformin could target in the treatment of HGSOC. We downloaded GSE69428 and GSE69429 in the Gene Expression Omnibus database and performed the bioinformatics analysis. Subsequently, we analyzed the effect of Metformin in HGSOC through biological experiments. Molecular simulation docking was used to predict the interaction of Metformin and CCNE1. We chose CCNE1 for the study based on bioinformatics analysis, literature studies, and preliminary data. We evaluated that CCNE1 is overexpressed in HGSOC tissues and found that HGSOC cells with high CCNE1 expression increase sensitivity to Metformin treatment in the analysis of cell proliferation and anchorage-independent growth. Metformin could inhibit the expression of CCNE1, which is associated with the anti-proliferative effect of tumor cells. Moreover, Metformin could ameliorate the tumor growth in syngeneic orthotopic transplantation mouse models and xenograft tumorigenesis models. Furthermore, molecular simulation docking showed that Metformin may bind to CCNE1 protein, suggesting that CCNE1 could be a potential target for Metformin. Our data revealed that Metformin has antitumor effects on ovarian cancer and CCNE1 could be a potential target for Metformin.

Long Non-coding RNA LINC00473 Promotes Breast Cancer Progression via miR-424-5p/CCNE1 Pathway.

BACKGROUND: There has been a large increase in the incidence of breast cancer (BC) among women. LINC00473 is a cancer-related lncRNA, participating in the progression of many cancers, but its role in the progression of BC awaits more elaboration. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to quantify LINC00473, miR-424-5p, and cyclin E1 (CCNE1) mRNA expression levels in BC tissues and cells. Cell counting kit-8 (CCK-8) assay was employed to detect the cell viability; the cell migration and invasion abilities were evaluated by the Transwell assay. Western blot and immunohistochemistry (IHC) were adopted to study CCNE1 protein expression; dual-luciferase reporter assay was performed to clarify the targeting relationships among LINC00473, miR-424-5p, and CCNE1. RESULTS: LINC00473 expression was elevated in BC tissues and cell lines, which was associated with lymph node metastasis and higher clinical stage of the patients with BC. LINC00473 proved to be a molecular sponge for miR-424-5p; LINC00473 knockdown impeded the growth, migration, invasion, and epithelial-mesenchymal transition of BC cells, while these effects were abolished by miR-424-5p inhibitors; miR-424-5p targeted CCNE1 to restrain its expression. LINC00473 positively regulated CCNE1 expression, and CCNE1 restoration counteracted the effects induced by LINC00473 knockdown in BC cells. CONCLUSION: LINC00473 facilitates the progression of BC through miR-424-5p/CCNE1 axis.

CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study.

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Identification of the prognostic and therapeutic values of cyclin E1 (CCNE1) gene expression in Lung Adenocarcinoma and Lung Squamous Cell Carcinoma: A database mining approach.

Cyclin E1 (CCNE1) is a protein-coding gene that belongs to the Cyclin family of genes which controls the G1/S phase transition of the cell cycle. Previously, its abnormal expression pattern has been examined and found to be correlated with ovarian and breast cancer progression. Herein, we exploited a bioinformatics and database mining strategy to unveil the therapeutic and prognostic significance of CCNE1 gene expression in Lung Adenocarcinoma (LUAD) and Lung Squamous Cell Carcinoma (LUSC). CCNE1 gene was reported to be highly expressed in LUAD and LUSC tissues. Its promoter and coding sequences were reported to be aberrantly methylated in LUAD and LUSC tissues than in normal tissues. Moreover, around 12 somatic mutations (frequency: 0.7%) were recorded in the CCNE1 coding region from different studies involving LUAD and LUSC patients' whole genome sequences. The CCNE1 gene expression was also correlated with LUAD and LUSC patients' overall and disease-specific survival. Immune infiltration analysis revealed the association between CCNE1 gene expression and the abundance of numerous immune cells (i.e., T cells and B Cells) infiltration in LUAD and LUSC patients. Two previously known genes involved in oncogenic processes i.e., CDC45 and PDCD5 were identified as the most highly co-expressed genes of CCNE1 in LUAD and LUSC tissues. Altogether, the CCNE1 gene and its transcriptional and translational products may serve as a prognostic or therapeutic target in the diagnosis and treatment of LUAD and LUSC patients. The scientific findings of this study should assist in translating CCNE1 into clinical practice for lung cancer diagnosis and treatment.

TP53 and TP53-associated genes are correlated with the prognosis of paediatric neuroblastoma.

BACKGROUND: TP53 is rarely mutated in paediatric neuroblastoma. The prognosis of TP53 and TP53-associated genes in paediatric neuroblastoma is unclear. The objectives of the study were to analyse datasets of 2477 paediatric neuroblastoma patients from eight independent cohorts to reveal the prognosis of TP53 and TP53-associated genes. RESULTS: High TP53 mRNA expression was associated with shortened event-free survival and overall survival in paediatric neuroblastoma. Moreover, a higher enrichment score of the TP53 signalling pathway was associated with worse clinical outcomes of paediatric neuroblastoma. Among the genes associated with TP53, CCNE1, CDK2 and CHEK2 were correlated with unfavourable clinical outcomes, while SESN1 was correlated with favourable clinical outcomes of paediatric neuroblastoma in the eight independent neuroblastoma cohorts. TP53, CCNE1, CDK2 and CHEK2 were overexpressed in neuroblastoma patients with MYCN amplification, while SESN1 was downregulated in neuroblastoma patients with MYCN amplification. CCNE1, SESN1, MYCN amplification and age at diagnosis were independent prognostic markers of neuroblastoma. CCNE1 was also highly expressed in paediatric neuroblastoma patients with an age at diagnosis ≥ 18 months, while SESN1 was downregulated in paediatric neuroblastoma patients with an age at diagnosis ≥ 18 months. Combinations of CCNE1 with age at diagnosis or combinations of SESN1 with age at diagnosis achieved superior prognostic effects in paediatric neuroblastoma. Finally, we constructed a nomogram risk model of paediatric neuroblastoma based on age and TP53, CCNE1, CDK2, CHEK2 and SESN1 expression. The nomogram model could predict the overall survival of paediatric neuroblastoma and MYCN nonamplified paediatric neuroblastoma with high specificity and sensitivity. CONCLUSIONS: TP53 and TP53-associated genes CCNE1, CDK2, CHEK2 and SESN1 were significantly associated with the clinical outcomes of paediatric neuroblastoma.

LncRNA OXCT1-AS1 promotes the proliferation of non-small cell lung cancer cells by targeting the miR-195/CCNE1 axis.

Background: Long non-coding RNAs (lncRNAs) are involved in various biological processes in non-small cell lung cancer (NSCLC). This study aimed to investigate the key lncRNA OXCT1-AS1/miR-195/CCNE1 axis in the development of NSCLC and its potential molecular mechanism. Methods: LncRNA OXCT1-AS1 is considered to be a competitive endogenous RNA (ceRNA) and its potential targeting microRNAs (miRNAs) were predicted through LncBase predicted v.2. The expression of OXCT1-AS1 and miR-195 in NSCLC tissues and cells was detected by reverse transcription polymerase chain reaction (RT-PCR). The Cell Counting Kit-8 (CCK-8) and cell colony-forming test were used to detect the effect of cell proliferation. RT-PCR was used to detect the expression changes of CCND1 and CCNE1. Western Blot was used to detect the changes of the CCNE1 cell cycle protein. Dual luciferase activity was used to determine the potential mechanism of lncRNA OXCT1-AS1. Results: LncRNA OXCT1-AS1 was highly expressed and miR-195 was lowly expressed in NSCLC tissues and cell lines. LncBase predicted v.2.0 reported a high-scoring binding between OXCT1-AS1 and miR-195. The luciferase reporter assay defined the regulatory relationship between OXTC1-AS1 and miR-195. In NSCLC cells, knockdown of OXCT1-AS1 significantly increased the expression of miR-195, decreased the proliferation and colony formation number of cancer cells, and reduced the expression of CCND1 and CCNE1. Meanwhile, overexpression of miR-195 significantly inhibited the cell proliferation and colony formation number, and reduced the expression of CCND1 and CCNE1. Furthermore, according to the results of the dual-luciferase activity assay, miR-195 targeted the 3' untranslated regions (3' UTRs) of CCNE1, validating that CCNE1 is a direct target of miR-195. Overexpression of CCNE1 restored the role of OXCR1-AS1 in NSCLC cells. Conclusions: LncRNA OXCT1-AS1 can regulate the proliferation of NSCLC cells via miR-195/CCNE1 signaling. Therefore, OXCT1-AS1 may act as a prospective biomarker and therapeutic target for patients with NSCLC.