Neoplasma最新文献

Minichromosome maintenance complex component 2 (MCM2) is a member of the MCM family and is involved in various cancers. However, the role of MCM2 in endometrial cancer (EC) remains unclear. In this study, we aim to determine the biological function of MCM2 in EC cells and identify the potential underlying mechanisms. MCM2 expression and prognostic significance were analyzed in TCGA-UCEC datasets. Combining bioinformatics analyses and experiments, stemness-related molecules and phenotypes were examined to evaluate the impact of MCM2 on stemness in EC cells. The major findings of these analyses are as follows: 1) MCM2 is expressed at higher levels in EC tissues than in normal endometrial tissues. High expression of MCM2 is related to the characteristics of poorly differentiated EC. High MCM2 expression is correlated with poor overall survival in EC patients; 2) MCM2 knockdown was found to decrease sphere formation ability, downregulate the expression of stemness-related molecules, and reduce the proportion of CD133+ cells, while MCM2 overexpression elicited the opposite effect in EC cells; 3) MCM2-mediated stemness features are dependent on the activation of Akt/β-catenin signaling pathways; and 4) MCM2 knockdown increases cisplatin sensitivity in EC cells. MCM2 regulates stemness by regulating the Akt/β-catenin signaling pathway in EC cells.

Radiotherapy and chemotherapy have improved the 5-year survival rate of nasopharyngeal carcinoma (NPC) patients, but the side effects generally lead to unsatisfactory clinical efficacy. It's imperative to explore the pathogenesis of NPC to find better diagnostic and therapeutic methods. Small nucleolar RNA host genes (SNHGs) are special lncRNAs, which can be further spliced to produce small nucleolar RNAs (snoRNAs). SNHG1 has been found to be associated with various cancers. However, only a few studies reported the relationship between SNHG1 and NPC. This study first analyzed the diagnostic performance and related signaling pathways of SNHG1 in NPC through bioinformatics. The expression of SNHG1 was verified by RT-qPCR, and the expression of the signaling pathway was detected using immunohistochemistry. Bioinformatics analysis results showed that SNHG1 was significantly overexpressed in head and neck squamous cell carcinoma (HNSC) and NPC tissues. RT-qPCR detection confirmed the significant overexpression of SNHG1 in NPC tissues. Enrichment analysis showed that SNHG1 may act on NPC through the PI3K-AKT signaling pathway. Immunohistochemistry experiment revealed PI3K-AKT signaling pathway proteins (PI3K AKT and EGFR) positively expressed and CASP3 weakly positively expressed in NPC tissues. Therefore, we concluded that SNHG1 is a prospective biomarker and may act on NPC through the PI3K-AKT signaling pathway.

Radiotherapy is widely used as the first-line treatment for nasopharyngeal carcinoma (NPC). However, the resistance of some patients to treatment lowers its clinical effectiveness. Compared to typical epithelial cells, NPC markedly lowers the Ras-association domain family 1A (RASSF1A) protein expression. RASSF1A overexpression sensitizes NPC cells to radiotherapy. Mechanistically, RASSF1A promotes the expression of Forkhead box O3a (FoxO3a) in the nucleus and inhibits the Nuclear factor E2-related factor 2 (Nrf2) signaling pathway via binding to the Kelch-like ECH-associated protein 1 (Keap1) promoter. Through elevating intracellular ROS levels, RASSF1A overexpression inhibits the expression of thioredoxin reductase 1 (TXNRD1), a crucial Nrf2 target gene, and increases NPC sensitivity to radiation. Immunohistochemical staining of NPC tissue sections revealed that the expression of RASSF1A is negatively correlated with that of TXNRD1. The traditional Chinese medicine component andrographolide (AGP), which induces RASSF1A expression, increased the sensitivity of NPC cells to radiotherapy in vitro and in vivo. Our findings implied that RASSF1A increases the sensitivity of NPC to radiation by increasing FoxO3a expression in the nucleus, inhibiting the Nrf2/TXNRD1 signaling pathway, and elevating intracellular ROS levels. AGP targets RASSF1A and may be a promising adjuvant sensitizer for enhancing radiosensitivity in NPC.

High cholesterol is an important factor inducing colorectal cancer (CRC). The study aims to determine the key genes and regulatory mechanism associated with tumor-infiltrating T cells underlying cholesterol-induced CRC. Gene expression data and clinical data from CRCS in The Cancer Genome Atlas (TCGA) were selected for differential expression and survival analysis. A total of 5,815 DEGs and 21 cholesterol-associated KEGG pathways were identified. Subsequently, 128 CRCs and 127 patients without obvious intestinal lesions were recruited to analyze the relationship between GPX3 expression, cholesterol levels, and pathologic condition. The results showed that the expression of cholesterol-related gene GPX3 was negatively associated with cholesterol level, but positively correlated with Ki-67 proliferation index in CRC. The expression of GPX3 was higher in CRC patients who were in poorly differentiated and advanced stage. In addition, a mice model of high-cholesterol diet intervention was constructed to detect the levels of cholesterol and GPX3 in the peripheral blood of mice, and it was found that the expression level of GPX3 in high-cholesterol mice was lower than that in normal diet mice. CD8+ T cells were isolated from the spleen of mice and the T cell surface receptors were detected. It was found that the expression of CD69 in CD8+ T cells of mice interfered with the high-cholesterol diet, while the expression of PD1, TIM-3, and CTLA-4 was increased. CD8+ T cells were co-cultured with MC38 cells to detect the proliferation rate of CRC cells. The results showed that the tumor cell proliferation ratio in the high cholesterol group was higher than that in the control group. Furthermore, GPX3 downstream genes associated with m6A modification and tumor-infiltrating T cells were screened, and a T cell immune-related ceRNA network was constructed. In total, 53 GPX3 downstream genes associated with m6A modification and tumor-infiltrating T cells were identified. A PPI network that contained 45 nodes and 85 interaction pairs was constructed. The ceRNA network, including 39 miRNA-target and 43 lncRNA-miRNA regulatory pairs, was constructed. In conclusion, GPX3 is a potential target for cholesterol regulation of T cell immunity in CRC.

Retinal G protein-coupled receptor (RGR) serves a retinal photoisomerase function to mediate retinoid metabolism and visual chromophore regeneration in the human eyes. Retinoids display critical functions in cell proliferation, differentiation, and apoptosis. Abnormal retinoid metabolism may contribute to tumor development. However, in human tumor tissues, the expression of RGR remains uncharacterized. Herein, we performed the analysis of RGR expression in 620 samples from 24 types of tumors by immunohistochemistry (IHC) and 33 cancer types from the Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) databases by bioinformatic analyses. Furthermore, the biological role of RGR in glioma cells was investigated using molecular biology approaches in vitro. Notably, we found that brain lower grade glioma (LGG), in contrast to other tumor types, had the highest median score of IHC and RNA level of RGR expression. Survival analysis showed that low RGR expression was associated with worse overall survival in LGG (p<0.0001). RGR expression levels in glioma were also associated with pathological subtypes, grades, and isocitrate dehydrogenase (IDH) mutations. Moreover, its molecular function was closely associated with cadherin-related family member 1 (CDHR1), a tumor suppressive protein in glioma, suggesting that RGR might negatively regulate the tumorigenesis and progression of LGG through interacting with CDHR1. Our findings provide new insight into the role of RGR in human cancer, especially in glioma.

Programmed death-ligand 1 (PD-L1) is the most widely utilized predictive marker used to identify non-small cell lung carcinoma (NSCLC) patients most suitable for immunotherapy approaches. The relationship between PD-L1 expression, the presence of CD8+ T cells, and other clinicopathological characteristics of NSCLC patients has not been elucidated yet. In this retrospective study, we immunohistochemically determined PD-L1 expression (using clone 22C3) and CD8+ T cell count (using clone c8/144B) in surgical resection specimens from 698 advanced NSCLC patients. Results of PD-L1 expression and CD8+ T cell count were correlated to various clinicopathological characteristics, including the presence of desmoplasia in NSCLC. Regarding the immunological attributes of the tumor microenvironment, we identified major differences between desmoplastic and non-desmoplastic areas in NSCLC. Tumor areas without desmoplasia were significantly more often PD-L1 positive than tumor cell clusters encased in a dense collagenous stroma (p=0.004). Furthermore, the desmoplastic stroma contained significantly less often an immune cell infiltrate rich in CD8+ T cells (p<0.001). Also, the positivity of PD-L1 significantly correlated with advanced N-stage (p<0.001) and poor differentiation in adenocarcinomas (p=0.032) but not with other clinicopathological characteristics. In conclusion, to our knowledge, this is the first study that points to major differences in terms of immunological attributes between desmoplastic and non-desmoplastic areas in NSCLC. The desmoplastic component, therefore, may represent an immunologically distinct tumor area in which PD-L1 immunohistochemistry and CD8+ T cell count should be evaluated separately.

This study aimed to retrospectively evaluate the treatment strategies and possible prognostic factors in patients with brain metastases (BMs) from esophageal squamous cell carcinoma (ESCC). We retrospectively reviewed 30 patients with BMs from ESCC who were treated at our center between November 2011 and January 2022. Clinicopathological characteristics and clinical outcomes were analyzed. The median follow-up time was 2 (range, 0.5-33) months. The median survival time after diagnosis of BMs was 2 months. The 1-year overall survival (OS) rate was 13.6%. The OS was better in patients with intracranial benefit. Multivariate analysis showed that local treatment of BMs influenced OS. The median survival with or without local treatment of BMs was 4 and 1 month, respectively. The median time interval between the diagnosis of the primary tumor and BMs was 11 (range, 1-156) months. Among these BMs, 55.6% of the BM occurred within the first year after diagnosis of the primary tumor, 66.7% in the first 2 years, and 85.2% in the first 3 years. The median time interval from lung metastasis to BMs was 3 months, from liver metastasis to BMs 3.5 months, and from bone metastasis to BMs 0.5 months. Local treatment of BMs was an independent prognostic factor for patients with BMs from ESCC. Earlier detection followed by an aggressive local therapeutic approach for BMs had a great influence on treatment outcomes as well as the long-term prognosis and quality of life for appropriately selected patients.

Breast cancers are a heterogeneous group of tumors classified according to their histological growth patterns and receptor expression characteristics. Intratumor heterogeneity also exists, with subpopulations of cells with different phenotypes found in individual cancers, including cells with stem or progenitor cell properties. At least two types of breast cancer stem cells (CSCs) exist, the epithelial and the basal/mesenchymal subtypes, although how these phenotypes are controlled is unknown. ΔNp63 is a basal cell marker and regulator of stem/progenitor cell activities in the normal mammary gland and is expressed in the basal-like CSC subpopulation in some estrogen receptor-positive (ER+) and/or human epidermal growth factor receptor 2-positive (HER2+) breast adenocarcinomas. Whilst p63 is known to directly impart CSC properties in luminal breast cancer cells, how p63 is regulated and induced in these cells is unknown. We initially confirmed the existence of a small subpopulation of ΔNp63+ cells in lymph node metastases of ER+ human ductal adenocarcinomas, indicating together with previous reports that ΔNp63+ tumor cells are present in approximately 40% of these metastases. Notably, ΔNp63+ cells show a preferential location at the edge of tumor areas, suggesting possible regulation of ΔNp63 by the tumor microenvironment. Subsequently, we showed that the high levels of ΔNp63 in basal non-transformed MCF-10A mammary epithelial cells rely on insulin in their culture medium, whilst ΔNp63 levels are increased in MCF-7 ER+ luminal-type breast cancer cells treated with insulin or insulin-like growth factor 1 (IGF-1). Mechanistically, small molecule inhibitors and siRNA gene knockdown demonstrated that induction of ΔNp63 by IGF-1 requires PI3K, ERK1/2, and p38 MAPK activation, and acts through FOXO transcriptional inactivation. We also show that metformin inhibits ΔNp63 induction. These data reveal an IGF-mediated mechanism to control basal-type breast CSCs, with therapeutic implications to modify intratumor breast cancer cell heterogeneity and plasticity.

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Hepatocellular carcinoma (HCC) is a primary liver cancer characterized by high invasiveness, metastasis, and poor prognosis, which lacks effective treatments. Although the role of miR-192 in HCC development has been recognized, the underlying molecular mechanism is still poorly understood. This study aimed to explore the impact of mir-192 on HCC and its potential as a therapeutic strategy. Wound healing assay, Transwell assay, CCK-8 assay, and flow cytometry were performed to detect the impact of miR-192 on HCC cell metastasis, invasion, proliferation, and apoptosis, respectively. q-PCR and western blot were applied to measure the relative mRNA and protein expression of the GSK3β/Wnt/β-catenin pathway in miR-192-overexpressing cell lines. Immunofluorescence was carried out to detect the nuclear translocation of β-catenin. starBase website and dual luciferase reporter assay were used to verify the interaction between miR-192 and the target gene WNT10B 3'-untranslated region (3'-UTR) of the Wnt pathway. In addition, we developed algin/polyethyleneimine@miR-192 (AG/PEI@miR-192) nanohydrogel for in vivo delivery of miR-192-agomir. The results revealed that overexpressed miR-192 reduced the expression of HCC cell surface markers CD90, EpCAM, and CD133. Moreover, miR-192 overexpression inhibited HCC cell metastasis, invasion, and proliferation, promoted cell apoptosis, and reduced GSK3β/Wnt/β-catenin pathway expression. Additionally, AG/PEI@miR-192 exhibited good drug release and tumor inhibition. In conclusion, our study suggested that miR-192 inhibits HCC development by suppressing the GSK3β/Wnt/β-catenin pathway and proposed a promising hydrogel-based miR-192 delivery approach to hinder tumor growth.